Approach Considerations
The main treatment options for patients with von Willebrand disease (vWD) are as follows [31] :
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Desmopressin (DDAVP) - DDAVP is a synthetic analogue of the antidiuretic hormone vasopressin; it has enhanced antidiuretic activity and no pressor activity related to vasopressin.
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Recombinant von Willebrand factor (rVWF) - Indicated for on-demand treatment of minor or major hemorrhage in adults with vWD [32]
Recombinant von Willebrand factor (Vonvendi) was approved by the US Food and Drug Administration (FDA) in 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. [32]
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. [18]
Platelet transfusions may be helpful in some patients with vWD (eg, type 3) to control bleeding that is refractory to other therapies. [18] 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. [18, 19]
Surgery
A hematologist experienced in the management of bleeding disorders should be consulted prior to all surgical/dental procedures. For prophylaxis in major surgery, rVWF (with or without FVIII) or vWF-containing factor VIII (FVIII) concentrates are the treatment of choice. For emergency surgery, both vWF and FVIII are required to ensure hemostasis; however, for elective procedures, early infusion of rVWF will stabilize endogenous FVIII. Hemostatic levels are maintained until bleeding risk abates: usually 3 to 5 days for minor procedures and 7 to 14 days for major surgery. [33]
Patients with vWD who undergo major surgery, particularly those with more severe forms of vWD, require frequent monitoring of plasma levels and access to hemostatic. Repeated VWF supplementation (particularly with plasma-derived FVIII-containing products) may lead to accumulation of FVIII. [33]
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. [34]
vWF in pregnancy
During pregnancy, the vWF level increases in most patients with non–type 3 vWD. Thus, in patients with functionally normal vWF, labor and delivery usually proceed normally. Measurement of vWF levels is recommended in the third trimester of pregnancy to facilitate peri-partum planning. [35]
However, patients with type 2 disease may experience hemorrhagic problems. In particular, patients with type 2B may experience thrombocytopenia due to the increased plasma levels associated with abnormal vWF. There is no consensus on how these cases can best be managed. [36] 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.
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 1 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 [37] :
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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
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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. [4, 37]
Type 2 von Willebrand disease
Responses to DDAVP are variable in patients with type 2 disease; some patients respond while others should receive vWF concentrates. [37] United Kingdom guidelines recommend performing a trial infusion of DDAVP in patients with type 2A, 2M, and 2N vWD and measuring vWF antigen, vWF activity, and FVIII at baseline, 30–60 min, and 4–6 h. [4]
Many individuals with vWD type 2A 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 1. 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 2B, because of thrombocytopenia and possible thrombotic complications. DDAVP is usually not effective in patients with type 2M and is rarely effective in patients with type 2N.
Type 3 von Willebrand disease
Individuals with vWD type 3 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 3 (as with other vWD types unresponsive to DDAVP) is rVWF (with or without FVIII) [32] or virus-inactivated, vWF-containing FVIII concentrates that contain a near-normal complement of high-molecular-weight vWF multimers. [38] Most experience reported in the literature has been with the use of Humate-P, a plasma-derived FVIII/FVIII 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.
Products that contain vWF only have been shown to correct not only the primary vWF deficiency but also the secondary FVIII:C deficiency, and have demonstrated safety and efficacy in various clinical situations, including surgery. Recombinant vWF (Vonvendi), which was initially approved in 2015 for on-demand treatment of bleeding episodes in vWD, received expanded approval in 2018 for perioperative management of bleeding, and in 2022 for routine prophylaxis in patients with severe type 3 vWD who had been receiving on-demand therapy. [39]
A 12-month study of rVWF prophylaxis in 23 patients with severe vWD, 18 of them with type 3, found that patients who had previously received on-demand treatment with vWF products had a lower frequency of spontaneous bleeds requiring vWF treatment, and patients who switched from prophylaxis with plasma-derived vWF experienced similar levels of spontaneous bleeding events requiring treatment. Patients with type 3 vWD did experience some spontaneous bleeding events, but most were mucosal bleeds and/or menorrhagia; no fatal or life-threatening bleeds or spontaneous gastrointestinal (GI) bleeds occurred. [40]
However, the safety and efficacy of rVWF in pediatric patients has yet to be determined. Likewise, the value of vWF-only products for recurrent gastrointestinal bleeding due to angiodysplasia has yet to be explored. [31]
Alloantibody formation occurs in 10-15% of patients with type 3 disease. Therefore, the possibility of this complication must be managed appropriately, because these 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.
Off-label use of emicizumab, a bispecific, factor VIII-mimetic antibody approved for prophylaxis of hemophilia A, has been reported for treatment of active/recurrent bleeds in patients with type 3 vWD. Published case reports and case series suggest that emicizumab can provide effective hemostatic therapy in this setting. [41]
