Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 112-118
Пятилетний опыт удаленной диагностики болезни Виллебранда в России
https://doi.org/10.24287/1726-1708-2024-23-4-112-118Аннотация
Качественная своевременная лабораторная диагностика является залогом успеха при уточнении причин геморрагических проявлений у детей и взрослых. Однако ввиду редкости и разнообразия конкретных патологий полный спектр лабораторных исследований может быть недоступен в отдельном регионе или лечебном учреждении. Учитывая эти ограничения, в 2019 г. стартовала программа удаленной диагностики болезни Виллебранда (БВ). Целью настоящего исследования являлась оценка результатов данной программы. В соответствии с протоколом исследования образцы периферической крови пациентов с подозрением на БВ отбирались на местах и далее после первичной пробоподготовки направлялись для анализа в лабораторию клинического гемостаза НМИЦ ДГОИ им. Дмитрия Рогачева. Данное исследование не требовало одобрения этическим комитетом, так как в нем использовались обобщенные ретроспективные деперсонифицированные данные, полученные в ходе рутинной клинической практики. Коагулологический анализ образцов включал определение концентрации антигена фактора фон Виллебранда (vWF:Ag), ристоцетинкофакторной активности vWF (vWF:RCo), а также активности фактора свертывания крови VIII (FVIII). Всего с 04.11.2019 по 31.12.2023 было получено 512 замороженных образцов от 375 детей в возрасте до 18 лет (средний возраст 10 лет (1 месяц – 17 лет) и 139 взрослых пациентов (средний возраст 35 (18–72) лет) из 21 региона Российской Федерации. Ошибки преаналитического этапа были обнаружены в 42 (8,2%) пробах. Cнижение активности vWF < 50% отмечено у 125 (26,6%) пациентов. Активность vWF < 30% выявлена у 52 (11,1%) пациентов, а vWF:RCo < 50% и > 30% – у 73 (15,5%). Лабораторная картина соответствовала 1-му типу БВ у 68 (54,4%) пациентов, 2-му типу – у 50 (40%) и 3-му типу – у 7 (5,6%). Снижение отношения активности FVIII к vWF:Ag выявлено у 30 (6,4%) пациентов. У 1 женщины с низким уровнем FVIII был установлен 2N тип БВ (активность связывания FVIII с vWF – 2% (нормальные значения 70–130%)). Внедрение данной программы позволило уточнить диагноз у 125 пациентов без их очного присутствия вне зависимости от места жительства, что расширяет возможности выявления БВ у пациентов, проживающих в регионах с ограниченным диагностическим потенциалом.
Список литературы
1. Leebeek F.W.G., Eikenboom J.C.J. Von Willebrand’s Disease. N Engl J Med 2016; 375 (21): 2067–80.
2. Rodeghiero F., Castaman G., Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69 (2): 454–9.
3. 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.
4. 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.
5. Lippi G., Von Meyer A., Cadamuro J., Simundic A.-M. Blood sample quality. Diagnosis 2019; 6 (1): 25–31.
6. Timm A., Fahrenkrug J., Jørgensen H.L., Sennels H.P., Goetze J.P. Diurnal variation of von W illebrand factor in plasma: the B ispebjerg study of diurnal variations. Eur J Haematol 2014; 93 (1): 48–53.
7. Knol H., Kemperman R.F.J., Kluin-Nelemans H.C., Mulder A.B., Meijer K. Haemostatic variables during normal menstrual cycle: A systematic review. Thromb Haemost 2012; 107 (01): 22–9.
8. Desch K.C. Regulation of plasma von Willebrand factor. F1000Res 2018; 7: 96.
9. Sanders Y.V., Giezenaar M.A., Laros‐van Gorkom B.A.P., Meijer K., van der Bom J.G., Cnossen M.H., et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014; 12 (7): 1066–75.
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14. Eberl W. Diagnostic Challenges in Newborns and Infants with Coagulation Disorders. Hamostaseologie 2020; 40 (1): 84–7.
15. Salvagno G.L., Lippi G., Bassi A., Poli G., Guidi G.C. Prevalence and type of pre‐analytical problems for inpatients samples in coagulation laboratory. J Eval Clin Pract 2008;14 (2): 351–3.
16. Carraro P., Servidio G., Plebani M. Hemolyzed specimens: a reason for rejection or a clinical challenge? Clin Chem 2000; 46 (2): 306–7.
17. Favaloro E.J., Lippi G. Preanalytical issues that may cause misdiagnosis in haemophilia and von Willebrand disease. Haemophilia 2018; 24 (2): 198–210.
18. Böhm M., Täschner S., Kretzschmar E., Gerlach R., Favaloro E.J., Scharrer I. Cold storage of citrated whole blood induces drastic time-dependent losses in factor VIII and von Willebrand factor: potential for misdiagnosis of haemophilia and von Willebrand disease. Blood Coagul Fibrinolysis 2006; 17 (1): 39–45.
19. Favaloro E.J., Soltani S., McDonald J. Potential Laboratory Misdiagnosis of Hemophilia and von Willebrand Disorder Owing to Cold Activation of Blood Samples for Testing. Am J Clin Pathol 2004; 122 (5): 686–92.
20. Favaloro E. Von Willebrand Disease: Local Diagnosis and Management of a Globally Distributed Bleeding Disorder. Semin Thromb Hemost 2011; 37 (5): 440–55.
21. Annual Global Survey. World Federation of Hemophilia. 2021. [Electronic resource] https://wfh.org/usa/research-and-data-collection/annual-global-survey/. (accessed 25.11.2024).
22. Mehic D., Pabinger I., Gebhart J. Investigating patients for bleeding disorders when most of the “usual” ones have been ruled out. Res Pract Thromb Haemost 2023; 7 (8): 102242.
23. Oliver S., Lau K.K.E., Chapman K., Favaloro E.J. Laboratory Testing for Von Willebrand Factor Multimers. Hemostasis and Thrombosis. Methods Mol Biol 2017; 1646: 495–511.
24. Mazurier C., Goudemand J., Hilbert L., Caron C., Fressinaud E., Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14 (2): 337–47.
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 112-118
Five-year experience in remote diagnosis of von Willebrand disease in Russia
https://doi.org/10.24287/1726-1708-2024-23-4-112-118Abstract
Accurate and timely laboratory diagnosis plays a key role in specifying the causes of hemorrhagic events both in children and adults. However, due to the rarity and diversity of some bleeding disorders, a full spectrum of laboratory testing may not be available in certain regions or hospitals. Taking into account these limitations, a programme of remote diagnosis of von Willebrand disease (VWD) was initiated in 2019. The aim of our study was to assess the results of the programme. In accordance with the study protocol, peripheral blood samples from patients suspected of VWD were collected at local healthcare facilities and, after initial sample preparation, were transferred to the Laboratory of Clinical Hemostasis of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Ethical approval was not required since the study only involved the use of anonymized and generalized retrospective data obtained during routine clinical practice. Coagulation analysis included tests for von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor activity (vWF:RCo), and factor VIII (FVIII) clotting activity. From 04 November 2019 to 31 December 2023, we received a total of 512 frozen samples from 375 children aged under 18 years (the mean age was 10 years (1 month – 17 years)) and 139 adult patients (the mean age was 35 (18–72) years) from 21 regions of the Russian Federation. Pre-analytical errors were identified in 42 (8.2%) cases. Decreased vWF activity (< 50%) was found in 125 (26.6%) patients. VWF activity < 30% was registered in 52 (11.1%) patients, while vWF:RCo < 50% and > 30% – in 73 (15.5%) cases. In 68 (54.4%) patients, laboratory findings were consistent with vWD type 1, in 50 (40%) cases testing results were indicative of vWD type 2, and 7 (5.6%) patients had vWD type 3. Thirty (6.4%) patients had decreased FVIII/vWF:Ag ratio. Type 2N VWD was found in one woman with low FVIII activity (the FVIII binding activity of VWF was 2%, normal range: 70–130%). The implementation of this programme has allowed us to specify a diagnosis in 125 patients without their in-person presence and regardless of their place of residence. This expands our possibilities of detecting VWD in patients living in regions with limited diagnostic capacity.
References
1. Leebeek F.W.G., Eikenboom J.C.J. Von Willebrand’s Disease. N Engl J Med 2016; 375 (21): 2067–80.
2. Rodeghiero F., Castaman G., Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987; 69 (2): 454–9.
3. 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.
4. 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.
5. Lippi G., Von Meyer A., Cadamuro J., Simundic A.-M. Blood sample quality. Diagnosis 2019; 6 (1): 25–31.
6. Timm A., Fahrenkrug J., Jørgensen H.L., Sennels H.P., Goetze J.P. Diurnal variation of von W illebrand factor in plasma: the B ispebjerg study of diurnal variations. Eur J Haematol 2014; 93 (1): 48–53.
7. Knol H., Kemperman R.F.J., Kluin-Nelemans H.C., Mulder A.B., Meijer K. Haemostatic variables during normal menstrual cycle: A systematic review. Thromb Haemost 2012; 107 (01): 22–9.
8. Desch K.C. Regulation of plasma von Willebrand factor. F1000Res 2018; 7: 96.
9. Sanders Y.V., Giezenaar M.A., Laros‐van Gorkom B.A.P., Meijer K., van der Bom J.G., Cnossen M.H., et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost 2014; 12 (7): 1066–75.
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11. Clinical and Laboratory Standards Institute (CLSI). Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays and Molecular Hemostasis Assays (5th ed., H21- A5). 2008.
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13. James P.D., Connell N.T., Ameer B., Di Paola J., Eikenboom J., Giraud N., et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5 (1): 280–300.
14. Eberl W. Diagnostic Challenges in Newborns and Infants with Coagulation Disorders. Hamostaseologie 2020; 40 (1): 84–7.
15. Salvagno G.L., Lippi G., Bassi A., Poli G., Guidi G.C. Prevalence and type of pre‐analytical problems for inpatients samples in coagulation laboratory. J Eval Clin Pract 2008;14 (2): 351–3.
16. Carraro P., Servidio G., Plebani M. Hemolyzed specimens: a reason for rejection or a clinical challenge? Clin Chem 2000; 46 (2): 306–7.
17. Favaloro E.J., Lippi G. Preanalytical issues that may cause misdiagnosis in haemophilia and von Willebrand disease. Haemophilia 2018; 24 (2): 198–210.
18. Böhm M., Täschner S., Kretzschmar E., Gerlach R., Favaloro E.J., Scharrer I. Cold storage of citrated whole blood induces drastic time-dependent losses in factor VIII and von Willebrand factor: potential for misdiagnosis of haemophilia and von Willebrand disease. Blood Coagul Fibrinolysis 2006; 17 (1): 39–45.
19. Favaloro E.J., Soltani S., McDonald J. Potential Laboratory Misdiagnosis of Hemophilia and von Willebrand Disorder Owing to Cold Activation of Blood Samples for Testing. Am J Clin Pathol 2004; 122 (5): 686–92.
20. Favaloro E. Von Willebrand Disease: Local Diagnosis and Management of a Globally Distributed Bleeding Disorder. Semin Thromb Hemost 2011; 37 (5): 440–55.
21. Annual Global Survey. World Federation of Hemophilia. 2021. [Electronic resource] https://wfh.org/usa/research-and-data-collection/annual-global-survey/. (accessed 25.11.2024).
22. Mehic D., Pabinger I., Gebhart J. Investigating patients for bleeding disorders when most of the “usual” ones have been ruled out. Res Pract Thromb Haemost 2023; 7 (8): 102242.
23. Oliver S., Lau K.K.E., Chapman K., Favaloro E.J. Laboratory Testing for Von Willebrand Factor Multimers. Hemostasis and Thrombosis. Methods Mol Biol 2017; 1646: 495–511.
24. Mazurier C., Goudemand J., Hilbert L., Caron C., Fressinaud E., Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14 (2): 337–47.
