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Consensus statement
Spanish consensus statement for diagnosis and treatment of paroxysmal nocturnal haemoglobinuria
Consenso español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna
Ana Villegasa,
Corresponding author
, Beatriz Arrizabalagab, Santiago Bonanadc, Enrique Coladod, Anna Gayae, Ataúlfo Gonzáleza, Isidro Jarquec, Ramiro Núñezf, Emilio Ojedag, Alberto Orfaoh, José-María Riberai, Vicente Vicentej, Álvaro Urbano-Ispizuae, Grupo de Trabajo de HPN de la Sociedad Española de Hematología y Hemoterapia
a Servicio de Hematología, Hospital Clínico San Carlos de Madrid, Madrid, Spain
b Servicio de Hematología, Hospital Cruces, Bilbao, Spain
c Servicio de Hematología, Hospital La Fe, Valencia, Spain
d Servicio de Hematología y Área de Gestión Clínica de Laboratorio de Medicina, Hospital Universitario Central de Asturias, Oviedo, Spain
e Servicio de Hematología, Hospital Clínic, Barcelona, Spain
f Servicio de Hematología, Hospital Virgen del Rocío, Sevilla, Spain
g Servicio de Hematología, Hospital Puerta de Hierro, Madrid, Spain
h Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
i Servicio de Hematología Clínica, Instituto Catalán de Oncología-Hospital Germans Trias i Pujol, Badalona, Spain
j Servicio de Hematología, Hospital Morales Meseguer, Murcia, Spain
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            "entidad" => "Servicio de Hematolog&#237;a&#44; Hospital Cl&#237;nico San Carlos de Madrid&#44; Madrid&#44; Spain"
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            "entidad" => "Servicio de Hematolog&#237;a Cl&#237;nica&#44; Instituto Catal&#225;n de Oncolog&#237;a-Hospital Germans Trias i Pujol&#44; Badalona&#44; Spain"
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        "titulo" => "Consenso espa&#241;ol para el diagn&#243;stico y tratamiento de la hemoglobinuria parox&#237;stica nocturna"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Algorithm diagnosis&#44; monitoring and treatment of PNH&#46; <span class="elsevierStyleSup">a</span>Full&#44; reticulocyte blood count&#44; <span class="elsevierStyleItalic">lactate dehydrogenase</span> &#40;LDH&#41;&#44; indirect bilirubin&#44; haptoglobin&#44; plasma haemoglobin&#44; haemoglobinuria&#44; haemosidenuria&#44; vitamin B12&#44; serum erythropoietin&#44; iron&#44; folic acid&#44; direct Coombs&#44; creatinine&#44; estimated glomerular filtration rate &#40;eGFR&#41;&#44; proteinuria&#46; <span class="elsevierStyleSup">b</span>Abdominal and cardiac ecodoppler&#44; cranial MRI or angiography through helical computed tomography &#40;annual or clinical changes&#41;&#46; <span class="elsevierStyleSup">c</span>Assess each case individually&#46; BNP&#58; B-type natriuretic peptide&#59; Hb&#58; haemoglobin&#59; HLA&#58; <span class="elsevierStyleItalic">Human Leucocyte Antigen</span>&#59; PNH&#58; paroxysmal nocturnal haemoglobinuria&#59; PH&#58; pulmonary hypertension&#59; PI&#58; pulmonary insufficiency&#59; RF&#58; renal failure&#59; CRF&#58; chronic renal failure&#59; NYHA&#58; New York Heart Association&#59; NMR&#58; nuclear magnetic resonance&#59; MDS&#58; myelodysplastic syndrome&#46;</p>"
        ]
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Paroxysmal nocturnal haemoglobinuria &#40;PNH&#41; is a clonal disorder of haematopoietic progenitor cells that originates from the acquired mutation of the phosphatidylinositol glycan group A gene &#40;PIGA-A&#41;&#44; located in the short arm of chromosome X&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">1</span></a> As a result of this mutation&#44; the glucosyl phosphatidyl inositol &#40;GPI&#41; anchor group does not synthesise&#44; a necessary action for many membrane proteins to bind to the cell surface&#46; Inside these proteins lies the membrane inhibitor of reactive lysis &#40;MIRL&#41; and the complement decay-accelerating factor DAF &#40;CD55&#41;&#44; both physiological inhibitors of complement activation&#46; As a result of this deficiency&#44; erythrocytes are more sensitive to the lytic action of complement&#44; causing haemolysis and platelet activation&#44; among other effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The disease can appear at any age&#44; with a higher incidence rate in the third decade of life&#59; gender distribution is similar&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Clinically&#44; PNH is characterised by intravascular haemolysis&#44; susceptibility to thrombosis and a variable component of bone marrow failure&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">4</span></a> Today PNH is considered a systemic disease &#8211; one which may affect several organs&#44; especially the liver&#44; kidney&#44; central nervous system&#44; lung and&#47;or heart &#8211; because of the deficiency of nitric oxide &#40;NO&#41; and thrombotic events&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">4&#44;5</span></a> Haemoglobinuria&#44; a sign that names the disease&#44; cannot be objectified&#59; only 26&#37; of cases initially show symptoms and 62&#37; at some point throughout the course of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">3&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Complications are a direct result of intravascular haemolysis and sequestration of NO by free haemoglobin&#46; NO depletion produces peripheral vasoconstriction&#44; occurring with dysphagia&#44; erectile dysfunction&#44; abdominal and chest pain and often with profound fatigue that prevents patients from carrying out a normal life&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The most common complications are thromboses&#44; the leading cause of death from PNH &#40;40&#8211;67&#37; depending on the type&#41;&#46; Thromboses are mainly venous&#44; and can be located in unusual places such as hepatic portal vein&#44; splenic vein and mesenteric vein&#44; inferior vena cava&#44; central nervous system veins&#44; skin veins or central retinal vein&#44; although it should be noted that approximately 15&#37; occur in blood circulation&#44; especially in brain and coronary arteries&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">7&#8211;9</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Pulmonary hypertension and renal failure may also be particularly serious complications of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">10&#44;11</span></a> Occasionally&#44; patients develop acute renal failure which is usually reversible but may require dialysis&#46; 65&#37; of patients have chronic renal failure&#44; and severe chronic renal failure &#40;stage 3 or higher&#41; in 21&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Pregnancy&#44; raising the risk of thrombosis&#44; complicates the natural course of the disease&#44; causing an increase in maternal-foetal morbidity and mortality&#46; It has been estimated that maternal mortality during pregnancy and the immediate post-partum period is 12&#8211;21&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">13&#44;14</span></a> There is also risk of miscarriage or premature birth&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">13&#44;14</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The association with bone marrow failure&#44; especially with aplastic anaemia&#44; is widely recognised in all patients&#44; preceding the diagnosis of PNH in many cases&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Until 2007&#44; haemolytic PNH patients were treated mainly with blood transfusions&#46; A great therapeutic advance has been the monoclonal antibody&#44; eculizumab&#44; approved both by the Food and Drug Administration &#40;FDA&#41; and the European Medicines Agency &#40;EMA&#41;&#46; It was first authorised in Spain for use in adult patients with PNH on June 20&#44; 2007&#44; and in April 2013 the indication was extended to paediatric patients&#46; Significantly&#44; on March 30&#44; 2015 the EMA changed the guideline criteria&#44; to include patients with a high activity of the disease&#44; defined as elevated haemolysis&#44; together with one or more of the clinical symptoms associated with it &#40;asthenia&#44; haemoglobinuria&#44; abdominal pain&#44; dyspnoea&#44; anaemia&#44; thrombosis&#44; dysphagia or erectile dysfunction&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Eculizumab is a humanised monoclonal antibody that acts by blocking complement protein C5&#44; preventing terminal complement activation and thus haemolysis&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">15&#44;16</span></a> The use of eculizumab stabilises the haemoglobin and reduces transfusion requirements and symptoms associated with dysfunction of the smooth muscle&#44; reducing fatigue and significantly improving quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">17</span></a> It has also been shown to reduce the relative risk of thromboembolism by 85&#37; and the reduction in the frequency of cases treated with anticoagulants for previous occlusive vascular episodes is 94&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">8</span></a> It also improves pulmonary hypertension and renal failure&#44; especially in the early stages&#46; Likewise&#44; it has been used in women with PNH who are pregnant&#44; with encouraging responses and without risk to the mother or the foetus&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">13&#44;18&#44;19</span></a> Recently&#44; the largest series of monitored cases of pregnant patients with PNH has been published&#44; demonstrating the safety and efficacy of eculizumab in this group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">20</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">At present&#44; after more than 12 years of treatment&#44; sufficient experience has been collected to confirm that treatment with eculizumab has changed the natural history of PNH&#46; In a disease that had a short life expectancy compared to the general population&#44; with a median survival of 10&#8211;15 years from diagnosis&#44; there are data showing that treatment with eculizumab produces a significant increase in life expectancy&#44; and its positive effect in improving the quality of life has been proven&#59; it is medication that has a safe profile and which is generally well tolerated&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">21</span></a> Recently&#44; a group of experts in PNH at a hospital in Leeds in England has published a retrospective study where eculizumab treatment improves the survival of patients with PNH relative to a control group of a healthy population of the same age and sex&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">22</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Due to the rapid pace of advances in knowledge of the disease and its treatment&#44; it has become necessary to standardise and adapt clinical practice guidelines in order to facilitate the monitoring of patients with classical or haemolytic PNH&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In order to address this need&#44; the Spanish PNH Working Group was created&#44; sponsored by the Spanish Society of Haematology and Haemotherapy&#44; which published in 2011 in <span class="elsevierStyleItalic">Medicina Cl&#237;nica</span> a first consensus document for management of PNH&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">23</span></a> New data released later that same year led the group to meet again in November 2011&#59; the results of this meeting included an update of the consensus Guide in May 2012&#46; Given the availability of new evidence a second meeting was held in December 2013 that led to another update of the guidelines in June&#44; 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">24</span></a> In January 2015 the Working Group met again in order to continue updating the document&#44; specifically in regard to the following areas&#58; the indication for the study of PNH populations&#44; detection of the PNH clone by flow cytometry&#44; the monitoring of patients with PNH and treatment of the disease&#46; Prior to the meeting&#44; articles that had been published with new information related to these areas were identified through searches on Medline and Embase&#46; The selection of articles to review was performed according to expert judgement&#46; The classification of selected publications based on levels of evidence was conducted by the Centre of Evidence-Based Medicine&#44; considering at level 1 randomised clinical trials&#59; at level 2&#44; cohort studies&#59; at level 3&#44; and case-control studies&#44; and level 4&#44; series of cases&#46; Due to the idiosyncrasies of PNH&#44; classified as an ultra-rare disease&#44; the degree of recommendation is categorised based on experts&#8217; clinical judgement and experience&#46; Additionally&#44; the update of this document has also considered information concerning the management of the disease in clinical practice recorded in the National and International PNH Registration database &#40;PNH registry&#41;&#46; During the meeting the selected evidence was presented and the recommendations contained therein were subsequently debated&#46; In order to establish the degree of consensus for each of the recommendations&#44; attendees expressed their level of agreement by voting&#44; considering accepted recommendations as those where at least 66&#37; of the participants agreed&#46; For the December 2013 meeting&#44; three haematologists who are experts in PNH were invited to attend as external evaluators for the review&#44; discussion and validation of the recommendations proposed in the successive updates of the consensus document&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">This article exposes the recommendations contained in the group&#39;s last meeting &#40;May 2015&#41; in regard to the four areas defined above &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Indications for the study of paroxysmal nocturnal haemoglobinuria populations</span><p id="par0075" class="elsevierStylePara elsevierViewall">The diagnosis of the PNH should be performed by flow cytometry&#46; The study of PNH populations is indicated in patients with one or more of the following symptoms&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0080" class="elsevierStylePara elsevierViewall">Haemolytic anaemia with negative Coombs&#8217; test&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0085" class="elsevierStylePara elsevierViewall">Haemoglobinuria&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0090" class="elsevierStylePara elsevierViewall">Unexplained&#44; venous or arterial thrombosis in patients who meet any of the following criteria&#58; young patients&#44; presence of thrombosis in unusual locations &#40;intra-abdominal veins&#44; Budd&#8211;Chiari syndrome&#44; brain&#44; skin&#44; etc&#46;&#41;&#44; evidence of haemolysis and&#47;or cytopenia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0095" class="elsevierStylePara elsevierViewall">Intermittent dysphagia or abdominal pain of unknown aetiology with evidence of haemolysis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0100" class="elsevierStylePara elsevierViewall">Medullary aplasia &#40;at diagnosis and annually during monitoring&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">Hypoplastic myelodysplastic syndrome&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Idiopathic and maintained cytopenias of uncertain significance&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">PNH clone detection by flow cytometry</span><p id="par0115" class="elsevierStylePara elsevierViewall">Currently&#44; analysis is done by flow cytometry&#44; in addition to screening diagnosis&#44; to monitor and treat the disease &#40;see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Sample type and cell populations of interest</span><p id="par0120" class="elsevierStylePara elsevierViewall">The study of PNH populations is done routinely in peripheral blood samples&#46; A deficiency of GPI expression is initially identified in neutrophil granulocytes and monocytes&#46; In cases where the presence of cells with GPI anchored proteins deficiency &#40;PNH clone&#41; have been demonstrated&#44; a study of red cells is carried out in a second step&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The analysis of the leucocyte for the detection of PNH populations is the best method available to properly assess the size of the deficient clone in GPI&#46; Lymphocytes&#44; because of their long half-life and variable expression of different GPI proteins&#44; do not constitute an adequate population&#59; whereas monocytes and neutrophils are suitable populations given their number&#44; the correlation between the size of clone between themselves and that they can be easily assessed in parallel&#46; The study in leucocytes is the technique of choice for detecting PNH clones&#44; both for low and high sensitivity studies&#44; and for monitoring patients with PNH clone&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">25&#44;26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Markers associated with glycosyl phosphatidyl inositol</span><p id="par0130" class="elsevierStylePara elsevierViewall">There are several ways to create the neutrophilic granulocytes and monocytes selection strategy&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">25</span></a> FLAER is particularly useful for researching the deficit of expression of proteins associated to GPI in these populations&#44; it is a fluorescent derivative of the bacterial toxin aerolysin that binds to GPI in different leucocyte populations&#44; in combination with CD157 markers&#46; Another option is to perform the analysis in these sub-populations with FLAER and CD24 &#40;or CD16&#41; and CD14 markers&#46; If FLAER is not available&#44; an alternative is to use CD157PE markers in combination with CD24 &#40;or CD16&#41; and CD14&#46; The combination of CD45 and CD10 markers facilitates identification of neutrophilic granulocytes&#44; whereas for monocytes CD45 and CD64 markers are used&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In the case of detecting deficiencies in expression of proteins associated with GPI in neutrophilic granulocytes or monocytes&#44; carrying out the second step is necessary which consists of evaluating the CD59 in red blood cells&#46; CD59 expression is more informative than CD55 expression and other antigens such as CD58&#44; as they are found in greater numbers on the surface of red blood cells&#46; Although other options can work&#44; using PE-conjugated antibodies for GPI molecules detection is recommended as there is more experience with that process&#46; Simultaneous markers of CD55 and CD59 are not recommended&#44; since they require careful titration of reagents to avoid agglutination between the red blood cells&#46; In the case of performing highly sensitive techniques&#44; using antigens for positive selection of red blood cells is essential&#44; where there is only information of CD235a utility&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Combinations of markers</span><p id="par0140" class="elsevierStylePara elsevierViewall">For the above mentioned first and second steps&#44; leucocytes and erythrocytes detection respectively&#44; different combinations of antibodies can be used according to the laboratory&#39;s capabilities &#40;see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The correct identification of sub-populations and GPI deficient clones can be performed using negative and positive controls or positive controls with different fluorescence intensity for each marker &#40;see <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Evaluation of patients once the diagnosis of paroxysmal nocturnal haemoglobinuria has been confirmed</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Clinical history</span><p id="par0145" class="elsevierStylePara elsevierViewall">PNH is a systemic disease with multiple clinical manifestations&#46; For this reason&#44; the patient&#39;s medical history should be detailed so the presence of the most characteristic symptoms and signs of intravascular haemolysis can be detected&#44; &#40;dark urine&#44; jaundice&#41;&#44; anaemia&#44; dysfunction of smooth muscles &#40;severe asthenia&#44; dysphagia&#44; abdominal pain&#44; chest pain and erectile dysfunction&#41; and previous thrombosis &#40;abdominal pain&#44; dyspnoea&#44; neurological deficit and chronic headache among others&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Mandatory explorations</span><p id="par0150" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0155" class="elsevierStylePara elsevierViewall">Laboratory tests include a complete blood count with haemoglobin&#44; neutrophils&#44; platelets&#44; reticulocytes&#44; biochemical study of <span class="elsevierStyleItalic">lactate dehydrogenase</span> &#40;LDH&#41; direct and indirect bilirubin&#44; haptoglobin&#44; plasma haemoglobin&#44; haemoglobinuria&#44; haemosiderinuria&#44; ferric profile &#40;sideremia&#44; transferrin&#44; saturation index transferrin and ferritin&#41; levels of vitamin B12&#44; folic acid&#44; serum erythropoietin and direct Coombs test&#46; An assessment of renal function through analysing plasma levels of creatinine should also be conducted&#44; creatinine clearance&#44; proteinuria and urinary sediment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Bone marrow aspirate to carry out a morphological and iron staining study&#46; To perform a differential diagnosis&#44; including a cytogenetic study is also advisable&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Bone marrow biopsy if the analytical data suggests a bone marrow aplasia&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Thrombophilia studies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Abdominal ultrasound with Doppler&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Doppler echocardiography&#58; if there is evidence of pulmonary hypertension a pulmonary CT angiography must be requested&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0185" class="elsevierStylePara elsevierViewall">Determining proBNP or NT-proBNP&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Magnetic resonance imaging &#40;MRI&#41; or cranial computed tomography &#40;according to radiological criteria&#41; in case of headache or other neurological symptoms&#46;</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Other recommended explorations</span><p id="par0195" class="elsevierStylePara elsevierViewall">Depending on each case&#44; performing other examinations that complement those listed above could be considered&#46; In young patients&#44; a Human Leucocyte Antigen &#40;human leucocyte antigens&#41; typing is recommended because of the possibility of an eventual stem cell transplantation&#46; The radiological study by abdominal MRI is useful in assessing the degree of renal and hepatic iron deposit&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Monitoring</span><p id="par0200" class="elsevierStylePara elsevierViewall">PNH patients require comprehensive monitoring with quarterly analytical reviews and renal function assessments &#40;creatinine&#44; creatinine clearance&#44; sediment and proteinuria&#41; every 6 months&#46; Conducting an assessment of the clonal size by flow cytometry at 6 months of diagnosis is advisable to assess the patient&#39;s stability&#44; so that in such a case assessing the quantification of the clone annually can be valued&#46; Annual reassessments&#44; or if changes in clinical or biological behaviour of the disease are observed&#44; are recommended according to the characteristics of each patient by performing thoracic and abdominal MRI&#44; abdominal ultrasound with Doppler and Doppler echocardiography&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment of paroxysmal nocturnal haemoglobinuria</span><p id="par0205" class="elsevierStylePara elsevierViewall">The main objective of PNH treatment should be to reduce haemolysis and minimise the risk of complications given the systemic impact of the disease&#46; Additionally&#44; treatment of PNH may require supportive therapy including transfusions of concentrated red blood cells&#44; folic acid and iron supplements&#44; antithrombotic anticoagulant prophylaxis and treatment of thrombotic complications&#46; Corticosteroids have been widely used for years in the treatment of PNH&#44; however there is no clear evidence of their benefits&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">One great therapeutic advance has been the approval of the monoclonal antibody eculizumab&#44; which controls haemolysis and the pathophysiological consequences of the disease&#46; The only potentially curative treatment of PNH is allogeneic haematopoietic stem cell&#46; However&#44; despite the best results achieved with this procedure in recent years&#44; it is still associated with high morbidity and mortality and is reserved for highly selected patients&#44; especially those with very severe associated aplastic anaemia&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Eculizumab</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Indications</span><p id="par0215" class="elsevierStylePara elsevierViewall">Data supporting the use of eculizumab in PNH patients for any of the following&#58; indications is currently available&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">a&#41;</span><p id="par0220" class="elsevierStylePara elsevierViewall">Patients with chronic intravascular haemolytic anaemia that shows LDH at 1&#46;5 times the upper limit of normal and clinical symptoms due to haemolytic anaemia&#44; which may manifest&#44; among other symptoms&#44; as a significant impact on quality of life&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">b&#41;</span><p id="par0225" class="elsevierStylePara elsevierViewall">Patients with thrombosis attributable to PNH&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">c&#41;</span><p id="par0230" class="elsevierStylePara elsevierViewall">Patients with chronic renal failure attributable to PNH or repeated episodes of acute renal failure&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">d&#41;</span><p id="par0235" class="elsevierStylePara elsevierViewall">Patients with regular transfusional requirement due to haemolysis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">e&#41;</span><p id="par0240" class="elsevierStylePara elsevierViewall">Patients with lung failure who have dyspnoea and&#47;or chest pain resulting in a limitation of normal activity &#40;New York Heart Association class III or IV&#41; and&#47;or an established diagnosis of pulmonary hypertension when other causes of it have been excluded&#46;</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">f&#41;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Patients with involvement of smooth muscle who show recurrent episodes of severe pain &#40;abdominal&#44; lumbar or oesophageal spasm with a history of dysphagia&#41; requiring hospitalisation or taking opioid analgesics regularly&#46; Before these patients start treatment with eculizumab other causes must be ruled out&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">g&#41;</span><p id="par0250" class="elsevierStylePara elsevierViewall">Pregnancy in a patient with PNH involves a high risk of thrombosis for mother and foetus&#44; treatment with eculizumab may prevent these complications&#46; However&#44; it is recommended that its use should be assessed on an individual basis&#46;</p></li></ul></p><p id="par0255" class="elsevierStylePara elsevierViewall">The EMA recently approved an amendment of the indication criteria for treatment with eculizumab to include patients who have high disease activity&#44; regardless of the history of transfusions&#46; High disease activity is defined as elevated haemolysis together with one or more of associated clinical symptoms&#58; fatigue&#44; haemoglobinuria&#44; abdominal pain&#44; dyspnoea&#44; anaemia&#44; thrombosis&#44; dysphagia and&#47;or erectile dysfunction&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">PNH registration &#40;M07-001&#41; was used to assess the efficacy of eculizumab in PNH patients without a history of red blood cell transfusions&#46; These patients had high disease activity defined as high haemolysis &#40;LDH<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>LSN&#41; and the presence of one or more associated clinical symptoms&#59; fatigue&#44; haemoglobinuria&#44; abdominal pain&#44; shortness of breath &#40;dyspnoea&#41;&#44; anaemia &#40;haemoglobin<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>g&#47;dl&#41;&#44; severe adverse vascular events &#40;including thrombosis&#41;&#44; dysphagia or erectile dysfunction&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Vaccination against meningococcus with a conjugate vaccine that includes serotypes A&#44; C&#44; Y and W135&#44; in addition to vaccination against serotype B &#40;Bexero&#41; is mandatory at least 2 weeks before starting treatment with eculizumab&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Dosage</span><p id="par0270" class="elsevierStylePara elsevierViewall">Eculizumab is administered intravenously&#44; at a weekly dose of 600<span class="elsevierStyleHsp" style=""></span>mg for 4 weeks&#46; During the fifth week a dose of 900<span class="elsevierStyleHsp" style=""></span>mg is administered and thereafter doses of 900<span class="elsevierStyleHsp" style=""></span>mg are continuously administered approximately every 14 days &#40;between 12 and 16 days&#41;&#46; In patients with a body weight of less than 40<span class="elsevierStyleHsp" style=""></span>kg&#44; dosage varies depending on the weight &#40;see <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Monitoring</span><p id="par0275" class="elsevierStylePara elsevierViewall">Evaluation and monitoring of the treatment is conducted by regular laboratory analysis including complete blood count&#44; reticulocyte count and biochemical study of LDH&#46; Conducting a study every three months is recommended to assess renal function and ferric profile &#40;sideremia&#44; transferrin&#44; IST and ferritin&#41;&#46; In case of iron overload&#44; an abdominal MRI should be considered to analyse liver iron deposition&#44; and repeated every 12 months&#46; In addition to these parameters a general&#44; direct Coombs test and an anti-C3 test every 3&#8211;6 months should also be conducted&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Given the increased susceptibility to meningococcal sepsis in patients receiving eculizumab&#44; prophylactic antibiotic treatment is recommended with oral penicillin at 400<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h with the prophylactic antibiotic protocol established for each centre&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The possibility of a meningococcal infection not covered by vaccination should always be considered&#46; Such that&#44; in the case a patient being treated with eculizumab shows signs of headache&#44; fever&#44; nausea&#44; stiff neck&#44; back pain&#44; rashes&#44; confusion&#44; muscle pain&#44; sensitivity to light or other symptoms of illness&#44; they should contact their haematologist immediately or the emergency department of their nearest hospital or health centre and show their security card&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Criteria for continuity</span><p id="par0290" class="elsevierStylePara elsevierViewall">The benefits of treatment with eculizumab should be reviewed every 6 months according to the patient&#39;s clinical and laboratory evolution&#46; Additionally&#44; patients who have not complied with their therapy instructions of that of preventive measures are excluded from treatment&#46; However&#44; before stopping treatment a full assessment of the case and an evaluation of the pros and cons of the decision should be performed&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Allogeneic haematopoietic</span><p id="par0295" class="elsevierStylePara elsevierViewall">Allogeneic haematopoietic is recommended for patients with PNH and associated severe bone marrow failure that meet the criteria for allogeneic haematopoietic transplantation of the Pethema-GETH group for medullary aplasia&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">National and international registration of paroxysmal nocturnal haemoglobinuria</span><p id="par0300" class="elsevierStylePara elsevierViewall">PNH registration aims to observe the natural evolution of patients with PNH&#44; and the safety and efficacy of long term treatment with eculizumab&#46; Given the rarity of this disease&#44; centralising the data of patients with PNH in a national and international registration is advisable&#44; so that its management and treatment can be furthered&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">The profile of patients to include in the register are those with a GPI-deficient clone&#44; those with diagnosis of PNH in any of its variants and that are not in treatment&#44; and patients diagnosed with PNH who are receiving eculizumab&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Data collection is done in electronic notebooks through the website &#40;https&#58;<a href="http://www.webcrf.net/pnhregistry">www&#46;webcrf&#46;net&#47;pnhregistry</a>&#41;&#46; Questionnaires must be completed at the time of inclusion in the registry and every 6 months&#46; In Spain&#44; the company responsible for its implementation is ICON &#40;PNHregistry&#64;iconplc&#46;com&#41;&#46; They can be contacted for information on freephone &#40;0&#41; 80042662000&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflict of interest</span><p id="par0315" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Indications for the study of paroxysmal nocturnal haemoglobinuria populations"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Paroxysmal nocturnal haemoglobinuria &#40;PNH&#41; is an acquired clonal disorder of the haematopoietic progenitor cells due to a somatic mutation in the X-linked <span class="elsevierStyleItalic">phosphatidylinositol glycan class A gene</span>&#46; The disease is characterised by intravascular haemolytic anaemia&#44; propensity to thromboembolic events and bone marrow failure&#46; Other direct complications of haemolysis include dysphagia&#44; erectile dysfunction&#44; abdominal pain&#44; asthenia and chronic renal failure &#40;65&#37; of patients&#41;&#46; The disease appears more often in the third decade of life and there is no sex or age preference&#46; Detection of markers associated with glucosyl phosphatidyl inositol deficit by flow cytometry is currently used in the diagnosis of PNH&#46; For years&#44; transfusions have been the mainstay <span class="elsevierStyleItalic">of therapy</span> for <span class="elsevierStyleItalic">PNH&#46;</span> A breakthrough in treatment has been the approval of the humanised monoclonal antibody eculizumab&#44; which works by blocking the C5 complement protein&#44; preventing its activation and therefore haemolysis&#46; Several studies have confirmed that treatment with eculizumab avoids or decreases the need for transfusions&#44; decreases the probability of thrombosis&#44; improves the associated symptomatology and the quality of life in patients with PNH&#44; showing an increase in survival&#46; Because of rapid advances in the knowledge of the disease and its treatment&#44; it may become necessary to adapt and standardise clinical guidelines for the management of patients with PNH&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La hemoglobinuria parox&#237;stica nocturna &#40;HPN&#41; es una enfermedad clonal de las c&#233;lulas progenitoras hematopoy&#233;ticas originada por la mutaci&#243;n adquirida del gen fosfatidil-inositol-glicano del grupo A&#44; situado en el brazo corto del cromosoma X&#46; Se caracteriza por anemia hemol&#237;tica intravascular&#44; tendencia a la trombosis y un componente variable de insuficiencia medular&#46; Otras complicaciones derivadas de la hem&#243;lisis son disfagia&#44; disfunci&#243;n er&#233;ctil&#44; dolores abdominales&#44; astenia e insuficiencia renal cr&#243;nica &#40;un 65&#37; de los pacientes&#41;&#46; La enfermedad afecta por igual a ambos sexos y puede aparecer a cualquier edad&#44; con una mayor incidencia en la tercera d&#233;cada de la vida&#46; Actualmente&#44; el diagn&#243;stico se basa en la detecci&#243;n de poblaciones celulares con marcadores asociados al d&#233;ficit de glucosil-fosfatidil-inositol mediante citometr&#237;a de flujo&#46; Durante a&#241;os&#44; el pilar terap&#233;utico de la HPN hemol&#237;tica era el soporte transfusional&#46; Un gran avance en el tratamiento ha sido la aprobaci&#243;n del anticuerpo monoclonal humanizado eculizumab&#44; que bloquea la prote&#237;na C5 del complemento impidiendo su activaci&#243;n&#44; y por tanto&#44; la hem&#243;lisis&#46; Diversos estudios han confirmado que el tratamiento con eculizumab evita o disminuye el requerimiento transfusional&#44; reduce la probabilidad de trombosis&#44; mejora la sintomatolog&#237;a asociada y la calidad de vida de los pacientes con HPN&#44; mostrando un aumento de la supervivencia&#46; Este r&#225;pido avance en el conocimiento de la enfermedad y su tratamiento hace necesario adaptar y homogeneizar las directrices de actuaci&#243;n cl&#237;nica en el manejo de pacientes con HPN&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Villegas A&#44; Arrizabalaga B&#44; Bonanad S&#44; Colado E&#44; Gaya A&#44; Gonz&#225;lez A&#44; et al&#46; Consenso espa&#241;ol para el diagn&#243;stico y tratamiento de la hemoglobinuria parox&#237;stica nocturna&#46; Med Clin &#40;Barc&#41;&#46; 2016&#59;146&#58;278&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Algorithm diagnosis&#44; monitoring and treatment of PNH&#46; <span class="elsevierStyleSup">a</span>Full&#44; reticulocyte blood count&#44; <span class="elsevierStyleItalic">lactate dehydrogenase</span> &#40;LDH&#41;&#44; indirect bilirubin&#44; haptoglobin&#44; plasma haemoglobin&#44; haemoglobinuria&#44; haemosidenuria&#44; vitamin B12&#44; serum erythropoietin&#44; iron&#44; folic acid&#44; direct Coombs&#44; creatinine&#44; estimated glomerular filtration rate &#40;eGFR&#41;&#44; proteinuria&#46; <span class="elsevierStyleSup">b</span>Abdominal and cardiac ecodoppler&#44; cranial MRI or angiography through helical computed tomography &#40;annual or clinical changes&#41;&#46; <span class="elsevierStyleSup">c</span>Assess each case individually&#46; BNP&#58; B-type natriuretic peptide&#59; Hb&#58; haemoglobin&#59; HLA&#58; <span class="elsevierStyleItalic">Human Leucocyte Antigen</span>&#59; PNH&#58; paroxysmal nocturnal haemoglobinuria&#59; PH&#58; pulmonary hypertension&#59; PI&#58; pulmonary insufficiency&#59; RF&#58; renal failure&#59; CRF&#58; chronic renal failure&#59; NYHA&#58; New York Heart Association&#59; NMR&#58; nuclear magnetic resonance&#59; MDS&#58; myelodysplastic syndrome&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Type of sample</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Peripheral blood&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Populations</span></td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">Step one</span><br>Neutrophilic granulocytes and monocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Step two</span><br>Red blood cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top"><span class="elsevierStyleItalic">GPI Markers</span></td><td class="td" title="table-entry  " align="left" valign="top">Step one &#40;granulocytes neutrophils and monocytes&#41;&#58; FLAER and CD157 or FLAER&#44; CD24 &#40;or CD16&#41; and CD14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Alternatively &#40;if FLAER is not available&#41;&#58; CD157PE&#44; CD24 &#40;or CD16&#41; and CD14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Step two &#40;red blood cells&#41;&#58; CD59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">Additional information</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Additional cell identification markers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CD45 and CD10 or CD15 for neutrophil granulocytes<br>CD45 and CD64 for monocytes<br>CD235a for red blood cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Combinations of markers to study leucocyte<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td><td class="td" title="table-entry  " align="left" valign="top">5-fluorescence &#40;in a tube&#41;&#58;<br>FLAER CD157-PE CD45-PerCP CD64-APC CD10-APCH7 or FLAER CD157-PE CD45-PECy7 CD64-ECD CD10-PECy5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4-fluorescence &#40;2 in a tubes&#41;&#58;<br>FLAER CD157 &#40;or CD24&#41;-PE CD45-PerCP CD10-APC and FLAER CD157 &#40;or CD14&#41;-PE CD45-PerCP CD10-APC or FLAER CD157 &#40;or CD24&#41;-PE CD45-PECy7 CD10-PECy5<br>FLAER CD157 &#40;or CD14&#41;-PE CD45-PECy7 CD64-PECy5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Combination of markers to study red blood cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CD235a-FITC&#44; CD59-PE &#40;clone of reference&#58; MEM43&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Internal &#40;positive and negative populations or with different fluorescence intensity for each marker&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Indications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Screening diagnostic&#59; monitoring of the disease and its treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Identification of deficient cells in <span class="elsevierStyleItalic">glucosyl phosphatidyl inositol</span> &#40;GPI&#41; by flow cytometry in diagnosis of PNH&#46;</p>"
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                  <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="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Initial phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Maintenance phase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Adult patients</span> &#40;&#8805;<span class="elsevierStyleItalic">18 years old&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg per week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">900<span class="elsevierStyleHsp" style=""></span>mg in the 5th week&#59; then 900<span class="elsevierStyleHsp" style=""></span>mg every 14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Paediatric patients with body weight</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>30&#8211;&#60;40<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg per week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">900<span class="elsevierStyleHsp" style=""></span>mg in the 3rd week&#59; then 900<span class="elsevierStyleHsp" style=""></span>mg every two weeks&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>20&#8211;&#60;30<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg per week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg in the 3rd week&#59; then 600<span class="elsevierStyleHsp" style=""></span>mg every two weeks&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>10&#8211;&#60;20<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">600<span class="elsevierStyleHsp" style=""></span>mg per week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg in the 2rd week&#59; then 300<span class="elsevierStyleHsp" style=""></span>mg every two weeks&#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="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>5&#8211;&#60;10<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg per week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300<span class="elsevierStyleHsp" style=""></span>mg in the 2nd week&#59; then 300<span class="elsevierStyleHsp" style=""></span>mg every three weeks&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Dosage of eculizumab&#46;</p>"
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