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The first peak occurs in children under 1 year of age (with a higher incidence in the neonatal period) as a result of physiological differences in haemostasis which, according to current evidence, seems to favour a prothrombotic tendency.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The second peak occurs in adolescence, related to the maturation of the haemostatic system and the occurrence of other risk factors such as smoking, obesity, pregnancy and hormonal treatment with oestrogens.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a> Finally, unlike in adults, up to 90% of paediatric patients present one or more risk factors: the most common is the use of central venous catheters in critically ill patients.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Several international expert groups have summarised the main recommendations for the management of VTD in the paediatric age group in various guidelines.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,8</span></a> The most recent, those of the American Society of Hematology (ASH)<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> from 2018, include a diagnostic and therapeutic approach in a total of 26 clinical situations. Of these, the expert panel only gives a level of recommendation in 4 of them but does so with a low level of evidence. For the rest, the panel only makes suggestions with a low or very low level of evidence. However, the expert panel made an effort to identify those points where research can help to improve knowledge in this field, something that several international groups have been working on in recent years.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Within the International Society on Thrombosis and Haemostasis, the Paediatric and Neonatal Thrombosis and Haemostasis Subcommittee has fostered several initiatives in this area. One of the most relevant, led by Dr. van Ommen, consisted of the creation of an International Paediatric Thrombosis Network [IPTN]) with the aim of developing a registry to facilitate observational studies and creating a network of paediatric centres with experience in conducting prospective studies.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The registry, which has been running for several years and is open to any interested centre, has already collected data from more than 1500 patients worldwide.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Another important milestone was the publication of the Kids-DOTT study, the first randomised trial to provide information on the duration of treatment for secondary VTD in the paediatric patient.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> The <span class="elsevierStyleItalic">American College of Chest Physician</span> guidelines<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and the ASH guidelines<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> recommended treatment of no more than 3 months for secondary VTD, but suggested that this could be somewhat shorter, a total of 6 weeks, in some cases: central venous catheter-related VTD, with rapid resolution in the first weeks of treatment. The aim of the Kids-DOTT study was to compare the recurrence rate and bleeding events in a group of paediatric patients who received anticoagulation therapy for 6 weeks versus 3 months. The study included 417 patients under 21 years of age with a first episode of secondary VTD. Patients with active or progressing cancer (patients in remission could be included), with systemic lupus erythematosus, presence of antiphospholipid antibodies (proven in 2 samples separated by at least 6 weeks), pulmonary thromboembolism, those in whom thrombolytic therapy had been used, in whom long-term anticoagulant therapy was planned, or those with moderate or severe protein C, protein S or antithrombin deficiency were excluded. After 6 weeks of anticoagulant therapy, all patients underwent an imaging test. Those who were found to have blood flow were randomised to discontinue treatment at that time, or to prolong treatment for up to 3 months. The cumulative recurrence rate was similar between the two treatment groups: 0.66% (95% CI 0%–1.95%) in the group receiving anticoagulation for 6 weeks of treatment and 0.70% (95% CI 0%–2.07%) in the group receiving 3 months. Similarly, the incidence of bleeding events was 0.65% (95% CI 0%–1.91%) and 0.70% (95% CI 0%–2.06%) respectively.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> Therefore, this study concludes that a treatment duration of 6 months can be considered in selected patients under 21 years of age with a first episode of secondary thrombosis. However, in addition to the fact that it took a total of 12 years to conclude this study, the drugs used were low molecular weight heparin, fondaparinux or warfarin. No patients received direct oral anticoagulants (DOACs); an important point given that their prescription is expected to increase over subsequent years. The results are likely to be similar, but it is not certain that the findings of the Kids-DOTT study can be extrapolated to patients receiving DOACs. On the other hand, when applying the results of this study in clinical practice, in addition to taking into account the exclusion criteria used to select patients, it is important to remember that an imaging test needs to be performed 6 weeks after starting anticoagulant treatment, as those patients in whom no blood flow is observed or, in our opinion, the resolution is minimal, treatment should be extended for a minimum of 3 months. Therefore, although this practice reduces the need for anticoagulant therapy in a significant percentage of patients, it also increases the use of hospital resources.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Another major development in recent years has been the implementation of comprehensive clinical trial programmes (including phase I and II studies) with DOACs in paediatric age-appropriate formulations.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Its importance lies in the fact that, for the first time, we now have anticoagulant treatments that have been authorised by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (until now only dalteparin was approved for paediatric use by the FDA, but not by the EMA).</p><p id="par0030" class="elsevierStylePara elsevierViewall">The pharmacokinetic characteristics of DOACs provide a number of benefits in the paediatric age group: oral administration, rapid onset of action, predictable pharmacokinetics, antithrombin level non-dependency, no interaction with food or other drugs, a wide therapeutic window, and the possibility of avoiding laboratory tests.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In contrast to the Kids-DOTT study, the phase III multicentre studies of dabigatran <span class="elsevierStyleItalic">(DIVERSITY)</span><a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> and rivaroxaban <span class="elsevierStyleItalic">(EINSTEIN-Junior)</span><a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> randomised a large number of patients in a short period of time. The EINSTEIN-Junior study was designed as a non-inferiority study, and randomised 500 VTD patients under 18 years of age with a 2:1 rivaroxaban (weight-adjusted dose equivalent to 20<span class="elsevierStyleHsp" style=""></span>mg in the adult patient, administered once daily in patients >30<span class="elsevierStyleHsp" style=""></span>kg weight; 2 times daily in patients aged 12–29.9<span class="elsevierStyleHsp" style=""></span>kg, and 3 times daily in <12<span class="elsevierStyleHsp" style=""></span>kg weight) versus standard anticoagulation therapy (heparin, fondaparinux and warfarin). All patients received parenteral anticoagulation for a minimum of 5 days before randomisation. This study demonstrated a low rate of VTD recurrence with rivaroxaban (1%) and with standard anticoagulation (3%). Patients receiving rivaroxaban had a higher proportion of complete resolution (38% vs. 26%, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012), with no increase in bleeding (3% vs. 2%).<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A substudy in patients with venous sinus thrombosis showed results in favour of rivaroxaban, which achieved a higher proportion of complete recanalisation (25% vs. 15%, p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.012).<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The phase 2b/3 DIVERSITY study, also designed as a non-inferiority trial, randomised 267 patients under 18 years of age to a 2:1 ratio of dabigatran (weight- and age-adjusted doses, administered twice daily) versus standard anticoagulation therapy. All patients received a minimum of 5 days of parenteral anticoagulation before randomisation. In this case, the dabigatran dose was allowed to be modified on one occasion to achieve trough levels between 50 and 250<span class="elsevierStyleHsp" style=""></span>ng/ml (required in 62 of 117 patients). The proportion of patients with complete resolution was 46% versus 42% in the standard treatment group, no VTD recurrence 96% versus 92% and VTD-related death 100% versus 99%. The rate of major bleeding was 2% in the 2 groups.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In addition, dabigatran was the subject of an open-label, single-arm trial evaluating its efficacy in secondary prevention of VTD. A total of 203 patients were included, with a recurrence rate of 1%, a major bleeding rate of 1.5%, and a post-thrombotic syndrome rate (in patients with a history of VTD in any limb) of 1.2%.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Following the publication of these trials, the British Society for Haematology recommended prescribing these drugs for the treatment of deep vein thrombosis in paediatric patients without antiphospholipid syndrome after at least 5 days of treatment with unfractionated heparin, low molecular weight heparin or fondaparinux (as performed in the clinical trials).<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Suspension, suspension granules and capsules are available, the dosage of which can be found in the SmPC of each of the products. However, their use in our country is still limited. Because this is a very rare complication, it is likely that healthcare professionals would rather not risk starting a new drug once or twice a year when their experience with low-molecular-weight heparin or vitamin K antagonists is good, preferring not to leave their “comfort zone”. Moreover, it should not be forgotten that although DOACs are funded by the National Health System for non-valvular atrial fibrillation, this is not the case for thrombosis, which can be a problem for families in vulnerable socio-economic situations.</p><p id="par0040" class="elsevierStylePara elsevierViewall">On the other hand, there are other negative aspects worth noting in the DOAC trials. The inclusion of children under 2 years of age was very low, as was the inclusion of cancer patients. No trials included patients with renal or hepatic impairment, so no information is available in this regard. As for plasma drug concentrations, it is not known whether monitoring is necessary because, although their pharmacokinetics are predictable, in the specific case of dabigatran, a total of 17 patients dropped out of the trial because they did not reach the desired trough levels.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> There are a number of strategies to answer these and many other questions, but most involve conducting real-life observational multicentre studies in the framework of established structures such as the IPTN registry. To this end, it is necessary to generate collaborative platforms in which departments with experience in these treatments within the paediatric age group provide support to smaller centres and allow the recording of data in order to shed light on the field of paediatric thrombosis in the shortest possible time.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Finally, the choice of whether or not to initiate anticoagulant treatment, as well as the choice of which drug to use, must be adapted to the patient’s age, clinical situation, possible comorbidities and the experience of each hospital. In our centre, heparins continue to be the initial treatment in all cases: unfractionated heparin in unstable situations, generally in critically ill patients, and low molecular weight heparin in the rest. We recommend dose adjustment according to the results of the anti-activated factor X assay, as it has been widely demonstrated that up to 50% of patients, especially those younger than 1 year, require dose escalation.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> For maintenance therapy, the choice of whether to continue with low molecular weight heparin, acenocoumarol/warfarin, or a DOAC should be made in consultation with the family, taking into account the patient's comorbidities and age, and explaining the pros and cons of each treatment in terms of safety, efficacy, available information, number of doses per day, and economic cost. It is likely that our recommendations will become more authoritative as we gain experience over the next few years. In the meantime, collaborative group participation and training will be key to providing our patients with individualised treatment.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0050" class="elsevierStylePara elsevierViewall">This article has not received any funding.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The author has received consultancy fees from <span class="elsevierStyleGrantSponsor" id="gs0005">Bayer</span>, <span class="elsevierStyleGrantSponsor" id="gs0010">CSL Behring</span>, <span class="elsevierStyleGrantSponsor" id="gs0015">Roche</span>, <span class="elsevierStyleGrantSponsor" id="gs0020">Novartis</span> and <span class="elsevierStyleGrantSponsor" id="gs0025">Boehringer Ingelheim</span>, speaking fees at conferences/congresses from CSL Behring, <span class="elsevierStyleGrantSponsor" id="gs0030">Amgen</span>, Novartis, Bayer, <span class="elsevierStyleGrantSponsor" id="gs0035">Sobi</span>, <span class="elsevierStyleGrantSponsor" id="gs0040">Novo Nordisk</span>, <span class="elsevierStyleGrantSponsor" id="gs0045">Takeda</span> and Roche, research grants from Sobi and staff grants from Roche.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How I treat pediatric venous thromboembolism" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G. 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Journal Information
Vol. 162. Issue 6.
Pages 280-282 (March 2024)
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Vol. 162. Issue 6.
Pages 280-282 (March 2024)
Editorial
Thrombosis in children: Treatment peculiarities and novelties
Trombosis en pediatría: peculiaridades y novedades en el tratamiento
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a Hematología Pediátrica, Hospital Sant Joan de Déu Barcelona, Universitat de Barcelona, Barcelona, Spain
b Institut de Recerca Pediàtrica, Hospital San Joan de Déu de Barcelona (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain
c Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
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