Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

von Willebrand Disease Treatment & Management

  • Author: Eleanor S Pollak, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP  more...
 
Updated: Dec 09, 2015
 

Approach Considerations

The main treatment options for patients with von Willebrand disease (vWD) are desmopressin (DDAVP), recombinant von Willebrand factor (rVWF), and von Willebrand factor/factor VIII (vWF/FVIII) concentrates. DDAVP is a synthetic analogue of the antidiuretic hormone vasopressin; it has enhanced antidiuretic activity and no pressor activity related to vasopressin. Recombinant von Willebrand factor is indicated for on-demand treatment of minor or major hemorrhage in adults with vWD.[13] Purified plasma-derived concentrates of vWF/FVIII are used for treatment of bleeds and for surgical prophylaxis when DDAVP is ineffective or contraindicated.[2, 8]

Recombinant von Willebrand factor (Vonvendi) was approved by the US Food and Drug Administration (FDA) in December 2015. Approval was based on a phase 3 trial that showed that rVWF was safe and effective in treating 192 bleeds in 22 patients with vWD and stabilized endogenous FVIII:C levels. Control of bleeding was rated good or excellent, with excellent control in 96.9% (119 of 122 minor bleeds, 59 of 61 moderate bleeds, and 6 of 7 major bleeds). A single infusion was effective in 81.8% of bleeds.[13]

In addition, antifibrinolytic drugs (ie, aminocaproic acid, tranexamic acid) can be used orally or intravenously to treat mild mucocutaneous bleeding. Topical agents (eg, fibrin sealants) may be considered as optional adjunctive therapy for dental surgery and for surface wound bleeding that is unresponsive to drugs and concentrates; however, the safety of these agents remains unconfirmed.[8]

Platelet transfusions may be helpful in some patients with vWD (eg, type 3) to control bleeding that is refractory to other therapies.[8] Cryoprecipitate and fresh frozen plasma contain functional von Willebrand factor (vWF) but should be avoided if at all possible because of the potential transmission of viral disease. An additional drawback of fresh frozen plasma is the large infusion volume most often required.[8, 9]

For prophylaxis in major surgery or for treatment of serious bleeding episodes, rVWF (with or without FVIII) or vWF-containing factor VIII (FVIII) concentrates are the treatment of choice. However, a hematologist experienced in the management of bleeding disorders should be consulted prior to all surgical/dental procedures.

In extremely rare cases, vWD patients who receive FVIII concentrates as prophylaxis for surgery may experience venous thromboembolic complications. A literature review by Franchini et al found only 11 reported cases, most of which involved orthopedic procedures. Nevertheless, these authors advise that the need for thromboprophylaxis with vWF/FVIII concentrates in patients with vWD who undergo major surgery should be individually assessed, after a careful risk/benefit analysis.[14]

vWF in pregnancy

During pregnancy, the vWF level increases in most patients with non–type III vWD. Thus, in patients with functionally normal vWF, labor and delivery usually proceed normally.

However, patients with type II disease may experience hemorrhagic problems. In particular, patients with type IIB may experience thrombocytopenia due to the increased plasma levels associated with abnormal vWF. All patients should be monitored for excessive bleeding, particularly during the first week post partum.

Deterrence

Advise patients to avoid aspirin-containing compounds. In addition, patients should be wary of any physical activity associated with an increased risk of hemorrhage.

Next

Type I von Willebrand disease

DDAVP is the treatment of choice for individuals with vWD type I. The infusion of DDAVP into healthy individuals and individuals with vWD type I results in a rapid increase in circulating levels of vWF:Ag and FVIII and RCoF activity.

Typically, a maximal rise of vWF and FVIII is observed in 30-60 minutes. The typical maximal rise is 2- to 4-fold for vWF and 3- to 6-fold for FVIII. Additionally, hemostatic levels of both factors are usually maintained for at least 6 hours.

DDAVP can be administered not only through intravenous infusion but also via a highly concentrated nasal spray; 300 mcg intranasally produces levels comparable to those observed with an intravenous infusion. Intranasal treatment is particularly useful for home therapy of menorrhagia and recurrent epistaxis.

DDAVP regimens are not standardized. A review by Neff notes the following[15] :

  • Dosing DDAVP at 24 hour intervals may reduce the risk of side effects without significantly compromising vWF activity/FVIII:C levels; most treatment centers will not prescribe more than three doses at this frequency
  • Standard intravenous and subcutaneous DDAVP doses are 0.3 µg/kg, but for patients over 50 kg, a fixed dose of 15 µg may provide acceptable efficacy with less risk of serious side effects

Fluid retention and hyponatremia are common complications of DDAVP therapy. Consequently, most treatment centers recommend weight-based fluid restriction, particularly in patients undergoing surgery, along with monitoring of serum sodium levels in children younger than 2 years and in patients receiving repeated doses of DDAVP.[2, 15]

Previous
Next

Type II von Willebrand disease

Responses to DDAVP are variable in patients with type II disease; some patients respond while others should receive vWF concentrates.[15] United Kingdom guidelines recommend performing a trial infusion of DDAVP in patients with type IIA, IIM, and IIN vWD and measuring vWF antigen, vWF activity, and FVIII at baseline, 30–60 min, and 4–6 h.[2]

Many individuals with vWD type IIA have a response to DDAVP, with peak vWF and FVIII levels at 30-60 minutes. This is similar to responses observed in patients with vWD type I. However, rapid loss of vWF, FVIII, and particularly ristocetin cofactor (RCoF) activity occurs as the high-molecular-weight multimers are degraded, with return to baseline levels at 4 hours post infusion. Although the response is transient, it may be adequate therapy in certain clinical situations.

DDAVP trials may be contraindicated in patients with type IIB, because of thrombocytopenia and possible thrombotic complications. DDAVP is usually not effective in patients with type IIM and is rarely effective in patients with type IIN.

Previous
Next

Type III von Willebrand disease

Individuals with vWD type III have a virtually complete deficiency of vWF. Thus, DDAVP, which causes the release of stored vWF, has no effect in patients with this disorder.

The treatment of choice for patients with vWD type III (as with other vWD types unresponsive to DDAVP) is rVWF (with or without FVIII)[13]  or virus-inactivated, vWF-containing FVIII concentrates that contain a near-normal complement of high-molecular-weight vWF multimers.[16] Most experience reported in the literature has been with the use of Humate-P, a plasma-derived product of intermediate purity. Two other FVIII concentrates, Alphanate and Koate-HP, have been reported to be effective in the treatment of vWD. Too little vWF is present in monoclonally purified FVIII concentrates and recombinant FVIII concentrates to allow their use in the treatment of vWD.

Alloantibody formation occurs in 10-15% of patients with type III disease. Therefore, the possibility of this complication must be managed appropriately, because patients are at increased risk for life-endangering anaphylactic reactions to vWF-FVIII preparations. With hemostatic stress in emergency situations, infusion of FVIII preparations devoid of vWF, while adjusting for the markedly decreased FVIII half-life, may be necessary.

Previous
 
 
Contributor Information and Disclosures
Author

Eleanor S Pollak, MD Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania

Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Chief Editor

Srikanth Nagalla, MBBS, MS, FACP Director, Clinical Hematology, Cardeza Foundation for Hematologic Research; Assistant Professor of Medicine, Division of Hematology, Associate Program Director, Hematology/Medical Oncology Fellowship, Assistant Program Director, Internal Medicine Residency, Jefferson Medical College of Thomas Jefferson University

Srikanth Nagalla, MBBS, MS, FACP is a member of the following medical societies: American Society of Hematology, Association of Specialty Professors

Disclosure: Nothing to disclose.

Acknowledgements

Marcel E Conrad, MD (Retired) Distinguished Professor of Medicine, University of South Alabama

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Koyamangalath Krishnan, MD, FRCP, FACP Paul Dishner Endowed Chair of Excellence in Medicine, Professor of Medicine and Chief of Hematology-Oncology, Program Director, Hematology-Oncology Fellowship, James H Quillen College of Medicine at East Tennessee State University

Koyamangalath Krishnan, MD, FRCP, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society of Hematology, and Royal College of Physicians

Disclosure: Nothing to disclose.

Steven Stein, MD, Assistant Professor, Department of Medicine, Division of Hematology/Oncology, University of Pennsylvania

Steven Stein, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

References
  1. Udvardy ML, Szekeres-Csiki K, Hársfalvi J. Novel evaluation method for densitometric curves of von Willebrand factor multimers and a new parameter (M(MW)) to describe the degree of multimersation. Thromb Haemost. 2009 Aug. 102(2):412-7. [Medline].

  2. [Guideline] Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014 Aug 12. [Medline]. [Full Text].

  3. Sutherland MS, Cumming AM, Bowman M, et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. 2009 Jul 30. 114(5):1091-8. [Medline].

  4. Stuijver DJ, Piantanida E, van Zaane B, Galli L, Romualdi E, Tanda ML, et al. Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study. Haemophilia. 2014 May. 20(3):326-32. [Medline].

  5. Waldow HC, Westhoff-Bleck M, Widera C, Templin C, von Depka M. Acquired von Willebrand syndrome in adult patients with congenital heart disease. Int J Cardiol. 2014 Aug 1. [Medline].

  6. Byams VR, Kouides PA, Kulkarni R, et al. Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. Haemophilia. 2011 Jul. 17 Suppl 1:6-13. [Medline].

  7. Sanders YV, Giezenaar MA, Laros-van Gorkom BA, Meijer K, van der Bom JG, Cnossen MH, et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost. 2014 Jul. 12(7):1066-75. [Medline].

  8. [Guideline] Nichols WL, Hultin MB, James AH, et al, and the NHLBI von Willebrand Disease Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, Md: National Heart, Lung, and Blood Institute. NIH publication no. 08-5832. December 2007. [Full Text].

  9. Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. 2009 Aug 6. 114(6):1158-65. [Medline]. [Full Text].

  10. Sanders YV, Fijnvandraat K, Boender J, Mauser-Bunschoten EP, van der Bom JG, et al. Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding. Am J Hematol. 2015 Sep 16. [Medline].

  11. Roberts JC, Flood VH. Laboratory diagnosis of von Willebrand disease. Int J Lab Hematol. 2015 May. 37 Suppl 1:11-7. [Medline].

  12. Hayward CP, Moffat KA, Graf L. Technological advances in diagnostic testing for von Willebrand disease: new approaches and challenges. Int J Lab Hematol. 2014 Jun. 36(3):334-40. [Medline].

  13. Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015 Oct 22. 126 (17):2038-46. [Medline]. [Full Text].

  14. Franchini M, Targher G, Montagnana M, Lippi G. Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?. J Thromb Thrombolysis. 2009 Aug. 28(2):215-9. [Medline].

  15. Neff AT. Current controversies in the diagnosis and management of von Willebrand disease. Ther Adv Hematol. 2015 Aug. 6 (4):209-16. [Medline].

  16. Di Paola J, Lethagen S, Gill J, et al. Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery. Haemophilia. 2011 Sep. 17(5):752-8. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.