von Willebrand disease: treatment with or without factor VIII?

In von Willebrand disease (VWD) hemostasis is impaired as a result of dual defects in platelet adhesion and in factor VIII (FVIII) coagulant activity, the latter requiring von Willebrand factor (VWF) as its carrier protein. Although not proven by clinical study, in patients with VWD the FVIII level appears to be the best predictor of soft tissue and surgical bleeding, and platelet-dependent VWF activity is the best predictor of mucosal bleeding [1,2]. The mainstay of treatment for most patients with VWD is desmopressin (1-desamino-8-d-arginine vasopressin). Desmopressin stimulates release of VWF from storage sites, resulting in a transient increase in both VWF and FVIII. However, for patients with qualitative deficiencies (type 2) or severe quantitative deficiencies (type 3), or for patients with milder disease requiring sustained VWF correction, replacement products containing VWF are needed.

Cryoprecipitate, a cold precipitate of plasma enriched in VWF and FVIII, long the mainstay of treatment of VWD was shown to normalize plasma levels of FVIII, shorten the bleeding time and stop or prevent bleeding in patients with VWD [3]. However, cryoprecipitate cannot be virally inactivated and treatment of patients with VWD and serious bleeding or major surgery can entail a large number of donor exposures. Virally-inactivated plasma-derived concentrates are now the treatment of choice for VWD when desmopressin is ineffective or contraindicated. Factor concentrates also allow easier outpatient and home treatment.

Some plasma-derived FVIII products developed for treatment of hemophilia A retain relatively intact VWF and have been used successfully in the treatment of VWD. Two such products (Humate-P^® [CSL Behring, King of Prussia, PA, USA] and Alphanate^® [Grifols International, S.A., Barcelona, Spain]) were studied prospectively in the treatment of bleeding and prophylaxis for surgery in VWD and have been shown to be highly effective [4–6]. However, a concern with these products is that patients with VWD synthesize FVIII normally, and continual infusions of FVIII may result in very high levels. As high endogenous FVIII levels have been identified as a risk factor for venous thrombosis, concern exists as to whether these treatments of VWD will result in thrombosis. In the Alphanate^® trial, two of 81 patients suffered thrombotic complications, one a superficial and one a deep venous thrombosis [6].

In this issue of Journal of Thrombosis and Haemostasis, Borel-Derlon et al. [7] describe the results of two open-label prospective trials of a high-purity VWF concentrate, Wilfactin^®, in the treatment of patients with VWD type 2 or 3 or desmopressin unresponsive type 1. The report includes two studies, one conducted in Europe and one confined to France with similar, although not identical, treatment protocols. Prior studies using a similar product infused in patients with severe VWD demonstrated a lag time in achieving therapeutic FVIII levels, requiring 6–12 h after a single infusion, which was then sustained for up to 24 h [8]. In the current study with Wilfactin^®, to account for the delay in FVIII increase, FVIII concentrate was administered initially with the VWF concentrate in patients with severe disease requiring immediate surgery, and in patients with non-mucosal, or with serious mucosal bleeding.

Dosing regimens used in the studies reported by Borel-Derlon et al. and previously for study of FVIII/VWF concentrates, have been based on pharmacokinetic data with loading doses ranging from 40–80 IU kg^–1 for treatment of bleeding or surgical prophylaxis. Treatment protocols for dosing after the loading dose were given in the Wilfactin^® and Humate-P^® trials, although the actual dosing regimen and length of treatment were left up to the treating physician in all trials. Subsequently the length of treatment and doses varied widely. However, all trials reported the treatments to be highly effective.

Why patients with VWD who are treated with factor concentrates develop thrombosis is not completely clear, but likely multifactorial. In patients with severe hemophilia receiving postoperative factor replacement venous thromboembolism (VTE) appears to be a very uncommon event. This does not appear to be true in patients with VWD, who, almost all have less severe defects in hemostasis as measured by FVIII activity than patients with moderate and severe hemophilia A. However, clinicians may withhold VTE prophylaxis because of perceived bleeding risks, and in fact, the degree of risk is unknown in this population. How much increased FVIII and VWF levels contribute to the thrombotic risk is unclear. As noted previously, persistently increased endogenous FVIII levels are a risk factor for VTE. The evidence for elevated VWF levels as a risk factor for VTE is less strong, but some studies have demonstrated an association [9]. Neither is clearly associated with an increased risk of arterial thrombosis.

In 2002, on behalf of the VWF Subcommittee of the Scientific and Standardization Committee of ISTH, Mannucci reported results of a survey of 520 hemophilia centers asking about thrombosis associated with VWF/FVIII concentrate treatment for VWD [10]. Seven cases were reported. Makris et al. [11] reported three additional cases, and two were reported in the Alphanate^® trial [6]. In these reports, three patients did not have FVIII levels and four did not have VWF levels reported. In five of the nine patients with FVIII levels reported, the value was > 200% and in three of those patients the VWF level was also > 200%. Two of the patients reported by Mannucci had FVIII levels < 90%. Of interest, one of the two patients in the Alphanate^® trial had VWF (ristocetin cofactor activity and antigen) levels significantly higher than FVIII, despite being given a concentrate containing more FVIII than VWF (FVIII/VWF = 1.6). Of note, factor levels were not always drawn at the time of the thrombotic event and most patients were given additional hemostatic agents and/or had additional risk factors for thrombosis. While no patient developed thrombosis in the Wilfactin^® trial and levels of both VWF and FVIII were maintained in the normal range, FVIII levels were higher than VWF levels from day 1 through to day 6 postoperatively, which was the last day values were reported.

High-purity VWF concentrates, such as Wilfactin^® or the recombinant VWF product under development, provide a more specific treatment for patients with VWD. Whether these carry less risk of thrombosis in this patient population would be best addressed by a randomized double-blind trial. Concentrates, with or without FVIII, have been shown to be highly effective in the treatment of patients in which desmopressin is ineffective or contraindicated. The data to date emphasize the variability in response among patients and the need to closely monitor both FVIII and VWF levels when treatment is prolonged. However, this alone will not eliminate the risk of VTE when other risk factors are present.

Laboratory response to VWF and FVIII/VWF infusions gives us clues to the biology of these factors. We should head these clues with further basic and clinical studies.

Disclosure of Conflict of Interests

The author states that she has no conflict of interest.