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Von Willebrand Factor Propeptide and Pathophysiological Mechanisms in European and Iranian Patients With Type 3 Von Willebrand Disease Enrolled in the 3Winters-Ips Study Publisher Pubmed



Pagliari MT1 ; Rosendaal FR2 ; Ahmadinejad M3, 4 ; Badiee Z5 ; Baghaipour MR6 ; Baronciani L7 ; Benitez Hidalgo O8 ; Bodo I9 ; Budde U10 ; Castaman G11 ; Eshghi P4 ; Goudemand J12 ; Karimi M13 ; Keikhaei B14 Show All Authors
Authors
  1. Pagliari MT1
  2. Rosendaal FR2
  3. Ahmadinejad M3, 4
  4. Badiee Z5
  5. Baghaipour MR6
  6. Baronciani L7
  7. Benitez Hidalgo O8
  8. Bodo I9
  9. Budde U10
  10. Castaman G11
  11. Eshghi P4
  12. Goudemand J12
  13. Karimi M13
  14. Keikhaei B14
  15. Lassila R15
  16. Leebeek FWG16
  17. Lopez Fernandez MF17
  18. Mannucci PM7
  19. Marino R18
  20. Oldenburg J19
  21. Peake I20
  22. Santoro C21
  23. Schneppenheim R22
  24. Tiede A23
  25. Toogeh G24
  26. Tosetto A25
  27. Trossaert M26
  28. Yadegari H19
  29. Zetterberg EMK27
  30. Peyvandi F7, 28
  31. Federici AB29
  32. Eikenboom J30
Show Affiliations
Authors Affiliations
  1. 1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
  2. 2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands
  3. 3. Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
  4. 4. Pediatric Congenital Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Hemophilia-Thalassemia Center, Mashhad University of Medical Science, Mashad, Iran
  6. 6. Iranian Hemophilia Comprehensive Treatment Centre, Tehran, Iran
  7. 7. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
  8. 8. Hemophilia Unit, Hematology Department, Hospital Universitari Vall d’Hebron, Spain
  9. 9. Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
  10. 10. Hemostaseology Medilys Laborgesellschaft mbH, Hamburg, Germany
  11. 11. Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy
  12. 12. Department of Hematology and Transfusion, CHU Lille, University of Lille, Lille, France
  13. 13. Hematology Research Center, Nemazee Hospital, Shiraz University of Medical Science, Shiraz, Iran
  14. 14. Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
  15. 15. Research Program Unit in Oncology, University of Helsinki, Helsinki University Central Hospital, Coagulation Disorders, Helsinki, Finland
  16. 16. Department of Hematology, Erasmus Medical Center, Rotterdam, Netherlands
  17. 17. Complejo Hospitalario Universitario de A Coruna–Servicio de Hematologia y Hemoterapia, A Coruna, Spain
  18. 18. Hemophilia and Thrombosis Centre, University Hospital Policlinico, Bari, Italy
  19. 19. Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Bonn, Germany
  20. 20. Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, United Kingdom
  21. 21. Hematology, Hemophilia and Thrombosis Center, University Hospital Policlinico Umberto I, Rome, Italy
  22. 22. Department of Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  23. 23. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
  24. 24. Thrombosis Hemostasis Research Center, Tehran University of Medical Sciences, Tehran, Iran
  25. 25. Hemophilia and Thrombosis Center, Hematology Department, San Bortolo Hospital, Vicenza, Italy
  26. 26. Centre Regional de Traitement de l’Hemophilie–Laboratoire d’Hematologie, Nantes, France
  27. 27. Skane University Hospital, Malmo, Sweden
  28. 28. Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, Milan, Italy
  29. 29. Department of Oncology and Oncohematology, Hematology and Transfusion Medicine, L. Sacco University Hospital, University of Milan, Milan, Italy
  30. 30. Division of Thrombosis and Hemostasis, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands

Source: Journal of Thrombosis and Haemostasis Published:2022


Abstract

Background: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. Objective: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. Methods: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients’ diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman’s rank correlation. Results: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2–2.7; P =.016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0–4.2; P =.054]). FVIII:C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r =.024; P =.778). Conclusions: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype. © 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.
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