Recombinant VWF: is this the answer for treatment of von Willebrand disease?

Abstract

The use of replacement protein factors for treatment of blood clotting disorders has a long history that has involved both major advances and setbacks. Replacement therapies can be viewed as the gold standard treatment for the majority of factor deficiencies and, for certain conditions, such treatments are both highly developed and well established. For the common inherited bleeding disorders, hemophilia A and B, replacement FVIII and FIX concentrate has been in clinical use for many years, with recombinant product prophylaxis now in routine use in those countries that can afford it, and further improvements relating to increasing the half-life of these products at a fairly advanced stage [1]. However, not all factor deficiencies have the same level of development applied to their replacement concentrate therapies. von Willebrand disease (VWD), which results from a qualitative or quantitative deficiency of the multimeric plasma glycoprotein VWF, is a case in point. VWD is a complex disorder with three main subtypes that respond to treatment modalities in fundamentally different ways [2,3,101]. In contrast with hemophilia A, where FVIII replacement therapy is the standard treatment in individuals without complicating factors such as inhibitors, treatment of VWD using other agents such as desmopressin is an effective approach for some subtypes, notably mild type 1 and some mild qualitative type 2 VWD cases in shortterm treatment situations. However, in cases where such alternative treatments are contraindicated, and in type 3 and severe type 1 VWD, the use of replacement VWF concentrate for many clinical scenarios is required. Whilst there are several licensed VWF concentrates on the market, their state of development is, in some respects, not as advanced as that for FVIII or FIX replacement therapies. The currently licensed products in use all involve plasma-derived VWF from pools of donors. Whilst current processing techniques to purify these products, as with other available plasma-derived concentrates, mean that the risk of significant viral transmission is currently very low, there are other practical concerns for the clinician who wishes to use these nonrecombinant VWF concentrates in real-life treatment scenarios. The majority of licensed concentrates for the management of VWD contain both VWF and FVIII, but the relative proportions of each factor vary markedly, both between different products and batches of the same product, due to differing manufacturing processes that result in variable multimer composition and size distribution [3]. High-molecular weight (HMW) VWF multimers are the most biologically active and with each licensed product containing different amounts, this may be predicted to translate into variable hemostatic potential when administered to the patient. Another complication is the lack of information supplied in some locales relating specifically to VWF activity “...it is reasonable to expect ... that the treatment of VWD will evolve further over time to include more routine use of prophylaxis and a switch to recombinant products, where both clinical indicators and economic considerations permit.”