Long-term continuous use of concentrates to prevent bleeds, known as prophylaxis, is the standard of care in severe hemophilia A and B and is now being adopted in severe VWD. Patients with type 3 VWD or severe type 1 or type 2 VWD may experience recurrent bleeds into joints, nasal/oropharynx, or gastrointestinal tract or excessive menstrual bleeding. Retrospective cohort and case series suggest that prophylaxis improves quality of life; reduces the frequency of bleeding, need for transfusions, and hospitalizations; and prevents chronic joint disease.54,55 More recently, a prospective study confirmed that prophylaxis with VWF concentrates at doses ranging from 50 IU VWF RCo/kg 1 to 3 times per week was highly effective at reducing bleeding rates, with annualized bleeding rates decreasing from 25 to 6.1 in 11 participants with either type 2A or type 3 VWD.56
VWF/FVIII concentrates are effective in more than 97% of events.57 Rarely, when infusion of a VWF/FVIII concentrate is ineffective at stopping bleeding, transfusion of platelet concentrates may be beneficial, presumably because they facilitate the delivery of small amounts of platelet VWF to the site of vascular injury. Highly purified FVIII concentrates (monoclonal antibody purified and recombinant) should not be used to treat VWD because they lack VWF.
A recombinant VWF concentrate (Vonvendi) combined initially with recombinant FVIII concentrate in a 1.3:1 ratio of VWF:RCo to FVIII:C has been shown to be safe and efficacious for the on-demand treatment of bleeds.58,59 After the initial FVIII dose, the patients’ endogenous FVIII levels are stabilized within 6 hours and further FVIII administration may not required. A prospective phase 3 trial investigating the efficacy of recombinant VWF in the prophylaxis of severe VWD is ongoing. Vonvendi has been licensed for on-demand treatment in the United States since 2015. For further dosing information, please refer to the product insert.
VWF is a complex protein with several important and distinct functional domains: binding sites to collagen, FVIII, and platelet GPIbα; an ADAMTS13 cleavage site; and domains important for multimer formation. Mutations in any of these sites can result in a dysfunctional protein and as a result, VWD is a heterogeneous disorder with many specific assays available to determine the subtype. Despite this, the treatment of VWD is straightforward with only a small number of therapeutic options: indirect therapies such as antifibrinolytic agents, or direct therapies that increase VWF levels, DDAVP, or VWF/FVIII concentrates. Management focuses on preventing bleeding complications associated with invasive procedures or promptly treating bleeding episodes.