Insights into von Willebrand factor proteolysis: clinical implications

Abstract

Summary The proteolysis of von Willebrand factor (VWF) by the recently discovered metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin repeats), is a normal processing step in VWF biochemistry. Emerging data indicate that this step may be influenced by a variety of factors, some of which favour increased proteolysis and some of which compromise proteolysis. The former may predispose to bleeding, whilst the latter appears to be the underlying mechanism for thrombotic thrombocytopenic purpura (TTP). The new insights support the concept of ‘risk’ in bleeding, particularly in the case of type 1 von Willebrand disease (VWD), in much the same way that risk is considered in venous thrombosis. This review presents relevant current knowledge of VWF proteolysis by ADAMTS13, and a novel model of how this may be implicated in type 1 VWD is proposed, based on events at the vessel wall at a time of haemostatic challenge.

Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

“…This suggests increased vWF proteolysis, possibly by ADAMTS13. 37 Thus, a unique situation for vWF cleavage may have occurred in the hTg G233V animal in which platelet-bound vWF is more susceptible to cleavage, and this is the focus of future studies. No similar situation has been reported for human Pt-vWD, but the model presented here does differ from human Pt-vWD in that a normal GP Ib␣ subunit is not present.…”

Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group

“…21 This observation led to the proposal that C1584 is a risk factor for bleeding and must be coinherited with other predisposing factors for a bleeding diathesis to result. 21,23 In 2 cohort studies, more than 90% of patients with type 1 VWD who were heterozygous for Y/C1584 had blood group O 19,21 (in contrast, 70% of type 1 VWD patients had blood group O 3 ). The reason for this association is unknown.…”

C1584: Effect on von Willebrand Factor Proteolysis and von Willebrand Factor Antigen Levels

“…The finding that proteolysis was marginally greater for group O VWF, together with the known enrichment for blood group O in type 1 VWD, led to the hypothesis that, independently of a possible effect on the VWF level, increased susceptibility to proteolysis may impact negatively on soft clot formation at the time of haemostatic challenge (see later and reviewed in Bowen and Collins [5]). To address this hypothesis, and continue to explore the possibility that VWF proteolysis and level may be related, proteolysis was assessed for VWF from several type 1 VWD patients and this led to the finding that, in 1 patient, plasma VWF had increased susceptibility to proteolysis [2].…”

“…This property may be highly relevant at a time of haemostatic challenge [5]. During normal clot formation, VWF multimers recruit platelets to the site of vessel damage, and are, at the same time, proteolysed by circulating ADAMTS13.…”

“…The enhanced proteolysis associated with C1584 is not as dramatic as the extreme scenario illustrated above, however it may be sufficient to have an adverse effect on haemostasis. Depending upon the extent of this within an individual, clinically relevant bleeding may result [5]. …”