Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura

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Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Sección de Hemostasia y Trombosis, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Servicio de Hematología y Hemoterapia, Hospital General de Alicante, Valencia, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Unidad de Aféresis y Terapia Celular, Servicio de Hemoterapia y Hemostasia, Institut Clínic de Malalties Hematològiques i Oncològiques (ICMHO), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Servicio de Hematología y 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Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal" "etiqueta" => "m" "identificador" => "aff0065" ] 13 => array:3 [ "entidad" => "Banc de Sang i Teixits de Catalunya, Barcelona, Spain" "etiqueta" => "n" "identificador" => "aff0070" ] 14 => array:3 [ "entidad" => "Servicio de Transfusión, Servicio de Hematología, Complexo Hospitalario Universitario de Ourense, Galicia, Spain" "etiqueta" => "o" "identificador" => "aff0075" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1770 "Ancho" => 2925 "Tamanyo" => 508137 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of thrombotic microangiopathies (TMA)." ] ] ] "textoCompleto" => "Glossary of terms of interestClinical response<a class="elsevierStyleCrossRef" href="#bib0005">1</a>: Platelet count above the lower limit of normality established at each center (usually 150 × 109/L) and LDH levels below 1.5 times the upper limit of normality at each center, after cessation of plasma exchange. The platelet count should be placed in the usual context of the patient's platelet count if known.Clinical remission<a class="elsevierStyleCrossRef" href="#bib0010">2</a>: A sustained clinical response with (a) no Therapeutic Plasma Exchange and no anti-vWF therapy in the last 30 days or (b) with attainment of ADAMTS13 remission (partial or complete), whichever occurs first.Partial ADAMTS13 remission<a class="elsevierStyleCrossRef" href="#bib0010">2</a>: Clinical remission situation in which the ADAMTS13 activity is greater than or equal to 20%, but below the lower limit of normality established in each center. Because there is biological variability in ADAMTS13 activity, as well as variability in its laboratory measurement, it is recommended to perform multiple measurements to confirm the ADAMTS13 values.Complete ADAMTS13 remission<a class="elsevierStyleCrossRef" href="#bib0010">2</a>: Clinical remission situation in which the ADAMTS13 activity is greater than or equal to the lower limit of normality established in each center. Because there is biological variability in ADAMTS13 activity, as well as variability in its laboratory measurement, it is recommended to perform multiple measurements to confirm the ADAMTS13 values.Refractory<a class="elsevierStyleCrossRef" href="#bib0005">1</a>: No significant increase in platelet count (less than 50 × 109/L) after the first 5 days of plasma exchange or clinical or laboratory deterioration during treatment with daily plasma exchange.Exacerbation–: Decreased platelet count and unjustified increase of LDH for reasons other than TTP, within 30 days of its cessation due to clinical response, forcing plasma exchange to resume. Decreases in 24 h of 10% of the platelet count after its normalisation forces extreme monitoring given the risk of exacerbation.Clinical relapse<a class="elsevierStyleCrossRef" href="#bib0010">2</a>: Platelet count drop to <150 × 109/L after reaching clinical remission, with or without clinical evidence of new ischemic organ injury, and always after previously ruling out other possible causes of thrombocytopenia. A clinical relapse must always be confirmed by documentation of severe ADAMTS13 deficiency (<10%).ADAMTS13 relapse<a class="elsevierStyleCrossRef" href="#bib0010">2</a>: ADAMTS13 level drops below 20% after ADAMTS13 remission (complete or partial). Because there is biological variability in ADAMTS13 level, as well as variability in its laboratory measurement, it is recommended to perform multiple measurements to confirm the ADAMTS13 values.Elaboration of recommendationsScope and objectivesThrombotic thrombocytopenic purpura (TTP) is a rare haematological disease characterised by the presence of microangiopathic haemolytic anaemia, thrombocytopenia, and systemic vascular events. In most cases it presents ADAMTS13 levels (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) lower than 10%. Its clinical evolution is characterised by the presence of acute episodes, relapses and exacerbations despite the correct therapeutic approach. In Spain, this pathology has an incidence of 2.67 cases/million inhabitants per year.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Much progress has been made in the field of TTP in recent years, especially with the appearance of new diagnostic tools and new treatments. In addition, special attention has been paid to the morbidity associated with acute TTP episodes, along with the resulting neurocognitive, vascular or renal sequelae.In the light of this new research, this group has raised the need to prepare a document that collects all the evidence generated to date in relation to this disease in order to develop recommendations that allow health professionals to standardise the treatment of TTP patients and also to serve as a reference framework in clinical practice, thus updating the guidelines already published in Spain in 2011.MethodologyThese recommendations have been developed following the guidelines specified in the AGREE methodology.The objectives and the questions that required answers with the present guides were formulated following a PICO type formula [P: population, I: intervention, C: comparison; O: outcome]. The final areas chosen to be addressed were: definition, clinical expression and suspicion of TTP in patients; current differential diagnostic scores and techniques; additional tests required during diagnosis and follow-up; treatment of acute episodes; mode of action in case of refractoriness, exacerbation and relapse; follow-up of the patient in remission; TTP in the paediatric population and in pregnancy; treatment of congenital PPT and approach to non-TTP thrombotic microangiopathies (TMAs) caused by transplants, infections, cancer or drugs.To prepare this paper, the authors responsible for each of the information blocks performed a bibliographic search of all the literature published during the last 10 years using the relevant MeSH terms for each unit of content. In order to establish the recommendations, the robustness of the collected information was evaluated and the necessary strengths and limitations in each of the sections were pointed out, taking into account the level of evidence. Following this, a peer review of each block of recommendations was carried out until a consensus was reached by the whole group.Participation of the parties involvedAll authors have contributed equally to the bibliographic review of the existing literature, as well as to the writing of this paper. JDRG, CPI, RS and MEMC have also taken the lead in reviewing and correcting the paper. MEMC and RS have also acted as project coordinators.MEMC has been responsible for writing the abstract, and the glossary of terms of interest; RS has co-authored the writing of the abstract; JDRG has been responsible for writing Chapter 1; HSP and LHM have been responsible for writing Chapter 2; JMN and AG have been responsible for writing Chapter 3; RG has been responsible for writing Chapter 4; AVL and JDR have been responsible for writing Chapter 5; CPI has written Chapter 6; JC has been responsible for Chapter 7; ES has been responsible for Chapter 8; FG has been responsible for Chapter 9; IGS and TF have been responsible for writing Chapter 10 and DVF has been responsible for writing Chapter 11.The project to elaborate these clinical recommendations has been supported and sponsored by the Grupo Español de Aféresis (GEA), the Sociedad Española de Hematología y Hemoterapia (SEHH), the Sociedad Española de Trombosis y Hemostasia (SETH) and the Sociedad Española de Transfusión Sanguínea y Terapia Celular (SETS).Introduction to acquired thrombotic thrombocytopenic purpuraTTP is a type of TMA, a term that describes an endothelial lesion of the microcirculation with thrombi that obstruct the vascular flow, causing mechanical haemolysis (appearance of schistocytes), ischaemia, and tissue damage (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). In the clinical setting, the term TMA has been extended to all syndromes with microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and organ damage.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Primary TMAs have their own entity and include TTP (congenital or acquired) and haemolytic uremic syndrome (HUS). <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the pathophysiological classification of the TMAs.<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Acquired TTP (aTTP) is an autoimmune disease in which autoantibodies directed against ADAMTS13 impede its activity (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Its estimated incidence in Spain in the population over the age of 16 is 2.67 patients per 106 inhabitants/year, and the prevalence is 22 patients per 106 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>In TTP, thrombus formation is due to the severe deficit (activity < 10% of normal) of the ADAMTS13 protease, responsible for breaking the very high molecular weight multimers (VHMWM) of the von Willebrand factor (vWF) newly secreted by the endothelium, which have a much higher sticking capacity than those normally circulating. When endothelial injury occurs, VHMWMs cause spontaneous platelet aggregation in the microcirculation, forming thrombi rich in platelets and vWF throughout the body (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Therefore, a severe deficiency of ADAMTS13 is necessary, but not always sufficient, to produce TTP, as precipitating factors exist, such as surgery, infection, or inflammatory conditions, that injure the endothelium and can trigger acute episodes of TTP.Suspicion, clinical expression and prognostic factors of evolution in TTPClassically, TTP is characterised by acute outbreaks of microangiopathic haemolytic anaemia and thrombocytopenia, associated or not with fluctuating neurological disorders, impaired renal function, and fever. However, these five classic symptoms coincide in less than 10% of cases of acute TTP.<a class="elsevierStyleCrossRefs" href="#bib0020">4–6</a> Kidney impairment is almost always mild and transient, although acute kidney failure has been reported in up to 27% of patients with TTP<a class="elsevierStyleCrossRef" href="#bib0020">4</a>; it should also be mentioned that although it is not a common sign and is more indicative of HUS, it does not rule out the diagnosis of TTP.In relation to the involvement of the central nervous system (CNS), symptoms can range from mild headache to severe manifestations such as changes in the level and course of consciousness, seizures, and motor and sensory deficits, among others.<a class="elsevierStyleCrossRefs" href="#bib0020">4,7</a> Regarding cardiac involvement, it is underdiagnosed because of the absence of cardiac symptoms and multiorgan involvement at the onset of TTP. However, it is common in these subjects and should be evaluated.<a class="elsevierStyleCrossRefs" href="#bib0020">4,8</a> Finally, the appearance of nonspecific abdominal pain, although more common in patients with HUS, may appear in TTP as a manifestation of intestinal ischaemia. In addition, the development of other autoimmune diseases occurs in up to 25% of subjects with TTP.<a class="elsevierStyleCrossRefs" href="#bib0005">1,7,8</a>The current mortality rate associated with TTP is less than 10% and usually occurs in the first days after diagnosis.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> This figure has remained stable since 1991 thanks to the introduction of plasma exchange as a first-line treatment in patients with autoimmune TTP.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The prognostic factors associated with mortality and relapses in aTTP are described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Preclinical risk assessment scales and current techniques for the differential diagnosis of TTPIn the laboratory, acute phase aTTP is characterised, except in exceptional cases, by a severe functional deficiency of ADAMTS13 (activity < 10%).<a class="elsevierStyleCrossRefs" href="#bib0005">1,11</a> Once this deficit is confirmed, the presence of anti-ADAMTS13 autoantibodies should be looked for, as finding these autoantibodies allows the TTP to be classified as acquired TTP. However, a negative result does not always imply the diagnosis of congenital TTP because antibodies are not identified in up to 20−25% of aTTP cases.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Therefore, in order to arrive at a definitive diagnosis of congenital TTP, the genetic study of the ADAMTS13 gene must be carried out (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>To determine both activity and antibodies, whole blood extraction in a citrate tube is required, since both tests are performed on plasma. This blood draw should be prior to the start of plasma therapy, and samples obtained with ethylenediaminetetraacetic acid (EDTA) should never be used because this compound completely inhibits the in vitro activity of ADAMTS13.ADAMTS13 activity can be measured by the use of different immunoassays. The most used assays measure the changes in fluorescence (FRETs) or absorbance (ELISA) that occur in the sample when ADAMTS13 cuts a fragment of vWF, although faster tests (chemiluminescence and test strips) have recently been developed that have shown sensitivities comparable to standardised methods.<a class="elsevierStyleCrossRefs" href="#bib0060">12–14</a>When identifying autoantibodies, the classical mix assay evaluates whether the patient's plasma is able to inhibit a control sample. This can help to identify inhibitory antibodies, but it does not detect antibodies that only accelerate the clearance of ADAMTS13. In addition, although several commercial assays are available that specifically identify IgG autoantibodies by ELISA, these do not differentiate whether they are inhibitory or not, and they are unable to detect autoantibodies of other classes (IgM, IgA, etc.).At present, the determination of ADAMTS13 is not available as an urgent test in ‘round-the-clock’ laboratories, and TTP requires an urgent therapeutic decision. For this reason, several clinical score systems have been developed to establish the pretest probability that a subject will have a severe deficit in ADAMTS13 activity, which should be confirmed later with the determination of ADAMTS13 levels.<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the most commonly used preclinical risk scales. It is important to note that less than 2% of patients with very low scores have ADAMTS13 deficiency, while in intermediate scores it is common to find patients with other causes of TMA. At high scores, at least 4 out of 5 patients have TTP.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Since all of these score systems have been developed using an adult population, it is important to note that these scores are not applicable to minors.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Additional tests that should be requested to complete the diagnosis of TTP and its follow-up in an acute situationRecommended complementary tests for the diagnosis and follow-up of patients with TTP are described in detail in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>. After remission, this follow-up is recommended once a month for 3 months, once every 3 months for 9 months, and then every 6 months for at least 2 years. In addition, it is recommended that screening for ADAMTS13 be performed weekly until it normalises. In the event that ADAMTS13 levels do not return to normal after clinical remission, it is recommended that the frequency of the determinations be decided in accordance with the proposed treatment/follow-up strategy.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Just to mention, in the case of atypical localised ischaemia (pancreatitis, intestinal ischaemia, etc.) additional targeted tests such as amylase, lipase and imaging levels are recommended. Also, although venous thromboembolic conditions are uncommon and are generally related to the use of catheters, when facing a clinical suspicion of the same, appropriate imaging tests are recommended as D-dimer is not very effective for screening these patients.<a class="elsevierStyleCrossRef" href="#bib0100">20</a>Treatment of a patient with acquired TTP in an acute situationaTTP treatment has 2 well-established pillars as initial treatment: plasma exchange (PE) and immunosuppressive therapy. There is also a third tool used, which is the prevention of platelet adhesion to the vWF, thus preventing the formation of thrombi. The proposed algorithm for the treatment of aTTP is detailed in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.<a class="elsevierStyleCrossRef" href="#bib0125">25</a><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Plasma exchangePE is the mainstay of TTP treatment and its superiority over plasma infusion was proven in a randomised study by the Canadian group in 1991.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> The most commonly used regimen is the plasma exchange of 1.5 plasma volumes (PV) for the first 3 days followed by 1 PV daily, although there are centres that only use 1 PV from the beginning. This PE should be continued every day until the platelet count is greater than 150 × 109/L in two separate determinations and lactate dehydrogenase (LDH) is normalised.Regarding the different types of plasma available, there are no randomised studies showing the superiority of inactivated plasma over untreated fresh-frozen plasma.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In fact, in a multicenter observational study, the use of inactivated plasma was associated with the presence of more exacerbations, and as no subsequent study has shown otherwise, the use of fresh-frozen plasma is recommended.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> In addition, if PE cannot be started early, 25−30 ml/kg of fresh plasma will be transfused as long as this is tolerated. There are experiences of plasma exchange with other solutions such as albumin, but this is not the usual practice.<a class="elsevierStyleCrossRefs" href="#bib0140">28–30</a>Finally, studies to date have not shown a significant benefit associated with the gradual reduction of PE,<a class="elsevierStyleCrossRef" href="#bib0155">31</a> so it is not a mandatory recommendation.GlucocorticoidsThe efficacy of glucocorticoids was demonstrated in 2 randomised studies.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> The most common regimen is prednisone (PRD) 2.5 mg/kg/day or methylprednisolone 1 g/day for 3 days followed by PRD 1 mg/kg/day which is gradually decreased depending on the response. When the platelets have recovered, start the gradual reduction of treatment after 5–7 days and stop at 3 weeks. High doses of steroids appear to reduce the number of PEs, but the choice between one regimen or another should be made based on the patient's comorbidities and tolerance of possible side effects.RituximabThe use of rituximab was initially limited to refractory aTTP, but observational studies have shown that it can accelerate recovery and decrease the incidence of exacerbations and relapses,<a class="elsevierStyleCrossRefs" href="#bib0170">34–36</a> although it has not been shown to increase survival. However, its early use during treatment has been proposed by the British group in a phase II study with a reduction in the duration of acute episodes,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> although there are no randomised studies to support these results. Therefore, international guidelines already recommend it (or propose the possibility of using it) as first-line treatment associated with steroids and PE if there is no contraindication for its use.<a class="elsevierStyleCrossRefs" href="#bib0075">15,37</a>Based on this evidence, it is recommended that rituximab be used as first-line treatment, provided that the presence of anti-ADAMTS13 antibodies has been previously confirmed. The most commonly used dose is 375 mg/m2/week, with two possible therapeutic regimens: 2 times a week or a total of 4 or 8 doses per week. Treatment should be given immediately after PE. Rituximab requires specific authorisation and informed consent as it is not currently indicated on the Summary of Product Characteristics in our environment.CaplacizumabCaplacizumab is a nanoantibody that binds to the A1 domain of vWF, thus inhibiting the interaction between vWF and GP1b-IX-V, in turn reducing platelet aggregation and microvascular thrombosis, and consequently, tissue ischaemia.The efficacy and safety of caplacizumab in adults who had an episode of aTTP were established in 2 randomised controlled studies: TITAN (phase II)<a class="elsevierStyleCrossRef" href="#bib0170">34</a> and HERCULES (phase III).<a class="elsevierStyleCrossRefs" href="#bib0100">20,38</a> The results showed that caplacizumab reduced the number of days until platelet counts were normalised (primary endpoint) as well as the composite variable for assessment of deaths, vascular events, and exacerbations with respect to the control arm. In addition, the risk of recurrence (exacerbation or relapse) was significantly lower among patients treated with caplacizumab (17.6% vs. 34.8%; = 0.004). Overall, during the period of treatment with caplacizumab associated with PE and glucocorticoids, in terms of relapse analysis, these were 22% and 8% in the TITAN and HERCULES trials, respectively. This difference was due to the possibility of prolonging caplacizumab treatment until the normalisation of the ADAMTS13 levels in the HERCULES study. Finally, the number of patients with refractory disease (the definition of refractory used in this guide is not the same as that used in these studies) was also significantly lower in the caplacizumab group (0 vs. 8; p = 0.0049). Another benefit of the triple treatment (PE, immunosuppression, and caplacizumab) was a reduction in the number of days of PE treatment (6.5 vs. 10.4).Regarding the safety profile, the main problem is bleeding diathesis similar to Von Willebrand’s disease, as this drug blocks the binding of vWF to the platelet. The most common serious bleeding adverse effects associated with caplacizumab were epistaxis (3%), upper gastrointestinal bleeding, and subarachnoid bleeding (1.5%). Almost all were self-limiting except one case where it was necessary to administer vWF concentrate to resolve a severe epistaxis. The incidence of global serious adverse events with caplacizumab and placebo was 16% and 28.2%, respectively.There is already experience of its clinical use with results similar to those of clinical trials, and proposals for its use guided by ADAMTS13 levels.<a class="elsevierStyleCrossRefs" href="#bib0195">39–41</a> The reduction in the number of caplacizumab-induced exacerbations and relapses would justify its use from the start of treatment, as we do not have predictive factors of exacerbation risk as other authors already point out.<a class="elsevierStyleCrossRef" href="#bib0210">42</a>The recommended dose in the SmPC<a class="elsevierStyleCrossRef" href="#bib0125">25</a> is the administration of two doses on the first day, one of 10 mg intravenous (i/v) before performing the PE, and then a second dose of 10 mg subcutaneously (s/c) when the PE has finished. After these first two doses, 10 mg s/c daily are recommended, to always be administered when the PE has finished. Once the PEs are finished, continue with a daily dose of 10 mg s/c up to 30 days after performing the last PE. Cases of suspending caplacizumab have been reported after reaching ADAMTS13 levels above 20% with good evolution.<a class="elsevierStyleCrossRef" href="#bib0215">43</a>Finally, and although international guidelines place it as front-line treatment when facing a high clinical suspicion or high score on the French or Plasmic scales,<a class="elsevierStyleCrossRefs" href="#bib0075">15,37</a> currently in Spain this drug can only be accessed as a foreign drug request, as it has no reimbursement price. Cost-benefit studies already exist in other countries, but to solve this situation we need studies that are appropriate to our environment.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>N-acetylcysteineN-acetylcysteine is an antioxidant that cleaves ultra-large vWF multimers, preventing the spread of platelet and vWF microthrombi. This treatment has been suggested as the first line treatment, although no studies prove its efficacy to date. The recommended dose is 150 mg/kg i/v in bolus followed by 150 mg/kg for 17 h.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>Platelet transfusionAlthough the most current patient case series do not show a worse prognosis in patients receiving platelet transfusions in TTP, it is advisable to restrict their use to situations of severe or vital bleeding, or prior to the implantation of a central catheter or interventional process.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>New therapeutic strategiesCurrent lines of research in the treatment of TTP propose new intervention strategies. These include platelet GPIb and vWF as well as the administration of recombinant ADAMTS13.Among the first strategies are drugs such as amphibatide and the anti-vWF aptamer ARC1779. There are currently no clinical trials of amphibatide in aTTP to support its usefulness. Also, Phase 2 studies were started but not completed with the anti-vWF aptamer ARC1779. The administration of recombinant ADAMTS13 is currently in Phase 2 and 3 clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0235">47,48</a>Moreover, it should not be forgotten that a fundamental part of the treatment of aTTP is that of immunosuppressive therapy. In addition to the drugs listed above, we find bortezomib within the possible treatment lines.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> Its efficacy has been described in isolated cases, and it has been linked to the ability of plasma cells to produce anti-ADAMTS13 antibodies, although there are as yet no consistent data on its efficacy and its neurological toxicity must be taken into account.In conclusion, the ideal global combination of aTTP-targeted therapy would be that capable of inhibiting the GPIa/vWF interaction while supplementing ADAMTS13 and inhibiting the production of antibodies with immunosuppressive therapy.Mode of action in case of refractoriness, exacerbation and relapse in aTTP. Patients in clinical remission with low levels of ADAMTS13To review the definitions of refractoriness, exacerbation, and relapse, go to the "glossary of terms of interest."Refractory aTTPaTTP is refractory to PE and glucocorticoids in approximately 10−15% of patients diagnosed with aTTP. No clinical data have been described in literature that enables refractoriness to be predicted. On the other hand, 15–53% of patients with an acute episode may experience an exacerbation and there are no identifiable risk factors for this situation.In the refractory situation, the first thing we have to do is reconsider the diagnosis, as it could be another type of TMA that does not respond to standard treatment (sepsis, cancer, medications). In all cases, treatment of refractory patients must be individualised (see <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>Recurrent aTTPThe risk of recurrence may occur in 34% of patients with aTTP.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Episodes of recurrence have decreased in recent years and this is probably due to the use of rituximab. Data published by George and Cuker,<a class="elsevierStyleCrossRef" href="#bib0250">50</a> from the Oklahoma Registry, support this claim, as 48% of patients relapsed in 1st year, 30% from the 1st to 3rd year, 22% from the 5th to 14th year.The symptoms of recurrence are usually less severe than in the initial diagnosis, and the most characteristic finding — usually in a regular check-up — is thrombocytopenia of less than 150 × 109/L. In these cases, PE will also be initiated urgently together with immunosuppressive therapy with corticosteroids and rituximab, after a plasma sample is drawn to determine the ADAMTS13 activity and to confirm the presence of anti-ADAMTS13 antibodies.<a class="elsevierStyleCrossRef" href="#bib0255">51</a><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> summarises the focus and treatment of the refractory, exacerbation, and relapse episodes.Patients with aTTP in clinical remission and low levels of ADAMTS13In the treatment of patients with autoimmune TTP and low levels of ADAMTS13 activity despite being in clinical remission, the recommendation is rituximab 375 mg/m2/week for 1–4 weeks, especially in cases where a decrease in ADAMTS13 activity and the appearance of anti-ADAMTS13 antibodies are detected during follow-up.<a class="elsevierStyleCrossRefs" href="#bib0300">60–64</a> In one study, ADAMTS13 activity increased after rituximab administration and remained above 10% at 3 months in 85% of patients.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> Taking into account these data, a possible approach would be to try to achieve an activity of 10−20% with rituximab; once that threshold is reached, it could be repeated fortnightly until normal (according to each laboratory), and then followed-up quarterly in the first year, biannually in the second year and annually thereafter.This recommendation is based on a favourable risk-benefit calculation, since if we assume that rituximab is efficient in 85% of patients and its use prevents a clinical relapse in 74% of patients, it would be sufficient to treat 1.6 patients to prevent one relapse [1/(0.85 × 0.74) = 1.58].<a class="elsevierStyleCrossRef" href="#bib0315">63</a> In addition, if the risk of mortality in a relapse is 5%, the estimated number of patients to be treated to avoid death is 32 [1/(0.85 × 0.74 × 0.05) = 31.8].<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Long-term follow-up of a patient with TTPClose clinical and biological follow-up of all the patients who have experienced an acute episode of aTTP should be performed. This must include, in addition to the blood count and haemolysis parameters, the determination of ADAMTS13 activity and the presence of the inhibitor. As for the frequency of reviews, a possible program would be: weekly for the first month; monthly during the next quarter, and quarterly until the first year is reached. Followed by every 6 months until the second year.Additionally, the effects of the disease on long-term survivors are beginning to be recognised today<a class="elsevierStyleCrossRef" href="#bib0325">65</a>:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">□Mental (depression) and cognitive impairments.</li><li class="elsevierStyleListItem" id="lsti0010">□Diagnosis of systemic lupus erythematosus and other autoimmune diseases.</li><li class="elsevierStyleListItem" id="lsti0015">□Although kidney function is stable, microalbuminuria and hypertension are frequently observed.</li><li class="elsevierStyleListItem" id="lsti0020">□Higher risk of death compared to the general population.</li><li class="elsevierStyleListItem" id="lsti0025">□Depression-type psychiatric disorders.</li></ul>In fact, in recent years a higher incidence of psychiatric conditions and cognitive impairment has been described in patients with TTP and therefore it would be advisable to incorporate annual cognitive tests and quality of life questionnaires in the long-term follow-up of these patients. Ideal scales have not been defined, but generic scales such as MOCA (Montreal Cognitive Assessment Scale)<a class="elsevierStyleCrossRef" href="#bib0330">66</a> for cognitive assessment or the SF-36 (Short Form-36 Health Survey)<a class="elsevierStyleCrossRef" href="#bib0335">67</a> and the EQ-5D (European Quality of Life-5 Dimensions)<a class="elsevierStyleCrossRef" href="#bib0340">68</a> for the quality of life could be useful.TTP is a very rare entity in children (children account for 10% of all TTP cases<a class="elsevierStyleCrossRefs" href="#bib0020">4,69</a>).Unlike adults (in whom aTTP accounts for 95% of cases), in paediatric TTP the acquired form is only slightly more common than congenital TTP.<a class="elsevierStyleCrossRefs" href="#bib0020">4,70</a> aTTP is most common in girls aged 4 months to 17 years (median 13 years).<a class="elsevierStyleCrossRef" href="#bib0350">70</a> The initial presentation is usually idiopathic (55%), and in the rest it is associated with a basic clinical context.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> Congenital TTP, on the other hand, should be suspected in any new born with severe jaundice and thrombocytopenia.<a class="elsevierStyleCrossRefs" href="#bib0355">71,72</a>In the classic form of child-onset TTP, the symptoms associated with organ ischaemia mainly affect the brain and, less frequently, the heart and kidney.The diagnosis of TTP in children is a challenge, as it is not the most common TMA at those ages, the anamnesis is more complicated and, in the case of a congenital TTP, renal involvement is common. In fact, typical HUS is the most common TMA in childhood, especially in children under 3 years of age, with 90% of cases due to Shiga toxin-producing Escherichia coli (STEC-HUS) infection.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> Therefore, in the paediatric age group, the differential diagnosis of aTTP should be made primarily with congenital TTP and with typical HUS. The tests to be performed are the same as in the adult.In terms of relapses, they have been described in 24% of aTTP patients and the mortality rate in children with aTTP is 9%. As in adults, TTP is a haematological emergency, and without proper treatment it has a mortality rate of 90%.In terms of treatment, it does not differ from the adult, although less experience is available. The therapeutic pillar is still PE, with the disadvantages of having to channel a central venous catheter in children, in addition to the risk of bleeding, infection or pneumothorax.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> As in adults, steroids are often associated as an adjuvant treatment for PE. Immunomodulatory treatment with rituximab may be considered in refractory patients or in cases of exacerbation of the disease. Other immunosuppressive drugs such as vincristine, cyclosporine A, cyclophosphamide pulse therapy, and even splenectomy may also be considered.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Other newer therapeutic alternatives such as recombinant ADAMTS13, caplacizumab, and N-acetylcysteine are also being studied in children.The incidence of TTP in pregnancy is estimated at 1/200,000 pregnancies, with it being congenital TTP in more than half of the cases.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> It usually manifests in or after the third trimester, more often from the 30th week or in the postpartum period. For this reason, in these cases the main differential diagnosis should be made with the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and with atypical HUS. The presence of TTP in pregnancy does not exclude the diagnosis of HELLP, and both conditions may be associated in the same patient.In cases where it starts between weeks 20 and 29, it is usually more severe for the child, with more frequent delayed intrauterine growth and/or foetal death.However, the diagnosis of TTP is not an indication for pregnancy termination and its appropriate treatment algorithm is described in <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>. In fact, adequate treatment protects against intrauterine growth retardation and foetal loss with a 60–70% success rate.<a class="elsevierStyleCrossRef" href="#bib0375">75</a><elsevierMultimedia ident="fig0020"></elsevierMultimedia>On the other hand, the risk of relapse in subsequent pregnancies is close to 100% in cases of congenital TTP (since in these cases the severe ADAMTS13 deficiency is constant) if not treated properly, while in the case of aTTP there is a very low relapse rate as remission is usually achieved and conception can occur with normal ADAMTS13 levels. Platelet counts should be followed monthly in women with a history of aTTP but normal ADAMTS13 levels at the onset of pregnancy, and more often if there is a prior history.<a class="elsevierStyleCrossRef" href="#bib0375">75</a>Congenital TTP, also called Upshaw-Schulman syndrome,<a class="elsevierStyleCrossRef" href="#bib0380">76</a> is the rarest form of TTP and is due to homozygous or heterozygous mutations composed of the gene ADAMTS13 causing severe plasma deficiency (<10%). In fact, more than 200 mutations have been identified, most of them private (i.e. exclusive to a family), although some stand out for their greater frequency in different geographical regions.<a class="elsevierStyleCrossRefs" href="#bib0380">76–79</a><a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> describes the most common symptoms in patients with congenital TTP and differential diagnoses to consider.<elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Early diagnosis is essential to prevent organ damage, but delays often occur due to its low prevalence and the fact that up to 30–50% of cases begin after the age of 12.<a class="elsevierStyleCrossRefs" href="#bib0390">78,79</a> An ADAMTS13 activity < 10%, which persistently remains below 10% in the remission phase and in the absence of anti-ADAMTS13 neutralizing antibodies (IgG detected by ELISA) and circulating anti-ADAMTS13 inhibitors (detected by sample mixing technique) lead to the hypothesis of a congenital TTP. However, this diagnosis must be confirmed by a genetic study.<a class="elsevierStyleCrossRef" href="#bib0385">77</a>As for acute episodes, they are often triggered by infections (40%), alcohol abuse in men (10%), pregnancy (10% in total, but 40–60% of adult women), inflammation from surgery or trauma (5%).<a class="elsevierStyleCrossRef" href="#bib0390">78</a> The treatment of acute episodes and the recommended prophylactic treatment are described in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>.<elsevierMultimedia ident="tbl0035"></elsevierMultimedia>The most common condition is neurological [headache (20−40%), transient ischaemic attack (TIA) (10%) and stroke (20%)], followed by renal [kidney failure (20−25%), haemodialysis or transplantation (∼10%)]. Heart conditions are an exception.<a class="elsevierStyleCrossRefs" href="#bib0390">78,79</a> In terms of treatment, 60–70% of patients will require prophylactic plasma infusions. However, approximately 35% receive treatment exclusively during the acute episodes, and up to 20% do not require treatment again after the onset.<a class="elsevierStyleCrossRef" href="#bib0395">79</a>Finally, in the face of the many genetic changes currently being detected, the prediction of pathogenicity according to the practical guidelines published by the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) has become crucial.<a class="elsevierStyleCrossRef" href="#bib0400">80</a> The identification of the variant profile in patients with TTP is necessary to establish the genotype-phenotype correlation, as the presence of a single pathogenic variant, or several variants, or even polymorphisms, may affect the ADAMTS13 activity<a class="elsevierStyleCrossRefs" href="#bib0380">76,77</a> or influence the age of onset. For example, homozygous mutations or the location of these in the prespacer domains are more likely to be associated with childhood onset. Moreover, phenotypic variability depends on the mutation profile of each patient, which influences the severity and recurrence of the episodes.<a class="elsevierStyleCrossRefs" href="#bib0385">77,80</a>Finally, it should be noted that the records of patients with TTP are essential to be able to widen the knowledge of this rare disease. These include the international initiative of the Swiss registry<a class="elsevierStyleCrossRef" href="#bib0405">81</a> and the Spanish TTP registry<a class="elsevierStyleCrossRef" href="#bib0410">82</a> which studies national cases with a high suspicion of congenital TTP.Mode of action in the context of non-TTP thrombotic microangiopathies due to transplantation, infections, cancer or drugsThere are other forms of TMA whose primary cause does not lie with an ADAMTS13 deficiency (it may be moderately reduced, but always >20%) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) but rather with other disorders such as cancer, infections, drugs and various types of transplantation. The therapeutic approach in these cases is usually aimed at correcting the root cause, and provide supporting treatment, with few therapeutic alternatives that have proven useful.The best known case is typical HUS or HUS associated with a bacterial infection that is triggered by Shiga toxin mainly in the context of gastroenteritis due to E. coli or by Shigella dysenteriae (and occasionally in patients with pneumonia due to Streptococcus pneumoniae). It is characterised by severe renal impairment, moderate thrombocytopenia, and a normal or slightly lowered ADAMTS13 level. In these cases, various treatments have been used with little success and the approach is mainly based on support therapies. In patients with renal impairment it has been suggested that eculizumab may be useful, although more data are needed.<a class="elsevierStyleCrossRef" href="#bib0415">83</a>However, 40–60% of cases of atypical HUS have mutations in various factors of the complement system, so in this type of TMA a genetic study of the genes encoding these factors must be done. Although there is no evidence of infection, gastrointestinal symptoms often occur. In these cases, treatment with eculizumab is considered the treatment of choice<a class="elsevierStyleCrossRefs" href="#bib0420">84–86</a> even in cases where no mutations in the complement system have been observed, as it usually proves to be equally effective.In the context of hematopoietic stem-cell transplantation, the diagnosis is based on the presence of thrombocytopenia and haemolytic anaemia not attributable to other causes. It is often associated with calcineurin inhibitors and its treatment is based on the withdrawal of these drugs and support therapy. Different groups have used other strategies such as PE, eculizumab or defibrotide, without a consensus at this moment on the best treatment.<a class="elsevierStyleCrossRef" href="#bib0435">87</a>Various neoplasms, usually in the disseminated phase, may present with a condition of TMA, generally chronic and of a mild-moderate nature, the approach of which is only supportive treatment.<a class="elsevierStyleCrossRef" href="#bib0440">88</a>Finally, there are multiple drugs that have been linked to the development of TMA, either by immune mechanisms or dose-related toxicity (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).In summary, the forms of TMA not associated with an ADAMTS13 deficiency are of multiple origin and the treatment always recommended in these cases is the correction of the trigger and the supply of support therapy, and in some cases it may be possible to use drugs such as eculizumab to avoid the action of the complement system that can play a relevant role in some of the forms.FundingThere is no funding, the guide has been put together with the funds of the Grupo Español de Aféresis (GEA).Conflict of interestAVL has received financial support from Sanofi SA for its participation in presentations.CPI has received fees for work as a consultant and external expert in projects for Boehringer Ingelheim and Sanofi SADVF declares having received fees for his role as a speaker and project advisor for Sanofi SA, AMGEN Inc., Bristol-Myers Squibb, Novartis, Takeda Pharmaceutical Company, Astellas Pharma, Merck Sharp & Dohme (MSD), Jazz Pharmaceuticals and Sobi SLJDRG has received fees for his role as a speaker for Takeda Pharmaceutical Company and for his role as an external expert witness for Sanofi SAJDR declares having received fees for his participation in expert sessions from AMGEN SA, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Sanofi SA, and Takeda Pharmaceutical Company.MEMC declares having received fees from Sanofi SA and Takeda Pharmaceutical Company for its participation as an expert in Advisory Boards. He also states that he has received a grant from Takeda Pharmaceutical Company.RG has received fees from Sanofi SA and Bristol-Myers Squibb for his participation as an expert in Advisory Boards and expert panel sessions.The other authors state having no conflicts of interest.ThanksWe would like to give thanks to the Sociedad Española de Hematología y Hemoterapia (SEHH), the Sociedad Española de Trombosis y Hemostasia (SETH), the Grupo Español de Aféresis (GEA) and the Sociedad Española de Transfusión Sanguínea y Terapia Celular (SETS) for their support in the development of this project." "textoCompletoSecciones" => array:1 [ "secciones" => array:18 [ 0 => array:3 [ "identificador" => "xres1738156" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1533266" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1738155" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1533267" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Glossary of terms of interest" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Elaboration of recommendations" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Scope and objectives" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Methodology" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Participation of the parties involved" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Introduction to acquired thrombotic thrombocytopenic purpura" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Suspicion, clinical expression and prognostic factors of evolution in TTP" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Preclinical risk assessment scales and current techniques for the differential diagnosis of TTP" ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Additional tests that should be requested to complete the diagnosis of TTP and its follow-up in an acute situation" ] 10 => array:3 [ "identificador" => "sec0050" "titulo" => "Treatment of a patient with acquired TTP in an acute situation" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0055" "titulo" => "Plasma exchange" ] 1 => array:2 [ "identificador" => "sec0060" "titulo" => "Glucocorticoids" ] 2 => array:2 [ "identificador" => "sec0065" "titulo" => "Rituximab" ] 3 => array:2 [ "identificador" => "sec0070" "titulo" => "Caplacizumab" ] 4 => array:2 [ "identificador" => "sec0075" "titulo" => "N-acetylcysteine" ] 5 => array:2 [ "identificador" => "sec0080" "titulo" => "Platelet transfusion" ] 6 => array:2 [ "identificador" => "sec0085" "titulo" => "New therapeutic strategies" ] ] ] 11 => array:3 [ "identificador" => "sec0090" "titulo" => "Mode of action in case of refractoriness, exacerbation and relapse in aTTP. Patients in clinical remission with low levels of ADAMTS13" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Refractory aTTP" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Recurrent aTTP" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Patients with aTTP in clinical remission and low levels of ADAMTS13" ] ] ] 12 => array:2 [ "identificador" => "sec0110" "titulo" => "Long-term follow-up of a patient with TTP" ] 13 => array:2 [ "identificador" => "sec0115" "titulo" => "Mode of action in the context of non-TTP thrombotic microangiopathies due to transplantation, infections, cancer or drugs" ] 14 => array:2 [ "identificador" => "sec0120" "titulo" => "Funding" ] 15 => array:2 [ "identificador" => "sec0125" "titulo" => "Conflict of interest" ] 16 => array:2 [ "identificador" => "sec0130" "titulo" => "Thanks" ] 17 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-02-06" "fechaAceptado" => "2021-03-16" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1533266" "palabras" => array:5 [ 0 => "Thrombotic thrombocytopenic purpura" 1 => "Thrombotic microangiopathies" 2 => "ADAMTS13" 3 => "Plasma exchange" 4 => "Haemolysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1533267" "palabras" => array:5 [ 0 => "Púrpura trombocitopénica trombótica" 1 => "Microangiopatía trombótica" 2 => "ADAMTS13" 3 => "Recambio plasmático" 4 => "Hemólisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) characterised by the development of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10% in most cases.Recently there have been numerous advances in the field of PTT, new, rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors. The massive sequencing systems facilitate the identification of polymorphisms in the ADAMTS13 gene. In addition, new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab.The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice.The recommendations set out in this document were prepared following the AGREE methodology. The research questions were formulated according to the PICO format. A search of the literature published during the last 10 years was carried out. The recommendations were established by consensus among the entire group, specifying the existing strengths and limitations according to the level of evidence obtained.In conclusion, this document contains recommendations on the management, diagnosis, and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La púrpura trombocitopénica trombótica (PTT) es una microangiopatía trombótica (MAT) caracterizada por el desarrollo de anemia hemolítica microangiopática, trombocitopenia y disfunción orgánica isquémica asociada a niveles de ADAMTS13 inferiores a 10% en la mayoría de los casos.Recientemente se han producido numerosos avances en el campo de la PTT. Se han desarrollado nuevas técnicas rápidas y accesibles capaces de cuantificar los niveles de ADAMTS13 y los posibles inhibidores. Los sistemas de secuenciación masiva del gen ADAMTS13 facilitan la identificación de polimorfismos en este gen. Además, han aparecido nuevos fármacos como caplacizumab y se plantean estrategias de prevención de recaídas con el uso de rituximab.Los registros de pacientes con PTT permiten ahondar en el conocimiento de esta enfermedad, pero la gran variabilidad en el diagnóstico y tratamiento hace necesaria la elaboración de un documento que homogenice la terminología y la práctica clínica.Las recomendaciones recogidas en el presente documento se han elaborado siguiendo la metodología AGREE. Las preguntas de investigación se formularon de acuerdo con el formato PICO. Se realizó una búsqueda bibliográfica de la literatura publicada durante los últimos 10 años. Las recomendaciones se establecieron por consenso entre todo el grupo puntualizando las fortalezas y limitaciones existentes de acuerdo al nivel de evidencia obtenido.En conclusión, en el presente documento se recogen recomendaciones sobre el tratamiento, diagnóstico y tratamiento de la PTT con el objetivo final de elaborar pautas basadas en la evidencia publicada hasta la fecha que permitan a los profesionales sanitarios optimizar el tratamiento de la PTT." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Mingot Castellano ME, Pascual Izquierdo C, González A, Viejo Llorente A, Valcarcel Ferreiras D, Sebastián E, et al. Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica. Med Clin (Barc). 2022;158:630." ] ] "multimedia" => array:11 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1770 "Ancho" => 2925 "Tamanyo" => 508137 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Pathophysiology of thrombotic microangiopathies (TMA)." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1394 "Ancho" => 2500 "Tamanyo" => 257097 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Diagnostic algorithm for thrombotic thrombocytopenic purpura (TTP)." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2153 "Ancho" => 3175 "Tamanyo" => 399230 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Therapeutic algorithm for acquired thrombotic thrombocytopenic purpura." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1773 "Ancho" => 3175 "Tamanyo" => 543470 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Management algorithm for thrombotic thrombocytopenic purpura during pregnancy." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Ac: antibodies; ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; MMACHC: Methylmalonic aciduria and homocystinuria; C: complement; CFH, CFI, CFB: complement factors H, I and B, respectively; DIC: disseminated intravascular coagulation; DGKE: diacylglycerol kinase; GVHD: graft-versus-host disease; VEGF: vascular endothelial growth factor; HT: hypertension; TMA: thrombotic microangiopathy; MCP: membrane cofactor protein; TTP: thrombotic thrombocytopenic purpura; HUS: haemolytic and uremic syndrome; THBD: thrombomodulin; HSCT: hematopoietic stem cell transplantations; SOT: solid organ transplant." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Etiopathogenesis \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Primary TMA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acquired autoimmune TTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ADAMTS13 deficit (<10%) due to anti-ADAMTS13 antibodies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Congenital TTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ADAMTS13 deficit (<10%) due to ADAMTS13 gene mutations \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Typical HUS due to infection E. Coli or S. pneumoniae \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shiga toxin induced renal endothelial injury \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Atypical HUS (aHUS) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C gene mutations: CFH, CFHR 1−5, CFI, CD46 (MCP), C3 and CFB \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMA due to coagulation disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DGKE mutations, plasminogen \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMA due to metabolic disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mutations in the gene causing MMACHC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMA due to anti-complement antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-Factor H autoantibodies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TMA secondary to other clinical conditions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HSCT, SOT Drugs: quinine, mitomycin C, gemcitabine, cisplatin, interferon, \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HSCT, SOT: infections + chemotherapy + radiation + calcineurin inhibitors + GVHD + coagulation activation and C. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VEGF inhibitors, clopidogrel, calcineurin inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drugs: immune mechanism or endothelial disorders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DIC, HELLP syndrome, catastrophic antiphospholipid syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Microvascular injury caused by each underlying disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoimmune diseases, rickettsia, viruses, fungi \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Scleroderma, malignant HT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metastatic cancer \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mechanical haemolysis: obstruction due to tumour cells \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Aetiopathogenic classification of TMA." ] ] 5 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; LDH: lactate dehydrogenase; TTP: thrombotic thrombocytopenic purpura." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mortality \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relapse \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Delay in diagnosis and start of treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Young age \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Old age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood group other than group O \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elevated LDH levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Previous recurrence \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe neurological disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rituximab treatment protects against recurrence in the first year after the initial episode \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Elevated troponin levels \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ADAMTS13 activity < 10% during follow-up \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Low levels of ADAMTS13 activity and high levels of anti-ADAMTS13 antibodies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lack of rapid response to plasma exchange treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Prognostic factors of mortality and relapse in acquired TTP." ] ] 6 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; Sp: specificity; INR: international normalised ratio; N: number of patients; TTP: thrombotic thrombocytopenic purpura; Se: sensitivity; HSCT: hematopoietic stem cell transplantation; MCV: mean corpuscular volume; NPV: negative predictive value; PPV: positive predictive value.The categories with a high probability of obtaining a severe ADAMTS13 deficiency are shown in bold. These categories are those used as cut-off points to assess the ability to classify scores." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">French scale<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>,<a class="elsevierStyleCrossRef" href="#bib0080">16</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ASAP scale<a class="elsevierStyleCrossRef" href="#bib0085">17</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Plasmic scale<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤ 68 years old (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Platelets \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 × 109/L (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">≤44 × 109/L (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><30 × 109/L (+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Creatinine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2.25 mg/dL (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Men: ≤2 mg/dL (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><2.25 mg/dL (+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Women: ≤1.9 mg/dL (+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No previous HSCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(+1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No HSCT or solid organ transplant (+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Indirect Bilirubin Haemolysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>2 mg/dL, Reticulocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>2.5% or Undetectable Haptoglobin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No active cancer (no treatment in last year) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">INR < 1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MCV < 90 fL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">(+1) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Original cohort \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N = 214 (160 TTP; 75%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N = 260 (56 TTP; 21.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N = 496 (150 TTP; 30.2%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">% of patients with ADAMTS13 deficiency in each category \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 0 (2%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 0–2 (1.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 0−4 (1%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 1 (70%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 3 (17%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 5 (11%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 2 (94%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 4 (85%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Score 6−7 (78.3%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sensitivity (Se), \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Se: 84% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Se: 87,7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Se: 85–90% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Specificity (Sp), PPV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sp: 83,8% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sp: 92,7% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sp: 58−92% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">and NPV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PPV: 70% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PPV: 84.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PPV: 51−72% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NPV: 92% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NPV: 94.3% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NPV: 92−98% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "The French score was developed from a cohort that did not include patients with secondary TMAs, so the percentage of patients with ADAMTS13 deficiency is overrepresented in each category compared to the other scores." ] ] ] "descripcion" => array:1 [ "en" => "Most used preclinical risk scales in TTP." ] ] 7 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0040" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Note: imaging tests will be requested according to clinical evolution.ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; ECG: electrocardiogram; EEG: electroencephalogram; LDH: lactate dehydrogenase; NRL: neurological; pro-BNP: Pro-type B natriuretic peptide; TTP: thrombotic thrombocytopenic purpura; MRI: MRI; CT scan: computed tomography." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complementary tests to be performed at diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemolytic markers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Lactate dehydrogenase (LDH) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Indirect bilirubin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Haptoglobin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Generic tissue ischaemia marker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→LDH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of cardiac tissue ischaemia (only 25% have clinical symptoms or electrical disturbances<a class="elsevierStyleCrossRef" href="#bib0105">21</a>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Cardiac troponin I or T (elevated in 68% of patients, increased the mortality rate by 6 times<a class="elsevierStyleCrossRef" href="#bib0110">22</a>) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Electrocardiogram (ECG) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Pro-B-type natriuretic peptide (pro-BNP) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Chest X-ray \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Echocardiogram (if affected) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Telemetry (if affected) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of cerebral tissue ischaemia (any type and severity of neurological focus) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Glasgow scale<a class="elsevierStyleCrossRef" href="#bib0110">22</a>,<a class="elsevierStyleCrossRef" href="#tblfn0010">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Emergency computed axial tomography (CAT) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Magnetic resonance imaging (MRI) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Electroencephalogram (EEG) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of renal tissue ischaemia<a class="elsevierStyleCrossRef" href="#bib0115">23</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Proteinuria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Albuminuria \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Creatinine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Glomerular filtration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Urinary sediment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of bleeding events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Imaging localization of bleeding (transformation to haemorrhagic stroke or bleeding in patients treated with caplacizumab, etc.)<a class="elsevierStyleCrossRef" href="#bib0100">20</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complementary tests for the follow-up of TTP in an acute situation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Analytical data<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Hemogram with reticulocytes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haemolytic markers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Schistocytes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→LDHb \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Indirect bilirubin<a class="elsevierStyleCrossRef" href="#tblfn0015">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Haptoglobin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Generic tissue ischaemia marker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→LDH \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risk of relapse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→ADAMTS13 activity levels \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Anti-ADAMTS13 antibodies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cardiac, renal, cerebral, or other tissue ischemia evaluation tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→If the affectation is the first or if there is a new appearance of signs or symptoms of organic ischemia: see previous section<a class="elsevierStyleCrossRefs" href="#bib0100">20,24</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of bleeding events \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→See previous section<a class="elsevierStyleCrossRef" href="#bib0100">20</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluation of neurological (NRL) or cognitive deficit and mood disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "Scoring 14 or lower increased the mortality rate by 9 times. The Glasgow scale does not replace the usual NRL physical examination (which must be reported)." ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "Complementary tests during follow-up are recommended to be performed daily until remission, and twice a week until discharge. After discharge the tests are to be performed once a week for the first 4 weeks." ] ] ] "descripcion" => array:1 [ "en" => "Recommended complementary tests in the diagnosis and follow-up of patients with TTP." ] ] 8 => array:9 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: George and Cuker<a class="elsevierStyleCrossRef" href="#bib0250">50</a>; Sayani and Abrams<a class="elsevierStyleCrossRef" href="#bib0260">52</a>." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0045" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; i/v: intravenous; oral: oral (by mouth); aTTP: acquired thrombotic thrombocytopenic purpura; PE: plasma exchange." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment<a class="elsevierStyleCrossRef" href="#tblfn0020">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Refractoriness \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Re-determine ADAMTS13 activity and inhibitor presence \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">In the meantime: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Intensify the PEs to 1.5 times the blood volume \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Intensify the steroid regimen (e.g., methylprednisolone 1) g/day i/v for 3 days)<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Start rituximab 375 mg/m2/dose (after checking for anti-ADAMTS13 antibodies)<a class="elsevierStyleCrossRefs" href="#bib0170">34–36</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Two possible administration guidelines: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- → weekly on days 1, 7, 14, 21<a class="elsevierStyleCrossRef" href="#bib0170">34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- →days 1, 4, 7, 14<a class="elsevierStyleCrossRef" href="#bib0265">53</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Add caplacizumab/Cablivi® if not used as first line treatment or resume if discontinued (1 st dose 10 mg i/v, then 10 mg/day s/c in the first 4 h after PE)<a class="elsevierStyleCrossRefs" href="#bib0100">20,34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluate whether to add according to clinical-analytical evolution: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Vincristina 1 g/m2 (maximum 2 g) i/v<a class="elsevierStyleCrossRef" href="#bib0270">54</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Cyclophosphamide oral or i/v 500 mg/2 weeks (6 total doses)<a class="elsevierStyleCrossRef" href="#bib0275">55</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Bortezomib 1.3 mg/m2, 2 times a week for 2 weeks<a class="elsevierStyleCrossRef" href="#bib0280">56</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→N-acetylcysteine 150 mg/kg i/v daily for 17 days h<a class="elsevierStyleCrossRef" href="#bib0225">45</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Cyclosporine, 300 mg/day oral or 2−3 mg/kg/day<a class="elsevierStyleCrossRef" href="#bib0285">57</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Splenectomy, as last resort<a class="elsevierStyleCrossRefs" href="#bib0290">58,59</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exacerbation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Discard any cause of exacerbation, especially catheter-related sepsis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Add rituximab, if it has not been used<a class="elsevierStyleCrossRefs" href="#bib0170">34–36,53</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Resume PE, if it has not yet been withdrawn<a class="elsevierStyleCrossRef" href="#bib0005">1</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Intensify the steroid regimen<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Add caplacizumab (if not administered initially, or if it has been discontinued)<a class="elsevierStyleCrossRefs" href="#bib0100">20,34</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relapse \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Start PE 1−1.5 blood volume<a class="elsevierStyleCrossRef" href="#bib0005">1</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Immunosuppression with glucocorticoids: methylprednisolone 1 g/day for 3 days, 1 mg/kg/day<a class="elsevierStyleCrossRef" href="#bib0165">33</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Rituximab 375 mg/m2/d weekly on days 1, 7, 14, 21 or on days 1, 4, 7, 14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Caplacizumab/Cablivi® (1 st dose 10 mg i/v, after 10 mg/day s/c in the first 4 h after PE)<a class="elsevierStyleCrossRefs" href="#bib0170">34–36,53</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Splenectomy if the patient has multiple recurrences<a class="elsevierStyleCrossRefs" href="#bib0290">58,59</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "The order in which the treatments are herein presented does not imply preference in their use. The drugs listed in this table have references that support them, although not all have been subjected to randomised studies to endorse their efficacy. The indicated doses are always approximate, as there are no dose-effectiveness studies in this disease, and in no case should these indications replace the clinical judgment of the prescribing professional." ] ] ] "descripcion" => array:1 [ "en" => "Possible treatment options in case of refractoriness, exacerbation and relapse/recurrence in aTTP." ] ] 9 => array:9 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Hovinga and George<a class="elsevierStyleCrossRef" href="#bib0380">76</a>." "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0050" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Stroke: cerebrovascular accident; TIA: transient ischaemic attack; HDN: haemolytic disease of the new born; HELLP: haemolysis, elevated liver enzymes and low platelets; SLE: systemic lupus erythematosus; MAHA: microangiopathic haemolytic anaemia; ITP: immune thrombocytopenic purpura; cTTP: congenital thrombotic thrombocytopenic purpura; LBW: low birth weight." "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MAHA ± Thrombopenia<a class="elsevierStyleCrossRef" href="#tblfn0025">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neonatal/child \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Young adult \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pregnancy<a class="elsevierStyleCrossRef" href="#tblfn0030">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Suspect cTTP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neonatal jaundice, Exanguine-transfusion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ecchymosis, neurological symptoms, stroke, TIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">History of foetal loss, LBW, preeclampsia < 25 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Differential diagnosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HDN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ITP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preeclampsia, \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alloimmune thrombocytopenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evans syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S. of HELLP, SLE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gestational thrombopenia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "a" "nota" => "It can be moderate." ] 1 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "b" "nota" => "Most frequent onset in the third trimester and postpartum." ] ] ] "descripcion" => array:1 [ "en" => "Clinical conditions in which cTTP should be suspected." ] ] 10 => array:8 [ "identificador" => "tbl0035" "etiqueta" => "Table 7" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0055" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "ADAMTS13: A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13." "tablatextoimagen" => array:2 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment of acute crises</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fresh frozen plasma<a class="elsevierStyleCrossRef" href="#tblfn0035">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→10−15 ml/kg/day, for 1−3 days until platelet count normalizes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Follow-on spacing as required \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Disadvantages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Transmission of pathogens \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Allergic reactions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Alternatives \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Factor VIII concentrates (Koate, GLP 8Y: require higher frequency of administration). Not recommended in the guides<a class="elsevierStyleCrossRef" href="#bib0185">37</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→ADAMTS13 recombinant [BAX930, EC NCT03393975, phase 3 in progress] \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] 1 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prophylactic treatment</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fresh frozen plasma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Most common: 10−15 ml/kg every 2−3 weeks<a class="elsevierStyleCrossRef" href="#tblfn0040">b</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Individualize program according to platelet count and resolution of symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">When to establish prophylaxis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Most common in children (>90%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Recurrent episodes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→During pregnancy (achieves a very high success rate)<a class="elsevierStyleCrossRef" href="#bib0380">76</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Larvate symptoms despite normal blood count (headache, lethargy, abdominal discomfort) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">•→Silent organ damage (proteinuria, strokes)<a class="elsevierStyleCrossRef" href="#tblfn0045">c</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:3 [ 0 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "a" "nota" => "In Spain, classically predilection for quarantined plasma." ] 1 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "b" "nota" => "Although most patients reach basal levels within 10 days of infusion." ] 2 => array:3 [ "identificador" => "tblfn0045" "etiqueta" => "c" "nota" => "The appearance of kidney failure, or neurological impairment (depression, cognitive impairment, silent heart attacks on MRI) should be monitored periodically." ] ] ] "descripcion" => array:1 [ "en" => "Treatment of acute crises and prophylactic treatment." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:88 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/jth.13571" "Revista" => array:6 [ "tituloSerie" => "J Thromb Haemost" "fecha" => "2017" "volumen" => "15" "paginaInicial" => "312" "paginaFinal" => "322" "link" => array:1 [ …1] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Redefining outcomes in immune TTP: an international working group consensus report" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood.2020009150" "Revista" => array:3 [ "tituloSerie" => "Blood" "fecha" => "2021" "link" => array:1 [ …1] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Incidence, diagnosis, and outcome of acquired thrombotic thrombocytopenic purpura (aTTP): a nationwide survey by the Spanish registry of thrombotic thrombocytopenic purpura" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jca.21894" "Revista" => array:4 [ "tituloSerie" => "J Clin Apher" "fecha" => "2021" "volumen" => "134" "numero" => "March 29" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thrombotic thrombocytopenic purpura" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1182/blood-2016-10-709857" "Revista" => array:7 [ "tituloSerie" => "Blood" "fecha" => "2017" "volumen" => "129" "paginaInicial" => "2836" "paginaFinal" => "2846" "link" => array:1 [ …1] "itemHostRev" => array:3 [ …3] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "2015" "volumen" => "144" "paginaInicial" => "331" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies" "autores" => array:1 [ 0 => array:2 [ …2] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2141.2012.09167.x" "Revista" => array:6 [ "tituloSerie" => "Br J Haematol" "fecha" => "2012" "volumen" => "158" "paginaInicial" => "323" "paginaFinal" => "335" "link" => array:1 [ …1] ] ] ] ] ] ] 6 => array:3 [ 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Consensus statement

Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura

Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica

María Eva Mingot Castellanoa,

, Cristina Pascual Izquierdob, Ataulfo Gonzálezc, Aurora Viejo Llorented, David Valcarcel Ferreirase, Elena Sebastiánf, Faustino García Candelg, Héctor Sarmiento Palaoh, Inés Gómez Seguíi, Javier de la Rubiai, Joan Cidj, Jorge Martínez Nietok, Luis Hernández Mateoh, Rosa Goterris Viciedol, Teresa Fidalgom, Ramon Salinasn, Julio del Rio-Garmao,**, Spanish Apheresis Group (GEA)

a Servicio de Hematología, Hospital Universitario Virgen del Rocío, Sevilla, Spain

b Servicio de Hematología y Hemoterapia, Hospital Gregorio Marañón, Madrid, Spain

c Servicio de Hematología y Hemoterapia, Hospital Universitario de San Carlos, Madrid, Spain

d Servicio de Hematología, Área de Hemoterapia, Hospital Universitario La Paz, Madrid, Spain

e Unidad de Hematología Intensiva y Terapia Celular, Departamento de Hematología, Instituto de Oncología Vall d'Hebron (VHIO), Hospital Universitario Vall d’Hebron, Barcelona, Spain

f Servicio de Hematología y Hemoterapia, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

g Sección de Hemostasia y Trombosis, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

h Servicio de Hematología y Hemoterapia, Hospital General de Alicante, Valencia, Spain

i Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, Spain

j Unidad de Aféresis y Terapia Celular, Servicio de Hemoterapia y Hemostasia, Institut Clínic de Malalties Hematològiques i Oncològiques (ICMHO), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universidad de Barcelona, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain

k Servicio de Hematología y Hemostasia, Hospital Universitario Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdissC), Madrid, Spain

l Servicio de Hematología y Hemoterapia, Hospital Clínico Valencia, INCLIVA, Valencia, Spain

m Departamento de Hematología Clínica. Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

n Banc de Sang i Teixits de Catalunya, Barcelona, Spain

o Servicio de Transfusión, Servicio de Hematología, Complexo Hospitalario Universitario de Ourense, Galicia, Spain

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Clinical remission situation in which the ADAMTS13 activity is greater than or equal to the lower limit of normality established in each center&#46; Because there is biological variability in ADAMTS13 activity&#44; as well as variability in its laboratory measurement&#44; it is recommended to perform multiple measurements to confirm the ADAMTS13 values&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Refractory</span><a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#58; No significant increase in platelet count &#40;less than 50&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L&#41; after the first 5 days of plasma exchange or clinical or laboratory deterioration during treatment with daily plasma exchange&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Exacerbation</span>&#8211;&#58; Decreased platelet count and unjustified increase of LDH for reasons other than TTP&#44; within 30 days of its cessation due to clinical response&#44; forcing plasma exchange to resume&#46; Decreases in 24&#8239;h of 10&#37; of the platelet count after its normalisation forces extreme monitoring given the risk of exacerbation&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Clinical relapse</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#58; Platelet count drop to &#60;150&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L after reaching clinical remission&#44; with or without clinical evidence of new ischemic organ injury&#44; and always after previously ruling out other possible causes of thrombocytopenia&#46; A clinical relapse must always be confirmed by documentation of severe ADAMTS13 deficiency &#40;&#60;10&#37;&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ADAMTS13 relapse</span><a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a>&#58; ADAMTS13 level drops below 20&#37; after ADAMTS13 remission &#40;complete or partial&#41;&#46; Because there is biological variability in ADAMTS13 level&#44; as well as variability in its laboratory measurement&#44; it is recommended to perform multiple measurements to confirm the ADAMTS13 values&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Elaboration of recommendations</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Scope and objectives</span><p id="par0045" class="elsevierStylePara elsevierViewall">Thrombotic thrombocytopenic purpura &#40;TTP&#41; is a rare haematological disease characterised by the presence of microangiopathic haemolytic anaemia&#44; thrombocytopenia&#44; and systemic vascular events&#46; In most cases it presents ADAMTS13 levels &#40;a disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member 13&#41; lower than 10&#37;&#46; Its clinical evolution is characterised by the presence of acute episodes&#44; relapses and exacerbations despite the correct therapeutic approach&#46; In Spain&#44; this pathology has an incidence of 2&#46;67 cases&#47;million inhabitants per year&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Much progress has been made in the field of TTP in recent years&#44; especially with the appearance of new diagnostic tools and new treatments&#46; In addition&#44; special attention has been paid to the morbidity associated with acute TTP episodes&#44; along with the resulting neurocognitive&#44; vascular or renal sequelae&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">In the light of this new research&#44; this group has raised the need to prepare a document that collects all the evidence generated to date in relation to this disease in order to develop recommendations that allow health professionals to standardise the treatment of TTP patients and also to serve as a reference framework in clinical practice&#44; thus updating the guidelines already published in Spain in 2011&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Methodology</span><p id="par0060" class="elsevierStylePara elsevierViewall">These recommendations have been developed following the guidelines specified in the AGREE methodology&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The objectives and the questions that required answers with the present guides were formulated following a PICO type formula &#91;P&#58; population&#44; I&#58; intervention&#44; C&#58; comparison&#59; O&#58; outcome&#93;&#46; The final areas chosen to be addressed were&#58; definition&#44; clinical expression and suspicion of TTP in patients&#59; current differential diagnostic scores and techniques&#59; additional tests required during diagnosis and follow-up&#59; treatment of acute episodes&#59; mode of action in case of refractoriness&#44; exacerbation and relapse&#59; follow-up of the patient in remission&#59; TTP in the paediatric population and in pregnancy&#59; treatment of congenital PPT and approach to non-TTP thrombotic microangiopathies &#40;TMAs&#41; caused by transplants&#44; infections&#44; cancer or drugs&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">To prepare this paper&#44; the authors responsible for each of the information blocks performed a bibliographic search of all the literature published during the last 10 years using the relevant MeSH terms for each unit of content&#46; In order to establish the recommendations&#44; the robustness of the collected information was evaluated and the necessary strengths and limitations in each of the sections were pointed out&#44; taking into account the level of evidence&#46; Following this&#44; a peer review of each block of recommendations was carried out until a consensus was reached by the whole group&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Participation of the parties involved</span><p id="par0075" class="elsevierStylePara elsevierViewall">All authors have contributed equally to the bibliographic review of the existing literature&#44; as well as to the writing of this paper&#46; JDRG&#44; CPI&#44; RS and MEMC have also taken the lead in reviewing and correcting the paper&#46; MEMC and RS have also acted as project coordinators&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">MEMC has been responsible for writing the abstract&#44; and the glossary of terms of interest&#59; RS has co-authored the writing of the abstract&#59; JDRG has been responsible for writing Chapter 1&#59; HSP and LHM have been responsible for writing Chapter 2&#59; JMN and AG have been responsible for writing Chapter 3&#59; RG has been responsible for writing Chapter 4&#59; AVL and JDR have been responsible for writing Chapter 5&#59; CPI has written Chapter 6&#59; JC has been responsible for Chapter 7&#59; ES has been responsible for Chapter 8&#59; FG has been responsible for Chapter 9&#59; IGS and TF have been responsible for writing Chapter 10 and DVF has been responsible for writing Chapter 11&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The project to elaborate these clinical recommendations has been supported and sponsored by the Grupo Espa&#241;ol de Af&#233;resis &#40;GEA&#41;&#44; the Sociedad Espa&#241;ola de Hematolog&#237;a y Hemoterapia &#40;SEHH&#41;&#44; the Sociedad Espa&#241;ola de Trombosis y Hemostasia &#40;SETH&#41; and the Sociedad Espa&#241;ola de Transfusi&#243;n Sangu&#237;nea y Terapia Celular &#40;SETS&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Introduction to acquired thrombotic thrombocytopenic purpura</span><p id="par0090" class="elsevierStylePara elsevierViewall">TTP is a type of TMA&#44; a term that describes an endothelial lesion of the microcirculation with thrombi that obstruct the vascular flow&#44; causing mechanical haemolysis &#40;appearance of schistocytes&#41;&#44; ischaemia&#44; and tissue damage &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; In the clinical setting&#44; the term TMA has been extended to all syndromes with microangiopathic haemolytic anaemia &#40;MAHA&#41;&#44; thrombocytopenia&#44; and organ damage&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Primary TMAs have their own entity and include TTP &#40;congenital or acquired&#41; and haemolytic uremic syndrome &#40;HUS&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the pathophysiological classification of the TMAs&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Acquired TTP &#40;aTTP&#41; is an autoimmune disease in which autoantibodies directed against ADAMTS13 impede its activity &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Its estimated incidence in Spain in the population over the age of 16 is 2&#46;67 patients per 10<span class="elsevierStyleSup">6</span> inhabitants&#47;year&#44; and the prevalence is 22 patients per 10<span class="elsevierStyleSup">6</span> inhabitants&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In TTP&#44; thrombus formation is due to the severe deficit &#40;activity &#60;&#8239;10&#37; of normal&#41; of the ADAMTS13 protease&#44; responsible for breaking the very high molecular weight multimers &#40;VHMWM&#41; of the von Willebrand factor &#40;vWF&#41; newly secreted by the endothelium&#44; which have a much higher sticking capacity than those normally circulating&#46; When endothelial injury occurs&#44; VHMWMs cause spontaneous platelet aggregation in the microcirculation&#44; forming thrombi rich in platelets and vWF throughout the body &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Therefore&#44; a severe deficiency of ADAMTS13 is necessary&#44; but not always sufficient&#44; to produce TTP&#44; as precipitating factors exist&#44; such as surgery&#44; infection&#44; or inflammatory conditions&#44; that injure the endothelium and can trigger acute episodes of TTP&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Suspicion&#44; clinical expression and prognostic factors of evolution in TTP</span><p id="par0105" class="elsevierStylePara elsevierViewall">Classically&#44; TTP is characterised by acute outbreaks of microangiopathic haemolytic anaemia and thrombocytopenia&#44; associated or not with fluctuating neurological disorders&#44; impaired renal function&#44; and fever&#46; However&#44; these five classic symptoms coincide in less than 10&#37; of cases of acute TTP&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;6</span></a> Kidney impairment is almost always mild and transient&#44; although acute kidney failure has been reported in up to 27&#37; of patients with TTP<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#59; it should also be mentioned that although it is not a common sign and is more indicative of HUS&#44; it does not rule out the diagnosis of TTP&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In relation to the involvement of the central nervous system &#40;CNS&#41;&#44; symptoms can range from mild headache to severe manifestations such as changes in the level and course of consciousness&#44; seizures&#44; and motor and sensory deficits&#44; among others&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;7</span></a> Regarding cardiac involvement&#44; it is underdiagnosed because of the absence of cardiac symptoms and multiorgan involvement at the onset of TTP&#46; However&#44; it is common in these subjects and should be evaluated&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;8</span></a> Finally&#44; the appearance of nonspecific abdominal pain&#44; although more common in patients with HUS&#44; may appear in TTP as a manifestation of intestinal ischaemia&#46; In addition&#44; the development of other autoimmune diseases occurs in up to 25&#37; of subjects with TTP&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;7&#44;8</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The current mortality rate associated with TTP is less than 10&#37; and usually occurs in the first days after diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> This figure has remained stable since 1991 thanks to the introduction of plasma exchange as a first-line treatment in patients with autoimmune TTP&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The prognostic factors associated with mortality and relapses in aTTP are described in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Preclinical risk assessment scales and current techniques for the differential diagnosis of TTP</span><p id="par0120" class="elsevierStylePara elsevierViewall">In the laboratory&#44; acute phase aTTP is characterised&#44; except in exceptional cases&#44; by a severe functional deficiency of ADAMTS13 &#40;activity &#60;&#8239;10&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;11</span></a> Once this deficit is confirmed&#44; the presence of anti-ADAMTS13 autoantibodies should be looked for&#44; as finding these autoantibodies allows the TTP to be classified as acquired TTP&#46; However&#44; a negative result does not always imply the diagnosis of congenital TTP because antibodies are not identified in up to 20&#8722;25&#37; of aTTP cases&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Therefore&#44; in order to arrive at a definitive diagnosis of congenital TTP&#44; the genetic study of the ADAMTS13 gene must be carried out &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">To determine both activity and antibodies&#44; whole blood extraction in a citrate tube is required&#44; since both tests are performed on plasma&#46; This blood draw should be prior to the start of plasma therapy&#44; and samples obtained with ethylenediaminetetraacetic acid &#40;EDTA&#41; should never be used because this compound completely inhibits the in vitro activity of ADAMTS13&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">ADAMTS13 activity can be measured by the use of different immunoassays&#46; The most used assays measure the changes in fluorescence &#40;FRETs&#41; or absorbance &#40;ELISA&#41; that occur in the sample when ADAMTS13 cuts a fragment of vWF&#44; although faster tests &#40;chemiluminescence and test strips&#41; have recently been developed that have shown sensitivities comparable to standardised methods&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;14</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">When identifying autoantibodies&#44; the classical mix assay evaluates whether the patient&#39;s plasma is able to inhibit a control sample&#46; This can help to identify inhibitory antibodies&#44; but it does not detect antibodies that only accelerate the clearance of ADAMTS13&#46; In addition&#44; although several commercial assays are available that specifically identify IgG autoantibodies by ELISA&#44; these do not differentiate whether they are inhibitory or not&#44; and they are unable to detect autoantibodies of other classes &#40;IgM&#44; IgA&#44; etc&#46;&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">At present&#44; the determination of ADAMTS13 is not available as an urgent test in &#8216;round-the-clock&#8217; laboratories&#44; and TTP requires an urgent therapeutic decision&#46; For this reason&#44; several clinical score systems have been developed to establish the pretest probability that a subject will have a severe deficit in ADAMTS13 activity&#44; which should be confirmed later with the determination of ADAMTS13 levels&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> shows the most commonly used preclinical risk scales&#46; It is important to note that less than 2&#37; of patients with very low scores have ADAMTS13 deficiency&#44; while in intermediate scores it is common to find patients with other causes of TMA&#46; At high scores&#44; at least 4 out of 5 patients have TTP&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Since all of these score systems have been developed using an adult population&#44; it is important to note that these scores are not applicable to minors&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Additional tests that should be requested to complete the diagnosis of TTP and its follow-up in an acute situation</span><p id="par0150" class="elsevierStylePara elsevierViewall">Recommended complementary tests for the diagnosis and follow-up of patients with TTP are described in detail in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; After remission&#44; this follow-up is recommended once a month for 3 months&#44; once every 3 months for 9 months&#44; and then every 6 months for at least 2 years&#46; In addition&#44; it is recommended that screening for ADAMTS13 be performed weekly until it normalises&#46; In the event that ADAMTS13 levels do not return to normal after clinical remission&#44; it is recommended that the frequency of the determinations be decided in accordance with the proposed treatment&#47;follow-up strategy&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Just to mention&#44; in the case of atypical localised ischaemia &#40;pancreatitis&#44; intestinal ischaemia&#44; etc&#46;&#41; additional targeted tests such as amylase&#44; lipase and imaging levels are recommended&#46; Also&#44; although venous thromboembolic conditions are uncommon and are generally related to the use of catheters&#44; when facing a clinical suspicion of the same&#44; appropriate imaging tests are recommended as D-dimer is not very effective for screening these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Treatment of a patient with acquired TTP in an acute situation</span><p id="par0160" class="elsevierStylePara elsevierViewall">aTTP treatment has 2 well-established pillars as initial treatment&#58; plasma exchange &#40;PE&#41; and immunosuppressive therapy&#46; There is also a third tool used&#44; which is the prevention of platelet adhesion to the vWF&#44; thus preventing the formation of thrombi&#46; The proposed algorithm for the treatment of aTTP is detailed in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Plasma exchange</span><p id="par0165" class="elsevierStylePara elsevierViewall">PE is the mainstay of TTP treatment and its superiority over plasma infusion was proven in a randomised study by the Canadian group in 1991&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The most commonly used regimen is the plasma exchange of 1&#46;5 plasma volumes &#40;PV&#41; for the first 3 days followed by 1&#8239;PV daily&#44; although there are centres that only use 1&#8239;PV from the beginning&#46; This PE should be continued every day until the platelet count is greater than 150&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L in two separate determinations and lactate dehydrogenase &#40;LDH&#41; is normalised&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Regarding the different types of plasma available&#44; there are no randomised studies showing the superiority of inactivated plasma over untreated fresh-frozen plasma&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In fact&#44; in a multicenter observational study&#44; the use of inactivated plasma was associated with the presence of more exacerbations&#44; and as no subsequent study has shown otherwise&#44; the use of fresh-frozen plasma is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> In addition&#44; if PE cannot be started early&#44; 25&#8722;30&#8239;ml&#47;kg of fresh plasma will be transfused as long as this is tolerated&#46; There are experiences of plasma exchange with other solutions such as albumin&#44; but this is not the usual practice&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;30</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Finally&#44; studies to date have not shown a significant benefit associated with the gradual reduction of PE&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> so it is not a mandatory recommendation&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Glucocorticoids</span><p id="par0180" class="elsevierStylePara elsevierViewall">The efficacy of glucocorticoids was demonstrated in 2 randomised studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> The most common regimen is prednisone &#40;PRD&#41; 2&#46;5&#8239;mg&#47;kg&#47;day or methylprednisolone 1&#8239;g&#47;day for 3 days followed by PRD 1&#8239;mg&#47;kg&#47;day which is gradually decreased depending on the response&#46; When the platelets have recovered&#44; start the gradual reduction of treatment after 5&#8211;7 days and stop at 3 weeks&#46; High doses of steroids appear to reduce the number of PEs&#44; but the choice between one regimen or another should be made based on the patient&#39;s comorbidities and tolerance of possible side effects&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Rituximab</span><p id="par0185" class="elsevierStylePara elsevierViewall">The use of rituximab was initially limited to refractory aTTP&#44; but observational studies have shown that it can accelerate recovery and decrease the incidence of exacerbations and relapses&#44;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36</span></a> although it has not been shown to increase survival&#46; However&#44; its early use during treatment has been proposed by the British group in a phase II study with a reduction in the duration of acute episodes&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> although there are no randomised studies to support these results&#46; Therefore&#44; international guidelines already recommend it &#40;or propose the possibility of using it&#41; as first-line treatment associated with steroids and PE if there is no contraindication for its use&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;37</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Based on this evidence&#44; it is recommended that rituximab be used as first-line treatment&#44; provided that the presence of anti-ADAMTS13 antibodies has been previously confirmed&#46; The most commonly used dose is 375&#8239;mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week&#44; with two possible therapeutic regimens&#58; 2 times a week or a total of 4 or 8 doses per week&#46; Treatment should be given immediately after PE&#46; Rituximab requires specific authorisation and informed consent as it is not currently indicated on the Summary of Product Characteristics in our environment&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Caplacizumab</span><p id="par0195" class="elsevierStylePara elsevierViewall">Caplacizumab is a nanoantibody that binds to the A1 domain of vWF&#44; thus inhibiting the interaction between vWF and GP1b-IX-V&#44; in turn reducing platelet aggregation and microvascular thrombosis&#44; and consequently&#44; tissue ischaemia&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">The efficacy and safety of caplacizumab in adults who had an episode of aTTP were established in 2 randomised controlled studies&#58; TITAN &#40;phase II&#41;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> and HERCULES &#40;phase III&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;38</span></a> The results showed that caplacizumab reduced the number of days until platelet counts were normalised &#40;primary endpoint&#41; as well as the composite variable for assessment of deaths&#44; vascular events&#44; and exacerbations with respect to the control arm&#46; In addition&#44; the risk of recurrence &#40;exacerbation or relapse&#41; was significantly lower among patients treated with caplacizumab &#40;17&#46;6&#37; vs&#46; 34&#46;8&#37;&#59;&#8239;&#61;&#8239;0&#46;004&#41;&#46; Overall&#44; during the period of treatment with caplacizumab associated with PE and glucocorticoids&#44; in terms of relapse analysis&#44; these were 22&#37; and 8&#37; in the TITAN and HERCULES trials&#44; respectively&#46; This difference was due to the possibility of prolonging caplacizumab treatment until the normalisation of the ADAMTS13 levels in the HERCULES study&#46; Finally&#44; the number of patients with refractory disease &#40;the definition of refractory used in this guide is not the same as that used in these studies&#41; was also significantly lower in the caplacizumab group &#40;0 vs&#46; 8&#59; p&#8239;&#61;&#8239;0&#46;0049&#41;&#46; Another benefit of the triple treatment &#40;PE&#44; immunosuppression&#44; and caplacizumab&#41; was a reduction in the number of days of PE treatment &#40;6&#46;5 vs&#46; 10&#46;4&#41;&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Regarding the safety profile&#44; the main problem is bleeding diathesis similar to Von Willebrand&#8217;s disease&#44; as this drug blocks the binding of vWF to the platelet&#46; The most common serious bleeding adverse effects associated with caplacizumab were epistaxis &#40;3&#37;&#41;&#44; upper gastrointestinal bleeding&#44; and subarachnoid bleeding &#40;1&#46;5&#37;&#41;&#46; Almost all were self-limiting except one case where it was necessary to administer vWF concentrate to resolve a severe epistaxis&#46; The incidence of global serious adverse events with caplacizumab and placebo was 16&#37; and 28&#46;2&#37;&#44; respectively&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">There is already experience of its clinical use with results similar to those of clinical trials&#44; and proposals for its use guided by ADAMTS13 levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#8211;41</span></a> The reduction in the number of caplacizumab-induced exacerbations and relapses would justify its use from the start of treatment&#44; as we do not have predictive factors of exacerbation risk as other authors already point out&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The recommended dose in the SmPC<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> is the administration of two doses on the first day&#44; one of 10&#8239;mg intravenous &#40;i&#47;v&#41; before performing the PE&#44; and then a second dose of 10&#8239;mg subcutaneously &#40;s&#47;c&#41; when the PE has finished&#46; After these first two doses&#44; 10&#8239;mg s&#47;c daily are recommended&#44; to always be administered when the PE has finished&#46; Once the PEs are finished&#44; continue with a daily dose of 10&#8239;mg s&#47;c up to 30 days after performing the last PE&#46; Cases of suspending caplacizumab have been reported after reaching ADAMTS13 levels above 20&#37; with good evolution&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Finally&#44; and although international guidelines place it as front-line treatment when facing a high clinical suspicion or high score on the French or Plasmic scales&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;37</span></a> currently in Spain this drug can only be accessed as a foreign drug request&#44; as it has no reimbursement price&#46; Cost-benefit studies already exist in other countries&#44; but to solve this situation we need studies that are appropriate to our environment&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleItalic">N</span>-acetylcysteine</span><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">N</span>-acetylcysteine is an antioxidant that cleaves ultra-large vWF multimers&#44; preventing the spread of platelet and vWF microthrombi&#46; This treatment has been suggested as the first line treatment&#44; although no studies prove its efficacy to date&#46; The recommended dose is 150&#8239;mg&#47;kg i&#47;v in bolus followed by 150&#8239;mg&#47;kg for 17&#8239;h&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Platelet transfusion</span><p id="par0230" class="elsevierStylePara elsevierViewall">Although the most current patient case series do not show a worse prognosis in patients receiving platelet transfusions in TTP&#44; it is advisable to restrict their use to situations of severe or vital bleeding&#44; or prior to the implantation of a central catheter or interventional process&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">New therapeutic strategies</span><p id="par0235" class="elsevierStylePara elsevierViewall">Current lines of research in the treatment of TTP propose new intervention strategies&#46; These include platelet GPIb and vWF as well as the administration of recombinant ADAMTS13&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Among the first strategies are drugs such as amphibatide and the anti-vWF aptamer ARC1779&#46; There are currently no clinical trials of amphibatide in aTTP to support its usefulness&#46; Also&#44; Phase 2 studies were started but not completed with the anti-vWF aptamer ARC1779&#46; The administration of recombinant ADAMTS13 is currently in Phase 2 and 3 clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;48</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Moreover&#44; it should not be forgotten that a fundamental part of the treatment of aTTP is that of immunosuppressive therapy&#46; In addition to the drugs listed above&#44; we find bortezomib within the possible treatment lines&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Its efficacy has been described in isolated cases&#44; and it has been linked to the ability of plasma cells to produce anti-ADAMTS13 antibodies&#44; although there are as yet no consistent data on its efficacy and its neurological toxicity must be taken into account&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">In conclusion&#44; the ideal global combination of aTTP-targeted therapy would be that capable of inhibiting the GPIa&#47;vWF interaction while supplementing ADAMTS13 and inhibiting the production of antibodies with immunosuppressive therapy&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Mode of action in case of refractoriness&#44; exacerbation and relapse in aTTP&#46; Patients in clinical remission with low levels of ADAMTS13</span><p id="par0255" class="elsevierStylePara elsevierViewall">To review the definitions of refractoriness&#44; exacerbation&#44; and relapse&#44; go to the &#34;glossary of terms of interest&#46;&#34;</p><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Refractory aTTP</span><p id="par0260" class="elsevierStylePara elsevierViewall">aTTP is refractory to PE and glucocorticoids in approximately 10&#8722;15&#37; of patients diagnosed with aTTP&#46; No clinical data have been described in literature that enables refractoriness to be predicted&#46; On the other hand&#44; 15&#8211;53&#37; of patients with an acute episode may experience an exacerbation and there are no identifiable risk factors for this situation&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">In the refractory situation&#44; the first thing we have to do is reconsider the diagnosis&#44; as it could be another type of TMA that does not respond to standard treatment &#40;sepsis&#44; cancer&#44; medications&#41;&#46; In all cases&#44; treatment of refractory patients must be individualised &#40;see <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Recurrent aTTP</span><p id="par0270" class="elsevierStylePara elsevierViewall">The risk of recurrence may occur in 34&#37; of patients with aTTP&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Episodes of recurrence have decreased in recent years and this is probably due to the use of rituximab&#46; Data published by George and Cuker&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> from the Oklahoma Registry&#44; support this claim&#44; as 48&#37; of patients relapsed in 1st year&#44; 30&#37; from the 1st to 3rd year&#44; 22&#37; from the 5th to 14th year&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">The symptoms of recurrence are usually less severe than in the initial diagnosis&#44; and the most characteristic finding &#8212; usually in a regular check-up &#8212; is thrombocytopenia of less than 150&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L&#46; In these cases&#44; PE will also be initiated urgently together with immunosuppressive therapy with corticosteroids and rituximab&#44; after a plasma sample is drawn to determine the ADAMTS13 activity and to confirm the presence of anti-ADAMTS13 antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a> summarises the focus and treatment of the refractory&#44; exacerbation&#44; and relapse episodes&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Patients with aTTP in clinical remission and low levels of ADAMTS13</span><p id="par0285" class="elsevierStylePara elsevierViewall">In the treatment of patients with autoimmune TTP and low levels of ADAMTS13 activity despite being in clinical remission&#44; the recommendation is rituximab 375&#8239;mg&#47;m<span class="elsevierStyleSup">2</span>&#47;week for 1&#8211;4 weeks&#44; especially in cases where a decrease in ADAMTS13 activity and the appearance of anti-ADAMTS13 antibodies are detected during follow-up&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">60&#8211;64</span></a> In one study&#44; ADAMTS13 activity increased after rituximab administration and remained above 10&#37; at 3 months in 85&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> Taking into account these data&#44; a possible approach would be to try to achieve an activity of 10&#8722;20&#37; with rituximab&#59; once that threshold is reached&#44; it could be repeated fortnightly until normal &#40;according to each laboratory&#41;&#44; and then followed-up quarterly in the first year&#44; biannually in the second year and annually thereafter&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">This recommendation is based on a favourable risk-benefit calculation&#44; since if we assume that rituximab is efficient in 85&#37; of patients and its use prevents a clinical relapse in 74&#37; of patients&#44; it would be sufficient to treat 1&#46;6 patients to prevent one relapse &#91;1&#47;&#40;0&#46;85&#8239;&#215;&#8239;0&#46;74&#41;&#8239;&#61;&#8239;1&#46;58&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> In addition&#44; if the risk of mortality in a relapse is 5&#37;&#44; the estimated number of patients to be treated to avoid death is 32 &#91;1&#47;&#40;0&#46;85&#8239;&#215;&#8239;0&#46;74&#8239;&#215;&#8239;0&#46;05&#41;&#8239;&#61;&#8239;31&#46;8&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Long-term follow-up of a patient with TTP</span><p id="par0295" class="elsevierStylePara elsevierViewall">Close clinical and biological follow-up of all the patients who have experienced an acute episode of aTTP should be performed&#46; This must include&#44; in addition to the blood count and haemolysis parameters&#44; the determination of ADAMTS13 activity and the presence of the inhibitor&#46; As for the frequency of reviews&#44; a possible program would be&#58; weekly for the first month&#59; monthly during the next quarter&#44; and quarterly until the first year is reached&#46; Followed by every 6 months until the second year&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Additionally&#44; the effects of the disease on long-term survivors are beginning to be recognised today<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#9633;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Mental &#40;depression&#41; and cognitive impairments&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#9633;</span><p id="par0310" class="elsevierStylePara elsevierViewall">Diagnosis of systemic lupus erythematosus and other autoimmune diseases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#9633;</span><p id="par0315" class="elsevierStylePara elsevierViewall">Although kidney function is stable&#44; microalbuminuria and hypertension are frequently observed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#9633;</span><p id="par0320" class="elsevierStylePara elsevierViewall">Higher risk of death compared to the general population&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#9633;</span><p id="par0325" class="elsevierStylePara elsevierViewall">Depression-type psychiatric disorders&#46;</p></li></ul></p><p id="par0330" class="elsevierStylePara elsevierViewall">In fact&#44; in recent years a higher incidence of psychiatric conditions and cognitive impairment has been described in patients with TTP and therefore it would be advisable to incorporate annual cognitive tests and quality of life questionnaires in the long-term follow-up of these patients&#46; Ideal scales have not been defined&#44; but generic scales such as MOCA &#40;Montreal Cognitive Assessment Scale&#41;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> for cognitive assessment or the SF-36 &#40;Short Form-36 Health Survey&#41;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> and the EQ-5D &#40;European Quality of Life-5 Dimensions&#41;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> for the quality of life could be useful&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">TTP is a very rare entity in children &#40;children account for 10&#37; of all TTP cases<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;69</span></a>&#41;&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">Unlike adults &#40;in whom aTTP accounts for 95&#37; of cases&#41;&#44; in paediatric TTP the acquired form is only slightly more common than congenital TTP&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;70</span></a> aTTP is most common in girls aged 4 months to 17 years &#40;median 13 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> The initial presentation is usually idiopathic &#40;55&#37;&#41;&#44; and in the rest it is associated with a basic clinical context&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> Congenital TTP&#44; on the other hand&#44; should be suspected in any new born with severe jaundice and thrombocytopenia&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#44;72</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">In the classic form of child-onset TTP&#44; the symptoms associated with organ ischaemia mainly affect the brain and&#44; less frequently&#44; the heart and kidney&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall">The diagnosis of TTP in children is a challenge&#44; as it is not the most common TMA at those ages&#44; the anamnesis is more complicated and&#44; in the case of a congenital TTP&#44; renal involvement is common&#46; In fact&#44; typical HUS is the most common TMA in childhood&#44; especially in children under 3 years of age&#44; with 90&#37; of cases due to Shiga toxin-producing <span class="elsevierStyleItalic">Escherichia coli</span> &#40;STEC-HUS&#41; infection&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> Therefore&#44; in the paediatric age group&#44; the differential diagnosis of aTTP should be made primarily with congenital TTP and with typical HUS&#46; The tests to be performed are the same as in the adult&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">In terms of relapses&#44; they have been described in 24&#37; of aTTP patients and the mortality rate in children with aTTP is 9&#37;&#46; As in adults&#44; TTP is a haematological emergency&#44; and without proper treatment it has a mortality rate of 90&#37;&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">In terms of treatment&#44; it does not differ from the adult&#44; although less experience is available&#46; The therapeutic pillar is still PE&#44; with the disadvantages of having to channel a central venous catheter in children&#44; in addition to the risk of bleeding&#44; infection or pneumothorax&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> As in adults&#44; steroids are often associated as an adjuvant treatment for PE&#46; Immunomodulatory treatment with rituximab may be considered in refractory patients or in cases of exacerbation of the disease&#46; Other immunosuppressive drugs such as vincristine&#44; cyclosporine A&#44; cyclophosphamide pulse therapy&#44; and even splenectomy may also be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Other newer therapeutic alternatives such as recombinant ADAMTS13&#44; caplacizumab&#44; and N-acetylcysteine are also being studied in children&#46;</p><p id="par0365" class="elsevierStylePara elsevierViewall">The incidence of TTP in pregnancy is estimated at 1&#47;200&#44;000 pregnancies&#44; with it being congenital TTP in more than half of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> It usually manifests in or after the third trimester&#44; more often from the 30th week or in the postpartum period&#46; For this reason&#44; in these cases the main differential diagnosis should be made with the HELLP syndrome &#40;haemolysis&#44; elevated liver enzymes and low platelets&#41; and with atypical HUS&#46; The presence of TTP in pregnancy does not exclude the diagnosis of HELLP&#44; and both conditions may be associated in the same patient&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">In cases where it starts between weeks 20 and 29&#44; it is usually more severe for the child&#44; with more frequent delayed intrauterine growth and&#47;or foetal death&#46;</p><p id="par0375" class="elsevierStylePara elsevierViewall">However&#44; the diagnosis of TTP is not an indication for pregnancy termination and its appropriate treatment algorithm is described in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#46; In fact&#44; adequate treatment protects against intrauterine growth retardation and foetal loss with a 60&#8211;70&#37; success rate&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0380" class="elsevierStylePara elsevierViewall">On the other hand&#44; the risk of relapse in subsequent pregnancies is close to 100&#37; in cases of congenital TTP &#40;since in these cases the severe ADAMTS13 deficiency is constant&#41; if not treated properly&#44; while in the case of aTTP there is a very low relapse rate as remission is usually achieved and conception can occur with normal ADAMTS13 levels&#46; Platelet counts should be followed monthly in women with a history of aTTP but normal ADAMTS13 levels at the onset of pregnancy&#44; and more often if there is a prior history&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a></p><p id="par0385" class="elsevierStylePara elsevierViewall">Congenital TTP&#44; also called Upshaw-Schulman syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> is the rarest form of TTP and is due to homozygous or heterozygous mutations composed of the gene <span class="elsevierStyleItalic">ADAMTS13</span> causing severe plasma deficiency &#40;&#60;10&#37;&#41;&#46; In fact&#44; more than 200 mutations have been identified&#44; most of them private &#40;i&#46;e&#46; exclusive to a family&#41;&#44; although some stand out for their greater frequency in different geographical regions&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#8211;79</span></a><a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> describes the most common symptoms in patients with congenital TTP and differential diagnoses to consider&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0390" class="elsevierStylePara elsevierViewall">Early diagnosis is essential to prevent organ damage&#44; but delays often occur due to its low prevalence and the fact that up to 30&#8211;50&#37; of cases begin after the age of 12&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;79</span></a> An ADAMTS13 activity &#60;&#8239;10&#37;&#44; which persistently remains below 10&#37; in the remission phase and in the absence of anti-ADAMTS13 neutralizing antibodies &#40;IgG detected by ELISA&#41; and circulating anti-ADAMTS13 inhibitors &#40;detected by sample mixing technique&#41; lead to the hypothesis of a congenital TTP&#46; However&#44; this diagnosis must be confirmed by a genetic study&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">As for acute episodes&#44; they are often triggered by infections &#40;40&#37;&#41;&#44; alcohol abuse in men &#40;10&#37;&#41;&#44; pregnancy &#40;10&#37; in total&#44; but 40&#8211;60&#37; of adult women&#41;&#44; inflammation from surgery or trauma &#40;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a> The treatment of acute episodes and the recommended prophylactic treatment are described in <a class="elsevierStyleCrossRef" href="#tbl0035">Table 7</a>&#46;</p><elsevierMultimedia ident="tbl0035"></elsevierMultimedia><p id="par0400" class="elsevierStylePara elsevierViewall">The most common condition is neurological &#91;headache &#40;20&#8722;40&#37;&#41;&#44; transient ischaemic attack &#40;TIA&#41; &#40;10&#37;&#41; and stroke &#40;20&#37;&#41;&#93;&#44; followed by renal &#91;kidney failure &#40;20&#8722;25&#37;&#41;&#44; haemodialysis or transplantation &#40;&#8764;10&#37;&#41;&#93;&#46; Heart conditions are an exception&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">78&#44;79</span></a> In terms of treatment&#44; 60&#8211;70&#37; of patients will require prophylactic plasma infusions&#46; However&#44; approximately 35&#37; receive treatment exclusively during the acute episodes&#44; and up to 20&#37; do not require treatment again after the onset&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">79</span></a></p><p id="par0405" class="elsevierStylePara elsevierViewall">Finally&#44; in the face of the many genetic changes currently being detected&#44; the prediction of pathogenicity according to the practical guidelines published by the American College of Medical Genetics and Genomics&#47;Association for Molecular Pathology &#40;ACMG&#47;AMP&#41; has become crucial&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">80</span></a> The identification of the variant profile in patients with TTP is necessary to establish the genotype-phenotype correlation&#44; as the presence of a single pathogenic variant&#44; or several variants&#44; or even polymorphisms&#44; may affect the ADAMTS13 activity<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">76&#44;77</span></a> or influence the age of onset&#46; For example&#44; homozygous mutations or the location of these in the prespacer domains are more likely to be associated with childhood onset&#46; Moreover&#44; phenotypic variability depends on the mutation profile of each patient&#44; which influences the severity and recurrence of the episodes&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">77&#44;80</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that the records of patients with TTP are essential to be able to widen the knowledge of this rare disease&#46; These include the international initiative of the Swiss registry<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">81</span></a> and the Spanish TTP registry<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">82</span></a> which studies national cases with a high suspicion of congenital TTP&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Mode of action in the context of non-TTP thrombotic microangiopathies due to transplantation&#44; infections&#44; cancer or drugs</span><p id="par0415" class="elsevierStylePara elsevierViewall">There are other forms of TMA whose primary cause does not lie with an ADAMTS13 deficiency &#40;it may be moderately reduced&#44; but always &#62;20&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; but rather with other disorders such as cancer&#44; infections&#44; drugs and various types of transplantation&#46; The therapeutic approach in these cases is usually aimed at correcting the root cause&#44; and provide supporting treatment&#44; with few therapeutic alternatives that have proven useful&#46;</p><p id="par0420" class="elsevierStylePara elsevierViewall">The best known case is typical HUS or HUS associated with a bacterial infection that is triggered by Shiga toxin mainly in the context of gastroenteritis due to <span class="elsevierStyleItalic">E&#46; coli</span> or by <span class="elsevierStyleItalic">Shigella dysenteriae</span> &#40;and occasionally in patients with pneumonia due to <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>&#41;&#46; It is characterised by severe renal impairment&#44; moderate thrombocytopenia&#44; and a normal or slightly lowered ADAMTS13 level&#46; In these cases&#44; various treatments have been used with little success and the approach is mainly based on support therapies&#46; In patients with renal impairment it has been suggested that eculizumab may be useful&#44; although more data are needed&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">83</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">However&#44; 40&#8211;60&#37; of cases of atypical HUS have mutations in various factors of the complement system&#44; so in this type of TMA a genetic study of the genes encoding these factors must be done&#46; Although there is no evidence of infection&#44; gastrointestinal symptoms often occur&#46; In these cases&#44; treatment with eculizumab is considered the treatment of choice<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">84&#8211;86</span></a> even in cases where no mutations in the complement system have been observed&#44; as it usually proves to be equally effective&#46;</p><p id="par0430" class="elsevierStylePara elsevierViewall">In the context of hematopoietic stem-cell transplantation&#44; the diagnosis is based on the presence of thrombocytopenia and haemolytic anaemia not attributable to other causes&#46; It is often associated with calcineurin inhibitors and its treatment is based on the withdrawal of these drugs and support therapy&#46; Different groups have used other strategies such as PE&#44; eculizumab or defibrotide&#44; without a consensus at this moment on the best treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">87</span></a></p><p id="par0435" class="elsevierStylePara elsevierViewall">Various neoplasms&#44; usually in the disseminated phase&#44; may present with a condition of TMA&#44; generally chronic and of a mild-moderate nature&#44; the approach of which is only supportive treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">88</span></a></p><p id="par0440" class="elsevierStylePara elsevierViewall">Finally&#44; there are multiple drugs that have been linked to the development of TMA&#44; either by immune mechanisms or dose-related toxicity &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0445" class="elsevierStylePara elsevierViewall">In summary&#44; the forms of TMA not associated with an ADAMTS13 deficiency are of multiple origin and the treatment always recommended in these cases is the correction of the trigger and the supply of support therapy&#44; and in some cases it may be possible to use drugs such as eculizumab to avoid the action of the complement system that can play a relevant role in some of the forms&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0450" class="elsevierStylePara elsevierViewall">There is no funding&#44; the guide has been put together with the funds of the Grupo Espa&#241;ol de Af&#233;resis &#40;GEA&#41;&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0455" class="elsevierStylePara elsevierViewall">AVL has received financial support from Sanofi SA for its participation in presentations&#46;</p><p id="par0460" class="elsevierStylePara elsevierViewall">CPI has received fees for work as a consultant and external expert in projects for Boehringer Ingelheim and Sanofi SA</p><p id="par0465" class="elsevierStylePara elsevierViewall">DVF declares having received fees for his role as a speaker and project advisor for Sanofi SA&#44; AMGEN Inc&#46;&#44; Bristol-Myers Squibb&#44; Novartis&#44; Takeda Pharmaceutical Company&#44; Astellas Pharma&#44; Merck Sharp &#38; Dohme &#40;MSD&#41;&#44; Jazz Pharmaceuticals and Sobi SL</p><p id="par0470" class="elsevierStylePara elsevierViewall">JDRG has received fees for his role as a speaker for Takeda Pharmaceutical Company and for his role as an external expert witness for Sanofi SA</p><p id="par0475" class="elsevierStylePara elsevierViewall">JDR declares having received fees for his participation in expert sessions from AMGEN SA&#44; Bristol-Myers Squibb&#44; GlaxoSmithKline&#44; Janssen-Cilag&#44; Sanofi SA&#44; and Takeda Pharmaceutical Company&#46;</p><p id="par0480" class="elsevierStylePara elsevierViewall">MEMC declares having received fees from Sanofi SA and Takeda Pharmaceutical Company for its participation as an expert in Advisory Boards&#46; He also states that he has received a grant from Takeda Pharmaceutical Company&#46;</p><p id="par0485" class="elsevierStylePara elsevierViewall">RG has received fees from Sanofi SA and Bristol-Myers Squibb for his participation as an expert in Advisory Boards and expert panel sessions&#46;</p><p id="par0490" class="elsevierStylePara elsevierViewall">The other authors state having no conflicts of interest&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Thanks</span><p id="par0495" class="elsevierStylePara elsevierViewall">We would like to give thanks to the Sociedad Espa&#241;ola de Hematolog&#237;a y Hemoterapia &#40;SEHH&#41;&#44; the Sociedad Espa&#241;ola de Trombosis y Hemostasia &#40;SETH&#41;&#44; the Grupo Espa&#241;ol de Af&#233;resis &#40;GEA&#41; and the Sociedad Espa&#241;ola de Transfusi&#243;n Sangu&#237;nea y Terapia Celular &#40;SETS&#41; for their support in the development of this project&#46;</p></span></span>"
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              "titulo" => "Participation of the parties involved"
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Introduction to acquired thrombotic thrombocytopenic purpura"
        ]
        7 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Suspicion&#44; clinical expression and prognostic factors of evolution in TTP"
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        8 => array:2 [
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          "titulo" => "Preclinical risk assessment scales and current techniques for the differential diagnosis of TTP"
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        9 => array:2 [
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          "titulo" => "Additional tests that should be requested to complete the diagnosis of TTP and its follow-up in an acute situation"
        ]
        10 => array:3 [
          "identificador" => "sec0050"
          "titulo" => "Treatment of a patient with acquired TTP in an acute situation"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Plasma exchange"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Glucocorticoids"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Rituximab"
            ]
            3 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Caplacizumab"
            ]
            4 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "N-acetylcysteine"
            ]
            5 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Platelet transfusion"
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            6 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "New therapeutic strategies"
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        ]
        11 => array:3 [
          "identificador" => "sec0090"
          "titulo" => "Mode of action in case of refractoriness&#44; exacerbation and relapse in aTTP&#46; Patients in clinical remission with low levels of ADAMTS13"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Refractory aTTP"
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            1 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Recurrent aTTP"
            ]
            2 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Patients with aTTP in clinical remission and low levels of ADAMTS13"
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          ]
        ]
        12 => array:2 [
          "identificador" => "sec0110"
          "titulo" => "Long-term follow-up of a patient with TTP"
        ]
        13 => array:2 [
          "identificador" => "sec0115"
          "titulo" => "Mode of action in the context of non-TTP thrombotic microangiopathies due to transplantation&#44; infections&#44; cancer or drugs"
        ]
        14 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Funding"
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        15 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Conflict of interest"
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        16 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Thanks"
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        17 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2021-02-06"
    "fechaAceptado" => "2021-03-16"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1533266"
          "palabras" => array:5 [
            0 => "Thrombotic thrombocytopenic purpura"
            1 => "Thrombotic microangiopathies"
            2 => "ADAMTS13"
            3 => "Plasma exchange"
            4 => "Haemolysis"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1533267"
          "palabras" => array:5 [
            0 => "P&#250;rpura trombocitop&#233;nica tromb&#243;tica"
            1 => "Microangiopat&#237;a tromb&#243;tica"
            2 => "ADAMTS13"
            3 => "Recambio plasm&#225;tico"
            4 => "Hem&#243;lisis"
          ]
        ]
      ]
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Thrombotic thrombocytopenic purpura &#40;TTP&#41; is a thrombotic microangiopathy &#40;TMA&#41; characterised by the development of microangiopathic haemolytic anaemia&#44; thrombocytopenia&#44; and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10&#37; in most cases&#46;</p><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Recently there have been numerous advances in the field of PTT&#44; new&#44; rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors&#46; The massive sequencing systems facilitate the identification of polymorphisms in the <span class="elsevierStyleItalic">ADAMTS13</span> gene&#46; In addition&#44; new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab&#46;</p><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice&#46;</p><p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">The recommendations set out in this document were prepared following the AGREE methodology&#46; The research questions were formulated according to the PICO format&#46; A search of the literature published during the last 10 years was carried out&#46; The recommendations were established by consensus among the entire group&#44; specifying the existing strengths and limitations according to the level of evidence obtained&#46;</p><p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">In conclusion&#44; this document contains recommendations on the management&#44; diagnosis&#44; and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0130" class="elsevierStyleSimplePara elsevierViewall">La p&#250;rpura trombocitop&#233;nica tromb&#243;tica &#40;PTT&#41; es una microangiopat&#237;a tromb&#243;tica &#40;MAT&#41; caracterizada por el desarrollo de anemia hemol&#237;tica microangiop&#225;tica&#44; trombocitopenia y disfunci&#243;n org&#225;nica isqu&#233;mica asociada a niveles de ADAMTS13 inferiores a 10&#37; en la mayor&#237;a de los casos&#46;</p><p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">Recientemente se han producido numerosos avances en el campo de la PTT&#46; Se han desarrollado nuevas t&#233;cnicas r&#225;pidas y accesibles capaces de cuantificar los niveles de ADAMTS13 y los posibles inhibidores&#46; Los sistemas de secuenciaci&#243;n masiva del gen <span class="elsevierStyleItalic">ADAMTS13</span> facilitan la identificaci&#243;n de polimorfismos en este gen&#46; Adem&#225;s&#44; han aparecido nuevos f&#225;rmacos como caplacizumab y se plantean estrategias de prevenci&#243;n de reca&#237;das con el uso de rituximab&#46;</p><p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Los registros de pacientes con PTT permiten ahondar en el conocimiento de esta enfermedad&#44; pero la gran variabilidad en el diagn&#243;stico y tratamiento hace necesaria la elaboraci&#243;n de un documento que homogenice la terminolog&#237;a y la pr&#225;ctica cl&#237;nica&#46;</p><p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">Las recomendaciones recogidas en el presente documento se han elaborado siguiendo la metodolog&#237;a AGREE&#46; Las preguntas de investigaci&#243;n se formularon de acuerdo con el formato PICO&#46; Se realiz&#243; una b&#250;squeda bibliogr&#225;fica de la literatura publicada durante los &#250;ltimos 10 a&#241;os&#46; Las recomendaciones se establecieron por consenso entre todo el grupo puntualizando las fortalezas y limitaciones existentes de acuerdo al nivel de evidencia obtenido&#46;</p><p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">En conclusi&#243;n&#44; en el presente documento se recogen recomendaciones sobre el tratamiento&#44; diagn&#243;stico y tratamiento de la PTT con el objetivo final de elaborar pautas basadas en la evidencia publicada hasta la fecha que permitan a los profesionales sanitarios optimizar el tratamiento de la PTT&#46;</p></span>"
      ]
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0050">Please cite this article as&#58; Mingot Castellano ME&#44; Pascual Izquierdo C&#44; Gonz&#225;lez A&#44; Viejo Llorente A&#44; Valcarcel Ferreiras D&#44; Sebasti&#225;n E&#44; et al&#46; Recomendaciones para el abordaje cl&#237;nico de pacientes con p&#250;rpura trombocitop&#233;nica tromb&#243;tica&#46; Med Clin &#40;Barc&#41;&#46; 2022&#59;158&#58;630&#46;</p>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ac&#58; antibodies&#59; ADAMTS13&#58; <span class="elsevierStyleItalic">A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member</span> 13&#59; MMACHC&#58; Methylmalonic aciduria and homocystinuria&#59; C&#58; complement&#59; CFH&#44; CFI&#44; CFB&#58; complement factors H&#44; I and B&#44; respectively&#59; DIC&#58; disseminated intravascular coagulation&#59; DGKE&#58; diacylglycerol kinase&#59; GVHD&#58; graft-versus-host disease&#59; VEGF&#58; vascular endothelial growth factor&#59; HT&#58; hypertension&#59; TMA&#58; thrombotic microangiopathy&#59; MCP&#58; membrane cofactor protein&#59; TTP&#58; thrombotic thrombocytopenic purpura&#59; HUS&#58; haemolytic and uremic syndrome&#59; THBD&#58; thrombomodulin&#59; HSCT&#58; hematopoietic stem cell transplantations&#59; SOT&#58; solid organ transplant&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Etiopathogenesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Primary TMA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acquired autoimmune TTP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ADAMTS13 deficit &#40;&#60;10&#37;&#41; due to anti-ADAMTS13 antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Congenital TTP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ADAMTS13 deficit &#40;&#60;10&#37;&#41; due to <span class="elsevierStyleItalic">ADAMTS13</span> gene mutations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Typical HUS due to infection <span class="elsevierStyleItalic">E&#46; Coli</span> or <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Shiga toxin induced renal endothelial injury&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atypical HUS &#40;aHUS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C gene mutations&#58; <span class="elsevierStyleItalic">CFH&#44; CFHR 1&#8722;5&#44; CFI&#44; CD46 &#40;MCP&#41;&#44; C3 and CFB</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMA due to coagulation disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">DGKE</span> mutations&#44; plasminogen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMA due to metabolic disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mutations in the gene causing MMACHC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMA due to anti-complement antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-Factor H autoantibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TMA secondary to other clinical conditions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSCT&#44; SOT Drugs&#58; quinine&#44; mitomycin C&#44; gemcitabine&#44; cisplatin&#44; interferon&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSCT&#44; SOT&#58; infections&#8239;&#43;&#8239;chemotherapy&#8239;&#43;&#8239;radiation&#8239;&#43;&#8239;calcineurin inhibitors&#8239;&#43;&#8239;GVHD&#8239;&#43;&#8239;coagulation activation and C&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VEGF inhibitors&#44; clopidogrel&#44; calcineurin inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Drugs&#58; immune mechanism or endothelial disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DIC&#44; HELLP syndrome&#44; catastrophic antiphospholipid syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Microvascular injury caused by each underlying disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoimmune diseases&#44; rickettsia&#44; viruses&#44; fungi&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Scleroderma&#44; malignant HT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metastatic cancer&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mechanical haemolysis&#58; obstruction due to tumour cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Aetiopathogenic classification of TMA&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0030"
            "detalle" => "Table "
            "rol" => "short"
          ]
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ADAMTS13&#58; <span class="elsevierStyleItalic">A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member</span> 13&#59; LDH&#58; lactate dehydrogenase&#59; TTP&#58; thrombotic thrombocytopenic purpura&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mortality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Delay in diagnosis and start of treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Young age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Old age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood group other than group O&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elevated LDH levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Previous recurrence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe neurological disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rituximab treatment protects against recurrence in the first year after the initial episode&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elevated troponin levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ADAMTS13 activity &#60;&#8239;10&#37; during follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low levels of ADAMTS13 activity and high levels of anti-ADAMTS13 antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lack of rapid response to plasma exchange treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Prognostic factors of mortality and relapse in acquired TTP&#46;</p>"
        ]
      ]
      6 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0035"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">ADAMTS13&#58; <span class="elsevierStyleItalic">A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member</span> 13&#59; Sp&#58; specificity&#59; INR&#58; international normalised ratio&#59; N&#58; number of patients&#59; TTP&#58; thrombotic thrombocytopenic purpura&#59; Se&#58; sensitivity&#59; HSCT&#58; hematopoietic stem cell transplantation&#59; MCV&#58; mean corpuscular volume&#59; NPV&#58; negative predictive value&#59; PPV&#58; positive predictive value&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The categories with a high probability of obtaining a severe ADAMTS13 deficiency are shown in bold&#46; These categories are those used as cut-off points to assess the ability to classify scores&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Variables&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">French scale<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#44;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ASAP scale<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Plasmic scale<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;&#8239;68 years old &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Platelets&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;30&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8804;44&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;30&#8239;&#215;&#8239;10<span class="elsevierStyleSup">9</span>&#47;L &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Creatinine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;2&#46;25&#8239;mg&#47;dL &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Men&#58; &#8804;2&#8239;mg&#47;dL &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;2&#46;25&#8239;mg&#47;dL &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Women&#58; &#8804;1&#46;9&#8239;mg&#47;dL &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No previous HSCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No HSCT or solid organ transplant &#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Indirect Bilirubin Haemolysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;2&#8239;mg&#47;dL&#44; Reticulocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;2&#46;5&#37; or Undetectable Haptoglobin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No active cancer &#40;no treatment in last year&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">INR&#8239;&#60;&#8239;1&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MCV&#8239;&#60;&#8239;90&#8239;fL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#40;&#43;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Original cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#8239;&#61;&#8239;214 &#40;160 TTP&#59; 75&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#8239;&#61;&#8239;260 &#40;56 TTP&#59; 21&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#8239;&#61;&#8239;496 &#40;150 TTP&#59; 30&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#37; of patients with ADAMTS13 deficiency in each category&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 0 &#40;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 0&#8211;2 &#40;1&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 0&#8722;4 &#40;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 1 &#40;70&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 3 &#40;17&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Score 5 &#40;11&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Score 2 &#40;94&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Score 4 &#40;85&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Score 6&#8722;7 &#40;78&#46;3&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sensitivity &#40;Se&#41;&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Se&#58; 84&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Se&#58; 87&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Se&#58; 85&#8211;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Specificity &#40;Sp&#41;&#44; PPV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sp&#58; 83&#44;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sp&#58; 92&#44;7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sp&#58; 58&#8722;92&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">and NPV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PPV&#58; 70&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PPV&#58; 84&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PPV&#58; 51&#8722;72&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPV&#58; 92&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPV&#58; 94&#46;3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NPV&#58; 92&#8722;98&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
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            0 => array:3 [
              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The French score was developed from a cohort that did not include patients with secondary TMAs&#44; so the percentage of patients with ADAMTS13 deficiency is overrepresented in each category compared to the other scores&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Most used preclinical risk scales in TTP&#46;</p>"
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        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Note&#58;</span> imaging tests will be requested according to clinical evolution&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">ADAMTS13&#58; <span class="elsevierStyleItalic">A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member</span> 13&#59; ECG&#58; electrocardiogram&#59; EEG&#58; electroencephalogram&#59; LDH&#58; lactate dehydrogenase&#59; NRL&#58; neurological&#59; pro-BNP&#58; Pro-type B natriuretic peptide&#59; TTP&#58; thrombotic thrombocytopenic purpura&#59; MRI&#58; MRI&#59; CT scan&#58; computed tomography&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complementary tests to be performed at diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Haemolytic markers</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Lactate dehydrogenase &#40;LDH&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Indirect bilirubin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Haptoglobin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Generic tissue ischaemia marker</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;LDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of cardiac tissue ischaemia</span> &#40;only 25&#37; have clinical symptoms or electrical disturbances<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Cardiac troponin I or T &#40;elevated in 68&#37; of patients&#44; increased the mortality rate by 6 times<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Electrocardiogram &#40;ECG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Pro-B-type natriuretic peptide &#40;pro-BNP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Chest X-ray&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Echocardiogram &#40;if affected&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Telemetry &#40;if affected&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of cerebral tissue ischaemia</span> &#40;any type and severity of neurological focus&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Glasgow scale<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>&#44;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Emergency computed axial tomography &#40;CAT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Magnetic resonance imaging &#40;MRI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Electroencephalogram &#40;EEG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of renal tissue ischaemia</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Proteinuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Albuminuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Creatinine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Glomerular filtration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Urinary sediment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of bleeding events</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Imaging localization of bleeding &#40;transformation to haemorrhagic stroke or bleeding in patients treated with caplacizumab&#44; etc&#46;&#41;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">Complementary tests for the follow-up of TTP in an acute situation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Analytical data</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Hemogram with reticulocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Haemolytic markers</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Schistocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;LDH<span class="elsevierStyleSup">b</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Indirect bilirubin<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Haptoglobin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Generic tissue ischaemia marker</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;LDH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Risk of relapse</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;ADAMTS13 activity levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Anti-ADAMTS13 antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cardiac&#44; renal&#44; cerebral&#44; or other tissue ischemia evaluation tests</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;If the affectation is the first or if there is a new appearance of signs or symptoms of organic ischemia&#58; see previous section<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of bleeding events</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;See previous section<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Evaluation of neurological &#40;NRL&#41; or cognitive deficit and mood disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Scoring 14 or lower increased the mortality rate by 9 times&#46; The Glasgow scale does not replace the usual NRL physical examination &#40;which must be reported&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Complementary tests during follow-up are recommended to be performed daily until remission&#44; and twice a week until discharge&#46; After discharge the tests are to be performed once a week for the first 4 weeks&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Recommended complementary tests in the diagnosis and follow-up of patients with TTP&#46;</p>"
        ]
      ]
      8 => array:9 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Source&#58; George and Cuker<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&#59; Sayani and Abrams<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#46;"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0045"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">ADAMTS13&#58; <span class="elsevierStyleItalic">A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member</span> 13&#59; i&#47;v&#58; intravenous&#59; oral&#58; oral &#40;by mouth&#41;&#59; aTTP&#58; acquired thrombotic thrombocytopenic purpura&#59; PE&#58; plasma exchange&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Refractoriness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Re-determine ADAMTS13 activity and inhibitor presence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">In the meantime&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Intensify the PEs to 1&#46;5 times the blood volume&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Intensify the steroid regimen &#40;e&#46;g&#46;&#44; methylprednisolone 1&#41;&#8239;g&#47;day i&#47;v for 3 days&#41;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Start rituximab 375&#8239;mg&#47;m<span class="elsevierStyleSup">2</span>&#47;dose &#40;after checking for anti-ADAMTS13 antibodies&#41;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Two possible administration guidelines&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>-&#8239;&#8594; weekly on days 1&#44; 7&#44; 14&#44; 21<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>-&#8239;&#8594;days 1&#44; 4&#44; 7&#44; 14<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Add caplacizumab&#47;Cablivi&#174; if not used as first line treatment or resume if discontinued &#40;1&#8239;st dose 10&#8239;mg i&#47;v&#44; then 10&#8239;mg&#47;day s&#47;c in the first 4&#8239;h after PE&#41;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Evaluate whether to add according to clinical-analytical evolution&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Vincristina 1&#8239;g&#47;m<span class="elsevierStyleSup">2</span> &#40;maximum 2&#8239;g&#41; i&#47;v<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Cyclophosphamide oral or i&#47;v 500&#8239;mg&#47;2 weeks &#40;6 total doses&#41;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Bortezomib 1&#46;3&#8239;mg&#47;m<span class="elsevierStyleSup">2</span>&#44; 2 times a week for 2 weeks<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;N-acetylcysteine 150&#8239;mg&#47;kg i&#47;v daily for 17 days&#8239;h<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Cyclosporine&#44; 300&#8239;mg&#47;day oral or 2&#8722;3&#8239;mg&#47;kg&#47;day<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Splenectomy&#44; as last resort<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Exacerbation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Discard any cause of exacerbation&#44; especially catheter-related sepsis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Add rituximab&#44; if it has not been used<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36&#44;53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Resume PE&#44; if it has not yet been withdrawn<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Intensify the steroid regimen<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Add caplacizumab &#40;if not administered initially&#44; or if it has been discontinued&#41;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;34</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Start PE 1&#8722;1&#46;5 blood volume<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Immunosuppression with glucocorticoids&#58; methylprednisolone 1&#8239;g&#47;day for 3 days&#44; 1&#8239;mg&#47;kg&#47;day<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Rituximab 375&#8239;mg&#47;m<span class="elsevierStyleSup">2</span>&#47;d weekly on days 1&#44; 7&#44; 14&#44; 21 or on days 1&#44; 4&#44; 7&#44; 14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Caplacizumab&#47;Cablivi&#174; &#40;1&#8239;st dose 10&#8239;mg i&#47;v&#44; after 10&#8239;mg&#47;day s&#47;c in the first 4&#8239;h after PE&#41;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#8211;36&#44;53</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Splenectomy if the patient has multiple recurrences<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#44;59</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">The order in which the treatments are herein presented does not imply preference in their use&#46; The drugs listed in this table have references that support them&#44; although not all have been subjected to randomised studies to endorse their efficacy&#46; The indicated doses are always approximate&#44; as there are no dose-effectiveness studies in this disease&#44; and in no case should these indications replace the clinical judgment of the prescribing professional&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Possible treatment options in case of refractoriness&#44; exacerbation and relapse&#47;recurrence in aTTP&#46;</p>"
        ]
      ]
      9 => array:9 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Source&#58; Hovinga and George<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a>&#46;"
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0050"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Stroke&#58; cerebrovascular accident&#59; TIA&#58; transient ischaemic attack&#59; HDN&#58; haemolytic disease of the new born&#59; HELLP&#58; haemolysis&#44; elevated liver enzymes and low platelets&#59; SLE&#58; systemic lupus erythematosus&#59; MAHA&#58; microangiopathic haemolytic anaemia&#59; ITP&#58; immune thrombocytopenic purpura&#59; cTTP&#58; congenital thrombotic thrombocytopenic purpura&#59; LBW&#58; low birth weight&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MAHA &#177; Thrombopenia<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neonatal&#47;child&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Young adult&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pregnancy<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suspect cTTP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neonatal jaundice&#44; Exanguine-transfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ecchymosis&#44; neurological symptoms&#44; stroke&#44; TIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">History of foetal loss&#44; LBW&#44; preeclampsia &#60;&#8239;25 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Differential diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HDN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ITP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preeclampsia&#44;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alloimmune thrombocytopenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evans syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">S&#46; of HELLP&#44; SLE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gestational thrombopenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              ]
            ]
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            0 => array:3 [
              "identificador" => "tblfn0025"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">It can be moderate&#46;</p>"
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            1 => array:3 [
              "identificador" => "tblfn0030"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0030">Most frequent onset in the third trimester and postpartum&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Clinical conditions in which cTTP should be suspected&#46;</p>"
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          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">ADAMTS13&#58; A disintegrin and metalloproteinase with a thrombospondin type 1 motif&#44; member 13&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment of acute crises</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fresh frozen plasma<a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;10&#8722;15&#8239;ml&#47;kg&#47;day&#44; for 1&#8722;3 days until platelet count normalizes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Follow-on spacing as required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disadvantages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Transmission of pathogens&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Allergic reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alternatives&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;Factor VIII concentrates &#40;Koate&#44; GLP 8Y&#58; require higher frequency of administration&#41;&#46; Not recommended in the guides<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226;&#8594;ADAMTS13 recombinant &#91;BAX930&#44; EC NCT03393975&#44; phase 3 in progress&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            1 => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prophylactic treatment</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fresh frozen plasma&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">When to establish prophylaxis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8226;&#8594;Most common in children &#40;&#62;90&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#8226;&#8594;Recurrent episodes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#8226;&#8594;During pregnancy &#40;achieves a very high success rate&#41;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">&#8226;&#8594;Silent organ damage &#40;proteinuria&#44; strokes&#41;<a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
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