Towards personalised therapy for von Willebrand disease: a future role for recombinant products

Abstract

von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for "personalised" management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment.

Figure 1

The domain structure of von Willebrand factor showing ligand binding sites and formation of multimers. VWF: von Willebrand factor; VWD: von Willebrand disease; FVIII: factor VIIII; GP: glycoprotein.

Figure 2

Algorithm summarising the author’s suggestive future landscape for personalised therapy in von Willebrand disease (VWD) with recombinant VWF and FVIII products. Solid continuous lines indicate the most likely main therapy to be applied in the future landscape of VWD treatment. Dotted lines indicate additional or alternate treatment options depending on extent of VWF and/or FVIII deficiency, reason for treatment and timing of therapy, and according to the concept of “personalised therapy”. Refer also to Table VI. VWF: von Willebrand factor; FVIII: factor VIII.