Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Treatment of von Willebrand disease

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


Von Willebrand disease (VWD) is the most common of the inherited bleeding disorders, with a prevalence of approximately 1 percent when random laboratory screening is performed. Although VWD is common, only a fraction of patients come to medical attention because of bleeding symptoms and are diagnosed as having VWD. This low incidence of bleeding is due to the mild nature of the disease in many patients, and to the lack of bleeding challenges and/or lack of recognition of minor excessive bleeding (eg, heavy menstrual bleeding) in others. Thus, symptomatic VWD seen at hemostasis centers has a prevalence of only approximately 0.01 percent.

VWD is characterized by mutations that lead to an impairment in the synthesis or function of von Willebrand factor (VWF). There are also acquired forms of VWD that are caused by several different pathophysiologic mechanisms. VWF plays an important role in primary hemostasis by binding to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures and between adjacent platelets at sites of endothelial injury. VWF also contributes to fibrin clot formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life unless it is bound to VWF.

The treatment of VWD will be reviewed here. Discussions of the function of VWF, and the pathophysiology, classification, clinical presentation, and diagnosis of VWD are presented separately.

(See "Biology and normal function of von Willebrand factor".)

(See "Classification and pathophysiology of von Willebrand disease".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Feb 2017. | This topic last updated: Mar 20, 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.
  1. Ratnoff OD, Saito H. Letter: Bleeding in von Willebrand's disease. N Engl J Med 1974; 290:1089.
  2. Lusher JM. Clinical guidelines for treating von Willebrand disease patients who are not candidates for DDAVP--a survey of European physicians. Haemophilia 1998; 4 Suppl 3:11.
  3. Federici AB, Mannucci PM. Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease. Haemophilia 1998; 4 Suppl 3:7.
  4. 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.
  5. http://www.nhlbi.nih.gov/guidelines/vwd/4_managementofvwd.htm (Accessed on July 31, 2013).
  6. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1:869.
  7. Moffat EH, Giddings JC, Bloom AL. The effect of desamino-D-arginine vasopressin (DDAVP) and naloxone infusions on factor VIII and possible endothelial cell (EC) related activities. Br J Haematol 1984; 57:651.
  8. Sutor AH. DDAVP is not a panacea for children with bleeding disorders. Br J Haematol 2000; 108:217.
  9. Aledort LM. Treatment of von Willebrand's disease. Mayo Clin Proc 1991; 66:841.
  10. Michiels JJ, van de Velde A, van Vliet HH, et al. Response of von Willebrand factor parameters to desmopressin in patients with type 1 and type 2 congenital von Willebrand disease: diagnostic and therapeutic implications. Semin Thromb Hemost 2002; 28:111.
  11. Mazurier C, Gaucher C, Jorieux S, Goudemand M. Biological effect of desmopressin in eight patients with type 2N ('Normandy') von Willebrand disease. Collaborative Group. Br J Haematol 1994; 88:849.
  12. Jiménez-Yuste V, Prim MP, De Diego JI, et al. Otolaryngologic surgery in children with von Willebrand disease. Arch Otolaryngol Head Neck Surg 2002; 128:1365.
  13. Witmer CM, Elden L, Butler RB, et al. Incidence of bleeding complications in pediatric patients with type 1 von Willebrand disease undergoing adenotonsillar procedures. J Pediatr 2009; 155:68.
  14. Lethagen S, Ragnarson Tennvall G. Self-treatment with desmopressin intranasal spray in patients with bleeding disorders: effect on bleeding symptoms and socioeconomic factors. Ann Hematol 1993; 66:257.
  15. Amesse LS, Pfaff-Amesse T, Leonardi R, et al. Oral contraceptives and DDAVP nasal spray: patterns of use in managing vWD-associated menorrhagia: a single-institution study. J Pediatr Hematol Oncol 2005; 27:357.
  16. Kouides PA, Byams VR, Philipp CS, et al. Multisite management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol 2009; 145:212.
  17. Lethagen S, Harris AS, Sjörin E, Nilsson IM. Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58:1033.
  18. Dunn AL, Powers JR, Ribeiro MJ, et al. Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients. Haemophilia 2000; 6:11.
  19. Byrnes JJ, Larcada A, Moake JL. Thrombosis following desmopressin for uremic bleeding. Am J Hematol 1988; 28:63.
  20. Mannucci PM, Lusher JM. Desmopressin and thrombosis. Lancet 1989; 2:675.
  21. Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992; 82:87.
  22. Shepherd LL, Hutchinson RJ, Worden EK, et al. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989; 114:470.
  23. Gomez García EB, Ruitenberg A, Madretsma GS, Hintzen RQ. Hyponatraemic coma induced by desmopressin and ibuprofen in a woman with von Willebrand's disease. Haemophilia 2003; 9:232.
  24. Sharma R, Stein D. Hyponatremia after desmopressin (DDAVP) use in pediatric patients with bleeding disorders undergoing surgeries. J Pediatr Hematol Oncol 2014; 36:e371.
  25. Mason JA, Robertson JD, McCosker J, et al. Assessment and validation of a defined fluid restriction protocol in the use of subcutaneous desmopressin for children with inherited bleeding disorders. Haemophilia 2016; 22:700.
  26. Mannucci PM. Treatment of von Willebrand disease. Haemophilia 1998; 4:661.
  27. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada. CMAJ 1995; 153:147.
  28. Federici AB, Mazurier C, Berntorp E, et al. Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study. Blood 2004; 103:2032.
  29. Castaman G, Lethagen S, Federici AB, et al. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood 2008; 111:3531.
  30. Federici AB, Berntorp E, Lee CA, et al. A standard trial infusion with desmopressin is always required before factor VIII/von Willebrand factor concentrates in severe type 1 and 2 von Willebrand disease: Results of a multicenter European study (abstract). Thromb Haemost 1999; (Suppl):795.
  31. Castaman G, Tosetto A, Federici AB, Rodeghiero F. Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. Thromb Haemost 2011; 105:647.
  32. Mannucci PM, Lombardi R, Bader R, et al. Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an abnormal von Willebrand factor. Blood 1985; 66:796.
  33. Gralnick HR, Williams SB, McKeown LP, et al. DDAVP in type IIa von Willebrand's disease. Blood 1986; 67:465.
  34. Batlle J, Lopez Fernandez MF, Campos M, et al. The heterogeneity of type IIA von Willebrand's disease: studies with protease inhibitors. Blood 1986; 68:1207.
  35. Holmberg L, Nilsson IM, Borge L, et al. Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand's disease. N Engl J Med 1983; 309:816.
  36. McKeown LP, Connaghan G, Wilson O, et al. 1-Desamino-8-arginine-vasopressin corrects the hemostatic defects in type 2B von Willebrand's disease. Am J Hematol 1996; 51:158.
  37. Casonato A, Steffan A, Pontara E, et al. Post-DDAVP thrombocytopenia in type 2B von Willebrand disease is not associated with platelet consumption: failure to demonstrate glycocalicin increase or platelet activation. Thromb Haemost 1999; 81:224.
  38. Mauz-Körholz C, Budde U, Kruck H, et al. Management of severe chronic thrombocytopenia in von Willebrand's disease type 2B. Arch Dis Child 1998; 78:257.
  39. Casonato A, Pontara E, Dannhaeuser D, et al. Re-evaluation of the therapeutic efficacy of DDAVP in type IIB von Willebrand's disease. Blood Coagul Fibrinolysis 1994; 5:959.
  40. Weiss HJ, Meyer D, Rabinowitz R, et al. Pseudo-von Willebrand's disease. An intrinsic platelet defect with aggregation by unmodified human factor VIII/von Willebrand factor and enhanced adsorption of its high-molecular-weight multimers. N Engl J Med 1982; 306:326.
  41. Miller JL, Castella A. Platelet-type von Willebrand's disease: characterization of a new bleeding disorder. Blood 1982; 60:790.
  42. Othman M, Notley C, Lavender FL, et al. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 2005; 105:4330.
  43. Miller JL. Platelet-type von Willebrand disease. Thromb Haemost 1996; 75:865.
  44. Mauz-Körholz C, Budde U, Körholz D, Göbel U. DDAVP treatment in a child with von Willebrand disease type 2M. Eur J Pediatr 1999; 158 Suppl 3:S174.
  45. Nishino M, Nishino S, Sugimoto M, et al. Changes in factor VIII binding capacity of von Willebrand factor and factor VIII coagulant activity in two patients with type 2N von Willebrand disease after hemostatic treatment and during pregnancy. Int J Hematol 1996; 64:127.
  46. Chang AC, Rick ME, Ross Pierce L, Weinstein MJ. Summary of a workshop on potency and dosage of von Willebrand factor concentrates. Haemophilia 1998; 4 Suppl 3:1.
  47. Pomper GJ, Rick ME, Epstein JS, et al. Management of severe VWD with cryoprecipitate collected by repeated apheresis of a single dedicated donor. Transfusion 2003; 43:1514.
  48. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm476065.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Accessed on December 09, 2015).
  49. Lillicrap D, Poon MC, Walker I, et al. Efficacy and safety of the factor VIII/von Willebrand factor concentrate, haemate-P/humate-P: ristocetin cofactor unit dosing in patients with von Willebrand disease. Thromb Haemost 2002; 87:224.
  50. Rivard GE, Aledort L, Alphanate Surgical Investigators. Efficacy of factor VIII/von Willebrand factor concentrate Alphanate in preventing excessive bleeding during surgery in subjects with von Willebrand disease. Haemophilia 2008; 14:271.
  51. Mannucci PM, Chediak J, Hanna W, et al. Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study. Blood 2002; 99:450.
  52. Berntorp E, Windyga J, European Wilate Study Group. Treatment and prevention of acute bleedings in von Willebrand disease--efficacy and safety of Wilate, a new generation von Willebrand factor/factor VIII concentrate. Haemophilia 2009; 15:122.
  53. Windyga J, von Depka-Prondzinski M, European Wilate® Study Group. Efficacy and safety of a new generation von Willebrand factor/factor VIII concentrate (Wilate®) in the management of perioperative haemostasis in von Willebrand disease patients undergoing surgery. Thromb Haemost 2011; 105:1072.
  54. Pasi KJ, Williams MD, Enayat MS, Hill FG. Clinical and laboratory evaluation of the treatment of von Willebrand's disease patients with heat-treated factor VIII concentrate (BPL 8Y). Br J Haematol 1990; 75:228.
  55. Goudemand J, Negrier C, Ounnoughene N, Sultan Y. Clinical management of patients with von Willebrand's disease with a VHP vWF concentrate: the French experience. Haemophilia 1998; 4 Suppl 3:48.
  56. Mazurier C. In vitro evaluation of the haemostatic value of the LFB-von Willebrand factor concentrate. Haemophilia 1998; 4 Suppl 3:40.
  57. Menache D. Pharmacokinetics of von Willebrand factor and factor VIII coagulant activity in patients with von Willebrand disease type 3 and type 2. Haemophilia 1998; 4 Suppl 3:44.
  58. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126:2038.
  59. Mannucci PM, Kempton C, Millar C, et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122:648.
  60. Scott JP, Montgomery RR. Therapy of von Willebrand disease. Semin Thromb Hemost 1993; 19:37.
  61. Mannucci PM. Treatment of von Willebrand's disease. J Intern Med Suppl 1997; 740:129.
  62. Castillo R, Escolar G, Monteagudo J, et al. Hemostasis in patients with severe von Willebrand disease improves after normal platelet transfusion and normalizes with further correction of the plasma defect. Transfusion 1997; 37:785.
  63. Makris M, Colvin B, Gupta V, et al. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand's disease. Thromb Haemost 2002; 88:387.
  64. Mannucci PM. Venous thromboembolism in von Willebrand disease. Thromb Haemost 2002; 88:378.
  65. Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med 2004; 351:683.
  66. Varon D, Martinowitz U. Continuous infusion therapy in haemophilia. Haemophilia 1998; 4:431.
  67. Lubetsky A, Schulman S, Varon D, et al. Safety and efficacy of continuous infusion of a combined factor VIII-von Willebrand factor (vWF) concentrate (Haemate-P) in patients with von Willebrand disease. Thromb Haemost 1999; 81:229.
  68. Fressinaud E, Veyradier A, Sigaud M, et al. Therapeutic monitoring of von Willebrand disease: interest and limits of a platelet function analyser at high shear rates. Br J Haematol 1999; 106:777.
  69. Meskal A, Vertessen F, Van der Planken M, Berneman ZN. The platelet function analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von willebrand concentrate in type III von willebrand disease. Ann Hematol 1999; 78:426.
  70. Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood Coagul Fibrinolysis 2005; 16 Suppl 1:S23.
  71. Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study. Thromb Haemost 2011; 105:597.
  72. Holm E, Abshire TC, Bowen J, et al. Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network. Blood Coagul Fibrinolysis 2015; 26:383.
  73. Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network. J Thromb Haemost 2015; 13:1585.
  74. Ortel TL, Charles LA, Keller FG, et al. Topical thrombin and acquired coagulation factor inhibitors: clinical spectrum and laboratory diagnosis. Am J Hematol 1994; 45:128.
  75. Alperin JB. Estrogens and surgery in women with von Willebrand's disease. Am J Med 1982; 73:367.
  76. Harrison RL, McKee PA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood 1984; 63:657.
  77. Bailar J. Hormone-replacement therapy and cardiovascular diseases. N Engl J Med 2003; 349:521.
  78. Ciavarella N, Schiavoni M, Valenzano E, et al. Use of recombinant factor VIIa (NovoSeven) in the treatment of two patients with type III von Willebrand's disease and an inhibitor against von Willebrand factor. Haemostasis 1996; 26 Suppl 1:150.
  79. Grossmann RE, Geisen U, Schwender S, Keller F. Continuous infusion of recombinant factor VIIa (NovoSeven) in the treatment of a patient with type III von Willebrand's disease and alloantibodies against von Willebrand factor. Thromb Haemost 2000; 83:633.
  80. Tengborn L, Petruson B. A patient with Glanzmann thrombasthenia and epistaxis successfully treated with recombinant factor VIIa. Thromb Haemost 1996; 75:981.
  81. Peters M, Heijboer H. Treatment of a patient with Bernard-Soulier syndrome and recurrent nosebleeds with recombinant factor VIIa. Thromb Haemost 1998; 80:352.
  82. Lisman T, Adelmeijer J, Heijnen HF, de Groot PG. Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation. Blood 2004; 103:1720.
  83. Basso IN, Keeling D. Myocardial infarction following recombinant activated factor VII in a patient with type 2A von Willebrand disease. Blood Coagul Fibrinolysis 2004; 15:503.
  84. Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003; 349:1443.
  85. Davis A, Godwin A, Lippman J, et al. Triphasic norgestimate-ethinyl estradiol for treating dysfunctional uterine bleeding. Obstet Gynecol 2000; 96:913.
  86. Rubin G, Wortman M, Kouides PA. Endometrial ablation for von Willebrand disease-related menorrhagia--experience with seven cases. Haemophilia 2004; 10:477.
  87. Kaunitz AM, Meredith S, Inki P, et al. Levonorgestrel-releasing intrauterine system and endometrial ablation in heavy menstrual bleeding: a systematic review and meta-analysis. Obstet Gynecol 2009; 113:1104.
  88. Huq FY, Al-Haderi M, Kadir RA. The outcome of endometrial ablation in women with inherited bleeding disorders. Haemophilia 2012; 18:413.
  89. Conti M, Mari D, Conti E, et al. Pregnancy in women with different types of von Willebrand disease. Obstet Gynecol 1986; 68:282.
  90. Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand's disease. Blood 1987; 69:786.
  91. Pacheco LD, Costantine MM, Saade GR, et al. von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment. Am J Obstet Gynecol 2010; 203:194.
  92. Kadir RA, Lee CA, Sabin CA, et al. Pregnancy in women with von Willebrand's disease or factor XI deficiency. Br J Obstet Gynaecol 1998; 105:314.
  93. Ito M, Yoshimura K, Toyoda N, Wada H. Pregnancy and delivery in patients with von Willebrand's disease. J Obstet Gynaecol Res 1997; 23:37.
  94. Mannucci PM. How I treat patients with von Willebrand disease. Blood 2001; 97:1915.
  95. Castaman G, Tosetto A, Rodeghiero F. Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations. Haematologica 2010; 95:963.
  96. The National Heart, Lung, and Blood Institute. The Evaluation and Management of Von Willebrand Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda 2007. Available at www.nhlbi.nih.gov/guidelines/vwd.
  97. Walker ID, Walker JJ, Colvin BT, et al. Investigation and management of haemorrhagic disorders in pregnancy. Haemostasis and Thrombosis Task Force. J Clin Pathol 1994; 47:100.
  98. Depret-Mosser S, Marey A, Parquet-Gernez A, et al. [Willebrand's disease and pregnancy. Fifteen cases]. J Gynecol Obstet Biol Reprod (Paris) 1996; 25:405.
  99. Mullaart RA, Van Dongen P, Gabreëls FJ, van Oostrom C. Fetal periventricular hemorrhage in von Willebrand's disease: short review and first case presentation. Am J Perinatol 1991; 8:190.