Von Willebrand disease

Introduction

Von Willebrand disease is considered to be the most common inherited bleeding disorder. The prevalence of VWD is not known, and estimates differ substantially based on the method used, as recently reviewed elsewhere. On the basis of the epidemiological studies, the reported prevalence approximates 1% of the population (viz. around 10 000 cases of VWD per million population). This would compare with the reported prevalence for haemophilia of less than 0.01% (or around 100 per million male populations). However, the vast majority of cases identified by epidemiological studies as possible 'VWD' do not show evidence of VWF genetic mutations and instead comprise mild deficiencies of VWF that are increasingly got recognized as representing a manageable risk factor for bleeding, but not necessarily reflecting a true' VWD in the classical sense. Thus, the prevalence of VWD based on bleeding disorder registry data, or data from VWD testing and clinical support centres, which better represents patients under clinical investigation or management for personal or familial bleeding, provides estimates closer to that of haemophilia A, or around 0.01% or 100 per million population.

Discussion

VWD gets classified into six different types, with type 1 identifying a (partial) quantitative deficiency of VWF, type 3 defining a (virtual) total deficiency of VWF and type 2 identifying four separate types (2A, 2B, 2M and 2N) characterized by qualitative defects. VWF has a multitude of functional roles in haemostasis in order to facilitate the arrest of bleeding following injury. However, the primary two best recognized functions are to promote adhesion of platelets to each other and to the vasculature ('primary haemostasis), and to bind, stabilize and protect FVIII (as delivered and utilized in 'secondary' haemostasis). These functions get facilitated by binding of VWF to FVIII, to VWF's major platelet receptor (viz. Glycoprotein Ib [alpha], GPIBA), to other platelet receptors (e.g. [alpha] IIb [beta] 3 or glycoprotein IIb/IIIa) and to sub endothelial matrix components such as collagen.

However, VWF has several additional functional-binding sites, including those for heparin and sulpha tides. The steady-state VWF plasma concentration and composition is also controlled by a complex process of manufacture, storage, secretion, proteolysis and clearance, with only some of the mechanisms elucidated. VWF also presents as a multimeric protein, with increasing multimer size reflecting increasing copies of the base VWF dimer unit and, therefore, greater overall adhesive power or higher haemostatic potential. The heterogeneity of VWD, therefore, reflects the large and complex multimeric protein that VWF represents as facilitating its myriad of functions, as well as the simple fact that many factors additional to the VWF gene can influence an individual's phenotype, bleeding risk or clinical presentation (Favaloro, 17).

Role of Adamts-13

ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin type 1 repeats) is protease- von Willebrand factor (VWF). If vascular gap, the VWF allows, thanks to its multimeric structure, platelet adhesion to sub endothelium and aggregation of platelets in the microcirculation, where the shear forces are high. ADAMTS13 regulates VWF activity by reducing the size of its multimers. A severe ADAMTS13 functional deficiency is ...