Current and Emerging Options for the Management of Inherited von Willebrand Disease

Abstract

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more “personalized” approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients’ needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries.

von Willebrand factor and factor VIII levels after desmopressin are associated with bleeding phenotype in type 1 VWD

“…However, it is well known that desmopressin response remains constant over time. 15,18,22,32 Furthermore, due to the long follow-up period, VWF and FVIII assays may have changed over time. However, we obtained levels from patient files that were centrally performed with routinely diagnostic assays in the same laboratory, which are highly reliable.…”

“…It is well known that certain circumstances, including stress, exercise, and surgery, are associated with an increase in both VWF and FVIII, a so-called hemostatic response. 7,8,[11][12][13][14][15] Patients who have a strong increase in VWF and FVIII levels during a hemostatic challenge may have less frequent or less severe bleeding episodes compared with patients with a smaller increase in VWF and FVIII levels.…”

How I manage severe von Willebrand disease

“…The goal of treatment in VWD patients is to primarily improve platelet adhesion and aggregation by increasing VWF and, secondly, to improve fibrin formation by increasing FVIII levels in the circulation (Heijdra et al , ). This can be achieved by stimulating endogenous VWF and FVIII release from Weibel‐Palade Bodies by desmopressin, or infusion of exogenous VWF with or without FVIII, (Castaman et al , ; Leebeek & Eikenboom, ).…”

Analysis of current perioperative management with Haemate® P/Humate P® in von Willebrand disease: Identifying the need for personalized treatment

“…The aim of treatment is to correct the VWF deficiency, and also to correct a FVIII deficiency, if this is present. In patients who do not respond adequately to DDAVP or have contra‐indications for its use, treatment usually consists of combined VWF/FVIII factor concentrates amongst which the ratios of VWF activity (VWF:Act) over FVIII may differ …”

“…In patients who do not respond adequately to DDAVP or have contra-indications for its use, treatment usually consists of combined VWF/FVIII factor concentrates amongst which the ratios of VWF activity (VWF:Act) over FVIII may differ. 4 Although clinical symptoms are generally milder than in haemophilia, dosing of perioperative treatment in VWD is more challenging due to variation in VWD types and mutations, 2,5 interpatient variability of residual endothelial VWF production, VWF secretion and clearance, as well as heterogeneity in types of factor concentrates with different ratios of VWF:Act/FVIII and VWF:Act/VWF antigen (VWF:Ag). 6,7 Previous studies have, however, reported that surgical procedures can be performed safely in patients with VWD and that treatment with VWF-containing concentrates is efficacious.…”