The VWF–ADAMTS13 interplay under normal hemostasis
VWF is a multimeric glycoprotein that plays a central role in hemostasis by facilitating platelet adhesion at sites of vascular injury and stabilizing coagulation factor VIII. It is synthesized by endothelial cells lining the blood vessels and stored in Weibel-Palade bodies as ultra-large (UL) VWF multimers. These multimers are released through both basal secretion and in response to stimuli such as vascular injury and inflammation.
Once released, UL-VWF multimers undergo shear-dependent unfolding, transitioning from a compact, globular form to an elongated conformation. This structural change exposes the ADAMTS13 cleavage site.
ADAMTS13, a plasma metalloprotease, is the primary regulator of VWF activity. It specifically cleaves these partially unfolded UL-VWF multimers into smaller, functionally active high-molecular-weight (HMW) multimers.
VWF’s hemostatic potency is directly linked to its size: HMW multimers are significantly more effective at anchoring platelets to damaged vessel walls. Following vascular injury, these HMW multimers rapidly recruit platelets, forming a stable VWF–platelet plug that prevents excessive blood loss.
Impaired hemostasis by excessive VWF cleavage
Under pathological conditions—such as increased shear stress or mutations in VWF—abnormal unfolding can lead to enhanced exposure of the ADAMTS13 cleavage site. This dysregulation of the VWF–ADAMTS13 axis may result in excessive cleavage of HMW multimers, reducing the availability of functionally active VWF.
The resulting loss of HMW multimers impairs platelet adhesion and compromises hemostatic function, resulting in VWF-related bleeding disorders.
Beyond its hemostatic role, VWF also contributes to vascular integrity. Experimental evidence suggests that VWF deficiency may promote aberrant angiogenesis. Clinically, patients with VWF-related disorders frequently present with gastrointestinal bleeding originating from vascular malformations such as angiodysplasia.
