Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 62-70
Особенности диагностики болезни Виллебранда 2B типа у детей
https://doi.org/10.24287/1726-1708-2024-23-4-62-70Аннотация
Несмотря на то, что болезнь Виллебранда (БВ) является распространенной коагулопатией, некоторые ее типы встречаются достаточно редко. Например, 2В тип регистрируется в 3–5% всех случаев БВ. Важными диагностическими маркерами данного типа являются тромбоцитопения, снижение активности фактора Виллебранда (vWF), повышение агрегации тромбоцитов с низкими дозами ристомицина и выявление мутаций в экзоне 28 гена vWF. Цель работы: продемонстрировать сложность дифференциальной диагностики и гетерогенность клинических и лабораторных проявлений БВ 2В типа. В ретроспективный анализ включили всех детей с диагнозом БВ 2В типа, установленным в НМИЦ ДГОИ им. Дмитрия Рогачева. Для анализа использовались деперсонифицированные данные, полученные в ходе рутинной клинической практики, поэтому одобрения локального этического комитета не требовалось. У всех пациентов проводилась оценка данных анамнеза, степени кровоточивости по шкале Pediatric Bleeding Questionnaire, выполнялось необходимое лабораторное обследование. Диагноз БВ 2В типа устанавливался на основании следующих критериев: наличие симптомов кровоточивости, тромбоцитопения, выраженное снижение ристомицин-кофакторной активности vWF, нормальное или умеренно пониженное значение антигена vWF, соотношение ристомицин-кофакторной активности и антигена vWF < 0,7, повышение агрегации тромбоцитов с низкими дозами ристомицина. Диагноз БВ 2В типа был установлен 7 детям. У 5 из них имелись жалобы на кровоточивость, еще у 2 был отягощен семейный анамнез по БВ. У всех детей на первом году жизни была выявлена тромбоцитопения. Диагноз иммунная тромбоцитопения первично был установлен в 5 случаях, из них 1 пациентка имела отягощенный семейный анамнез по БВ. Все пациенты с установленным диагнозом иммунной тромбоцитопении получили курсы внутривенных иммуноглобулинов, кроме того, 1 ребенок – курсы глюкокортикостероидов. Значимые кровотечения, потребовавшие госпитализации в стационар до постановки диагноза БВ, отмечались у 3 пациентов. Характерный лабораторный фенотип имели все пациенты, кроме того, в 5 случаях отмечалось снижение коллагенсвязывающей способности vWF. Двум пациентам с отягощенным семейным анамнезом диагноз был подтвержден генетически. В обоих случаях были выявлены мутации, как в экзоне 20, так и в экзоне 28 гена vWF. Полученные результаты согласуются с данными литературы о трудности дифференциальной диагностики данного типа БВ. Исследование агрегации тромбоцитов с низкими дозами ристомицина в совокупности с данными других лабораторных исследований позволяет эффективно дифференцировать лабораторный фенотип БВ 2В типа. Главной терапевтической опцией для пациентов со всеми типами БВ в нашей стране по-прежнему является заместительная факторная терапия.
Список литературы
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3. Sadler J.E., Mannucci P.M., Berntorp E., Bochkov N., Boulyjenkov V., Ginsburg D., et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84: 160–74.
4. Starke R.D., Ferraro F., Paschalaki K.E., Dryden N.H., McKinnon T.A., Sutton R.E., et al. Endothelial von Willebrand factor regulates angiogenesis. Blood. 2011; 117 (3): 1071– 80. DOI: 10.1182/blood-2010-01-264507
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13. Bury L., Malara A., Momi S., Petito E., Balduini A., Gresele P. Mechanisms of thrombocytopenia in platelet-type von Willebrand disease. Haematologica 2019; 104 (7): 1473–81. DOI: 10.3324/haematol.2018.200378
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20. Yuan Z.H., Zhu P. [Relationship of von Willebrand factor gene single-nucleotide polymorphism with thrombosis diseases]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2010; 18 (2): 549–52. [Chinese].
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40. Nurden A.T,. Federici A.B., Nurden P. Altered megakaryocytopoiesis in von Willebrand type 2B disease. J Thromb Haemost 2009; 7 Suppl 1: 277–81. DOI: 10.1111/j.1538-7836.2009.03371.x
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 62-70
Diagnosis of type 2B von Willebrand disease in children
https://doi.org/10.24287/1726-1708-2024-23-4-62-70Abstract
Even though von Willebrand disease (vWD) is a common bleeding disorder, it comprises some rare types as well. Type 2B vWD is usually diagnosed in 3-5% of all vWD cases. The important diagnostic markers of this disease subtype include thrombocytopenia, decreased von Willebrand factor (vWF) activity, increased low-dose ristocetin-induced platelet aggregation, and identification of mutations in exon 28 of the vWF gene. The purpose of this study was to highlight challenges associated with the differential diagnosis of vWD as well as to demonstrate heterogeneous clinical and laboratory signs of type 2B vWD. Here, we retrospectively analyzed all the cases of type 2B vWD diagnosed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. For the analysis, we used de-identified data collected during routine clinical care and hence did not need an approval from the Local Ethics Committee. All the patients had undergone medical history assessment and laboratory investigations and had been evaluated for bleeding disorders using the Pediatric Bleeding Questionnaire. Type 2B vWD was diagnosed based on the following criteria: bleeding symptoms, thrombocytopenia, significantly decreased vWF ristocetin-cofactor activity, normal or decreased vWF antigen levels, ristocetin-cofactor activity/vWF antigen ratio < 0.7; increased low-dose ristocetin-induced platelet aggregation. Type 2B vWD was diagnosed in 7 patients. Out of these, 5 had bleeding symptoms and 2 had a family history of vWD. All the children had been diagnosed with thrombocytopenia during their first year of life. Five patients had been initially diagnosed with immune thrombocytopenia, with one girl having a family history of vWD. All the patients with diagnosed immune thrombocytopenia had been treated with intravenous immunoglobulins, and one child had also undergone treatment with corticosteroids. Three patients had had to be admitted to hospital for major bleeding before they were diagnosed with vWD. All the patients had the typical laboratory phenotype, and five out of them demonstrated decreased vWF collagen-binding activity. In two patients with positive family history, the diagnosis was genetically verified, with both of them harboring mutations in exons 20 and 28 of the vWF gene. Our findings are consistent with the literature suggesting how challenging differential diagnosis of this vWD type is. Still, a low-dose ristocetin-induced platelet aggregation test along with other laboratory investigations can be used to effectively identify the type 2B vWD phenotype. In Russia, factor replacement therapy remains the primary treatment option for patients with any type of vWD.
References
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2. Werner E.J., Broxson E.H., Tucker E.L., Giroux D.S., Shults J., Abshire T.C. Prevalence of von Willebrand disease in children: a multiethnic study. J Pediatr 1993; 123 (6): 893–8. DOI: 10.1016/s0022-3476(05)80384-1
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4. Starke R.D., Ferraro F., Paschalaki K.E., Dryden N.H., McKinnon T.A., Sutton R.E., et al. Endothelial von Willebrand factor regulates angiogenesis. Blood. 2011; 117 (3): 1071– 80. DOI: 10.1182/blood-2010-01-264507
5. Nichols W.L., Hultin M.B., James A.H., Manco-Johnson M.J., Montgomery R.R., Ortel T.L., et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (2): 171–232. DOI: 10.1111/j.1365-2516.2007.01643.x
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7. Favaloro E.J., Dean E., Arunachalam S., Vong R., Mohammed S. Evaluating errors in the laboratory identification of von Willebrand disease using contemporary von Willebrand factor assays. Pathology 2022; 54 (3): 308–17. DOI: 10.1016/j.pathol.2021.07.001
8. Proud L., Ritchey A.K. Management of type 2b von Willebrand disease in the neonatal period. Pediatr Blood Cancer 2017; 64: 103–5. DOI: 10.1002/pbc.26168
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18. Sato T., Hiramatsu R., Iwaoka T., Fujii Y., Shimada T., Umeda T. Changes of Platelets, Serum Lactic Dehydrogenase, g-Glutamyltranspeptidase, Choline Esterase and Creatine Phosphokinase Levels in Patients with Cushing's Syndrome. Tohoku J Exp Med 1984; 142 (2): 195–200. DOI: 10.1620/tjem.142.195
19. Chopra A., Kumar R., Kishore K., Tandon N., Yusuf T., Kumar S., et al. Effect of glucocorticoids on von Willebrand factor levels and its correlation with von Willebrand factor gene promoter polymorphism. Blood Coagul Fibrinolysis 2012; 23 (6): 514–9. DOI: 10.1097/MBC.0b013e3283548dfc
20. Yuan Z.H., Zhu P. [Relationship of von Willebrand factor gene single-nucleotide polymorphism with thrombosis diseases]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2010; 18 (2): 549–52. [Chinese].
21. Nguyen A., Repesse Y., Ebbo M., Allenbach Y., Benveniste O., Vallat J.M., et al. IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans. Clin Exp Immunol 2021; 204 (2): 258–66. DOI: 10.1111/cei.13580
22. Denis C.V., Kwack K., Saffaripour S., Maganti S., André P., Schaub R.G., Wagner D.D. Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models. Blood 2001; 97 (2): 465–72. DOI: 10.1182/blood. v97.2.465
23. Ragni M.V., Novelli E.M., Murshed A., Merricks E.P., Kloos M.T., Nichols T.C. Phase II prospective open-label trial of recombinant interleukin-11 in desmopressin-unresponsive von Willebrand disease and mild or moderate haemophilia A. Thromb Haemost 2013; 109 (2): 248–54. DOI: 10.1160/TH12-06-0447
24. Wang Y., Niu Z.Y., Guo Y.J., Wang L.H., Lin F.R., Zhang J.Y. IL-11 promotes the treatment efficacy of hematopoietic stem cell transplant therapy in aplastic anemia model mice through a NF-kB/microRNA-204/ thrombopoietin regulatory axis. Exp Mol Med 2017; 49 (12): e410. DOI: 10.1038/emm.2017.217
25. Bonduel M., Frontroth J.P., Hepner M., Sciuccati G., Feliu-Torres A., Pieroni G. Von Willebrand disease in children: diagnosis and management of a pediatric cohort in one single center in Argentina. Semin Thromb Hemost 2011; 37 (5): 560–7. DOI: 10.1055/s-0031-1281043
26. Kranzhöfer D., Pavlova A., Schneider H., Franck P., Glonnegger H., Büchsel M., et al. Type 2B von Willebrand Disease: Early Manifestation as Neonatal Thrombocytopenia. Hamostaseologie 2021; 41 (6): 469– 74. DOI: 10.1055/a-1665-6185
27. Chapman K., Prasad R., Mohammed S., Favaloro E.J. 2B or not 2B? A diagnosis of von Willebrand disease a lifetime of 86 years in the making. Blood Coagul Fibrinolysis 2021; 32 (3): 229–33. DOI: 10.1097/MBC.0000000000000994
28. Espitia O., Ternisien C., Agard C., Boisseau P., Denis C.V., Fouassier M. Use of a thrombopoietin receptor agonist in von Willebrand disease type 2B (p.V1316M) with severe thrombocytopenia and intracranial hemorrhage. Platelets 2017; 28 (5): 518–20. DOI: 10.1080/09537104.2016.1246717
29. Zanon E., Pasca S., Bertomoro A., Mardari R., Simioni P. Spontaneous recurrent intracranial haemorrhage in a woman with type 2B von Willebrand disease: A clinical case and a brief literature review. Haemophilia 2019; 25 (4): e282–5. DOI: 10.1111/hae.13742
30. Seidizadeh O., Baronciani L., Pagliari M.T., Cozzi G., Colpani P., Cairo A., et al. Phenotypic and genetic characterizations of the Milan cohort of von Willebrand disease type 2. Blood Adv 2022; 6 (13): 4031–40. DOI: 10.1182/bloodadvances.2022007216
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