ABSTRACT
Blood flow in the circulation creates shear stress that affects cell functions and
cell-cell interactions. Recent studies reveal that shear stress is also critical in
the homeostasis of the plasma glycoprotein von Willebrand factor (vWF). Because of
its large molecular size, vWF has a flexible conformation that is uniquely responsive
to shear stress. Exposure to shear stress causes conformational unfolding of vWF,
enhancing its susceptibility to cleavage by a plasma zinc metalloprotease (a disintegrin
and metalloprotease with thrombospondin type 1 motif [ADAMTS13]). In the absence of
ADAMTS13, shear stress increases the capacity of vWF to support platelet aggregation.
In normal individuals, a balance between endothelial secretion of an ultralarge form
of vWF and intravascular proteolysis determines the size distribution of vWF multimers
that seems to be optimum for hemostasis without imposing the risk of unwarranted platelet
aggregation. In type 2A (group 2) von Willebrand disease, the mutant vWF is excessively
susceptible to cleavage by ADAMTS13, resulting in a decrease of large vWF multimers
and bleeding diathesis. In patients with aortic stenosis or the hemolytic-uremic syndrome,
abnormally high levels of shear stress across the stenotic valve or in the microcirculation
inflicted with thrombosis may promote cleavage of vWF by ADAMTS13, contributing to
the loss of large multimers commonly observed among these patients. Conversely, a
deficiency in ADAMTS13 because of genetic mutations or autoimmune inhibitors causes
vWF- and platelet-rich microvascular thrombosis characteristic of thrombotic thrombocytopenic
purpura.
KEYWORDS
Shear stress - von Willebrand factor - ADAMTS13 - proteolysis - thrombosis
