UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Acquired von Willebrand syndrome

Author
Margaret E Rick, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Inherited von Willebrand disease (VWD) is the most common inherited bleeding disorder. Acquired von Willebrand syndrome (aVWS; acquired deficiency or dysfunction of von Willebrand factor [VWF]), however, is much less common, and the diagnosis is not often suspected in a bleeding patient.

aVWS is associated with a number of medical conditions, and bleeding symptoms in an individual with any of these diseases should raise suspicion and prompt an evaluation for aVWS. Evaluation and management may be complex, especially in those for whom the underlying disorder requires antithrombotic therapy, such as anticoagulation for a prosthetic heart valve or aspirin for essential thrombocythemia.

This topic reviews the pathophysiology, evaluation, diagnosis, and management of aVWS. Inherited VWD and other causes of bleeding are discussed in separate topic reviews:

Inherited VWD diagnosis and classification – (See "Clinical presentation and diagnosis of von Willebrand disease".)

Inherited VWD treatment – (See "Treatment of von Willebrand disease".)

                                
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Mar 29, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6:217.
  2. Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 7:308.
  3. Brinkhous KM, Sandberg H, Garris JB, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci U S A 1985; 82:8752.
  4. Veyradier A, Jenkins CS, Fressinaud E, Meyer D. Acquired von Willebrand syndrome: from pathophysiology to management. Thromb Haemost 2000; 84:175.
  5. Federici AB, Rand JH, Bucciarelli P, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000; 84:345.
  6. Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand disease. Mayo Clin Proc 2002; 77:181.
  7. Franchini M, Lippi G. Acquired von Willebrand syndrome: an update. Am J Hematol 2007; 82:368.
  8. Tiede A, Rand JH, Budde U, et al. How I treat the acquired von Willebrand syndrome. Blood 2011; 117:6777.
  9. Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol 2006; 81:616.
  10. Mohri H, Motomura S, Kanamori H, et al. Clinical significance of inhibitors in acquired von Willebrand syndrome. Blood 1998; 91:3623.
  11. Dicke C, Schneppenheim S, Holstein K, et al. Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias. Ann Hematol 2016; 95:945.
  12. Ball J, Malia RG, Greaves M, Preston FE. Demonstration of abnormal factor VIII multimers in acquired von Willebrand's disease associated with a circulating inhibitor. Br J Haematol 1987; 65:95.
  13. Tiede A, Priesack J, Werwitzke S, et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008; 6:569.
  14. Handin RI, Martin V, Moloney WC. Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome. Blood 1976; 48:393.
  15. van Genderen PJ, Vink T, Michiels JJ, et al. Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. Blood 1994; 84:3378.
  16. Blackshear JL, Schaff HV, Ommen SR, et al. Hypertrophic obstructive cardiomyopathy, bleeding history, and acquired von Willebrand syndrome: response to septal myectomy. Mayo Clin Proc 2011; 86:219.
  17. Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR. Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood 1986; 67:758.
  18. Avila ML, Lee KJ, Bouskill V, et al. Acquired von Willebrand syndrome in paediatric patients with congenital heart disease: challenges in the diagnosis and management of this rare condition. Haemophilia 2015; 21:e89.
  19. Heilmann C, Geisen U, Beyersdorf F, et al. Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med 2012; 38:62.
  20. Klovaite J, Gustafsson F, Mortensen SA, et al. Severely impaired von Willebrand factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device (HeartMate II). J Am Coll Cardiol 2009; 53:2162.
  21. Tauber H, Ott H, Streif W, et al. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers. Anesth Analg 2015; 120:730.
  22. Nascimbene A, Neelamegham S, Frazier OH, et al. Acquired von Willebrand syndrome associated with left ventricular assist device. Blood 2016; 127:3133.
  23. Bracey AW, Wu AH, Aceves J, et al. Platelet dysfunction associated with Wilms tumor and hyaluronic acid. Am J Hematol 1987; 24:247.
  24. Richard C, Cuadrado MA, Prieto M, et al. Acquired von Willebrand disease in multiple myeloma secondary to absorption of von Willebrand factor by plasma cells. Am J Hematol 1990; 35:114.
  25. Tefferi A, Hanson CA, Kurtin PJ, et al. Acquired von Willebrand's disease due to aberrant expression of platelet glycoprotein Ib by marginal zone lymphoma cells. Br J Haematol 1997; 96:850.
  26. van Genderen PJ, Budde U, Michiels JJ, et al. The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count. Br J Haematol 1996; 93:962.
  27. Fabris F, Casonato A, Grazia del Ben M, et al. Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis. Br J Haematol 1986; 63:75.
  28. Lancellotti S, Dragani A, Ranalli P, et al. Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count. J Thromb Haemost 2015; 13:1226.
  29. Eikenboom JC, van der Meer FJ, Briët E. Acquired von Willebrand's disease due to excessive fibrinolysis. Br J Haematol 1992; 81:618.
  30. Dalton RG, Dewar MS, Savidge GF, et al. Hypothyroidism as a cause of acquired von Willebrand's disease. Lancet 1987; 1:1007.
  31. Michiels JJ, Budde U, van der Planken M, et al. Acquired von Willebrand syndromes: clinical features, aetiology, pathophysiology, classification and management. Best Pract Res Clin Haematol 2001; 14:401.
  32. Franchini M, Mannucci PM. Von Willebrand disease-associated angiodysplasia: a few answers, still many questions. Br J Haematol 2013; 161:177.
  33. Randi AM, Laffan MA. Von Willebrand factor and angiogenesis: basic and applied issues. J Thromb Haemost 2017; 15:13.
  34. Onimoe G, Grooms L, Perdue K, Ruymann F. Acquired von Willebrand Syndrome in congenital heart disease: does it promote an increased bleeding risk? Br J Haematol 2011; 155:622.
  35. Starke RD, Ferraro F, Paschalaki KE, et al. Endothelial von Willebrand factor regulates angiogenesis. Blood 2011; 117:1071.
  36. Fressinaud E, Meyer D. International survey of patients with von Willebrand disease and angiodysplasia. Thromb Haemost 1993; 70:546.
  37. Castaman G, Di Bona E, Rodeghiero F. Angiodysplasia and von Willebrand's disease. Thromb Haemost 1994; 71:527.
  38. Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand's syndrome: a single institution experience. Am J Hematol 2003; 72:243.
  39. Lavin M, Brophy TM, Rawley O, et al. Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy. J Thromb Haemost 2016; 14:1200.
  40. Callaghan MU, Wong TE, Federici AB. Treatment of acquired von Willebrand syndrome in childhood. Blood 2013; 122:2019.
  41. Simone JV, Cornet JA, Abildgaard CF. Acquired von Willebrand's syndrome in systemic lupus erythematosus. Blood 1968; 31:806.
  42. Kasatkar P, Ghosh K, Shetty S. Acquired von Willebrand syndrome: a rare disorder of heterogeneous etiology. J Postgrad Med 2013; 59:98.
  43. Koyama T, Fujimoto K, Shima M. Acquired von Willebrand syndrome associated with Hashimoto's thyroiditis and subcutaneous mucosa-associated lymphoid tissue lymphoma. Intern Med 2013; 52:2661.
  44. Alattar ML, Ciccone M, Gaballa MR, et al. Bleeding diathesis associated with acquired von Willebrand Syndrome in three patients with chronic lymphocytic leukemia. Leuk Lymphoma 2015; 56:3452.
  45. Voisin S, Hamidou M, Lefrançois A, et al. Acquired von Willebrand syndrome associated with monoclonal gammopathy: a single-center study of 36 patients. Medicine (Baltimore) 2011; 90:404.
  46. Mital A, Prejzner W, Bieniaszewska M, Hellmann A. Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients. Pol Arch Med Wewn 2015; 125:914.
  47. Mital A, Prejzner W, Świątkowska-Stodulska R, Hellmann A. Factors predisposing to acquired von Willebrand syndrome during the course of polycythemia vera - retrospective analysis of 142 consecutive cases. Thromb Res 2015; 136:754.
  48. Mital A, Prejzner W, Hellmann A. Acquired von Willebrand Syndrome During the Course of Myelofibrosis: Analysis of 32 Cases. Adv Clin Exp Med 2015; 24:1001.
  49. Binnetoğlu FK, Babaoğlu K, Filiz ŞG, et al. Acquired von Willebrand syndrome in children with aortic and pulmonary stenosis. Cardiovasc J Afr 2016; 27:222.
  50. Loeffelbein F, Funk D, Nakamura L, et al. Shear-stress induced acquired von Willebrand syndrome in children with congenital heart disease. Interact Cardiovasc Thorac Surg 2014; 19:926.
  51. Waldow HC, Westhoff-Bleck M, Widera C, et al. Acquired von Willebrand syndrome in adult patients with congenital heart disease. Int J Cardiol 2014; 176:739.
  52. Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349:343.
  53. Tamura T, Horiuchi H, Imai M, et al. Unexpectedly High Prevalence of Acquired von Willebrand Syndrome in Patients with Severe Aortic Stenosis as Evaluated with a Novel Large Multimer Index. J Atheroscler Thromb 2015; 22:1115.
  54. Kapila A, Chhabra L, Khanna A. Valvular aortic stenosis causing angiodysplasia and acquired von Willebrand's disease: Heyde's syndrome. BMJ Case Rep 2014; 2014.
  55. Draper K, Kale P, Martin B, et al. Thalidomide for treatment of gastrointestinal angiodysplasia in patients with left ventricular assist devices: case series and treatment protocol. J Heart Lung Transplant 2015; 34:132.
  56. Kalbhenn J, Schmidt R, Nakamura L, et al. Early diagnosis of acquired von Willebrand Syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy. J Atheroscler Thromb 2015; 22:265.
  57. Fosbury E, Szychot E, Slater O, et al. An 11-year experience of acquired von Willebrand syndrome in children diagnosed with Wilms tumour in a tertiary referral centre. Pediatr Blood Cancer 2017; 64.
  58. Coppes MJ, Zandvoort SW, Sparling CR, et al. Acquired von Willebrand disease in Wilms' tumor patients. J Clin Oncol 1992; 10:422.
  59. Stuijver DJ, Piantanida E, van Zaane B, et al. Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study. Haemophilia 2014; 20:326.
  60. Aberg M, Hedner U, Bergentz SE. Effect of dextran on factor VIII (antihemophilic factor) and platelet function. Ann Surg 1979; 189:243.
  61. Sanfelippo MJ, Suberviola PD, Geimer NF. Development of a von Willebrand-like syndrome after prolonged use of hydroxyethyl starch. Am J Clin Pathol 1987; 88:653.
  62. Jonville-Béra AP, Autret-Leca E, Gruel Y. Acquired type I von Willebrand's disease associated with highly substituted hydroxyethyl starch. N Engl J Med 2001; 345:622.
  63. Kreuz W, Linde R, Funk M, et al. Valproate therapy induces von Willebrand disease type I. Epilepsia 1992; 33:178.
  64. Yawn B, Nichols WL, Rick ME. Diagnosis and management of von Willebrand disease: guidelines for primary care. Am Fam Physician 2009; 80:1261.
  65. https://www.nhlbi.nih.gov/health-pro/guidelines/current/von-willebrand-guidelines (Accessed on February 06, 2017).
  66. Nichols WL, Hultin MB, James AH, 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; 14:171.
  67. http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/528.aspx (Accessed on February 06, 2017).
  68. Bellissimo DB, Christopherson PA, Flood VH, et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood 2012; 119:2135.
  69. Flood VH, Gill JC, Morateck PA, et al. Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor. Blood 2010; 116:280.
  70. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69:1691.
  71. O'Donnell J, Boulton FE, Manning RA, Laffan MA. Genotype at the secretor blood group locus is a determinant of plasma von Willebrand factor level. Br J Haematol 2002; 116:350.
  72. van den Burg PJ, Hospers JE, van Vliet M, et al. Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages. Thromb Haemost 1995; 74:1457.
  73. McGill SN, Ahmed NA, Christou NV. Increased plasma von Willebrand factor in the systemic inflammatory response syndrome is derived from generalized endothelial cell activation. Crit Care Med 1998; 26:296.
  74. van der Poll T, van Deventer SJ, Pasterkamp G, et al. Tumor necrosis factor induces von Willebrand factor release in healthy humans. Thromb Haemost 1992; 67:623.
  75. Sié P, Caron C, Azam J, et al. Reassessment of von Willebrand factor (VWF), VWF propeptide, factor VIII:C and plasminogen activator inhibitors 1 and 2 during normal pregnancy. Br J Haematol 2003; 121:897.
  76. Lee A, Sinclair G, Valentine K, et al. Acquired von Willebrand syndrome: von Willebrand factor propeptide to von Willebrand factor antigen ratio predicts remission status. Blood 2014; 124:e1.
  77. Frank RD, Kunz D, Wirtz DC. Acquired von Willebrand disease--hemostatic management of major orthopedic surgery with high-dose immunoglobulin, desmopressin, and continuous factor concentrate infusion. Am J Hematol 2002; 70:64.
  78. Patel SB, Rodgers GM. Continuous infusion of human plasma-derived von Willebrand factor concentrate as an effective therapy in a patient with acquired von Willebrand disease. Haemophilia 2014; 20:e411.
  79. Viallard JF, Pellegrin JL, Vergnes C, et al. Three cases of acquired von Willebrand disease associated with systemic lupus erythematosus. Br J Haematol 1999; 105:532.
  80. Sampson B, Anderson DR, Dugal M, et al. Acquired type 2a von Willebrand's disease: response to immunoglobulin infusion. Haemostasis 1997; 27:286.
  81. Federici AB, Stabile F, Castaman G, et al. Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches. Blood 1998; 92:2707.
  82. Friederich PW, Wever PC, Briët E, et al. Successful treatment with recombinant factor VIIa of therapy-resistant severe bleeding in a patient with acquired von Willebrand disease. Am J Hematol 2001; 66:292.
  83. Smaradottir A, Bona R. A case of acquired von Willebrand syndrome successfully treated with recombinant Factor VIIa during thyroidectomy. Thromb Haemost 2004; 92:666.
  84. Franchini M, Veneri D, Lippi G. The use of recombinant activated factor VII in congenital and acquired von Willebrand disease. Blood Coagul Fibrinolysis 2006; 17:615.
  85. Kanakry JA, Gladstone DE. Maintaining hemostasis in acquired von Willebrand syndrome: a review of intravenous immunoglobulin and the importance of rituximab dose scheduling. Transfusion 2013; 53:1730.