Locations of ADAMTS13 cleavage of VWF and its deficiency in TTP. Shown is a diagram illustrating the sites of VWF proteolysis by ADAMTS13. UL-VWF is synthesized by the endothelium and stored within Weibel-Palade bodies (WPB). VWF multimers of various sizes, including UL-VWF, can be secreted directly into the circulation. (A) Alternatively, a proportion of UL-VWF may attach to the endothelial surface during secretion and unravel in response to shear forces. Under these circumstances, the VWF A2 domain unfolds to enable ADAMTS13 (scissors) to cleave VWF and release the VWF string. VWF adopts a globular fold in plasma. However, during passage through the microvasculature, globular UL-VWF in the free circulation may partially/transiently unravel. (B) This permits the processing of the largest, most hemostatically active forms of VWF, resulting in their conversion to smaller plasma VWF multimers. At sites of vessel damage, endothelial damage results in exposure of subendothelial collagen; plasma VWF binds to this, unravels, and recruits platelets. The presence of collagen and thrombin induce rapid platelet activation, which, along with fibrin, consolidates the platelet plug. (C) Downstream of the site of injury (ie, in the absence of collagen and thrombin), VWF-platelet strings may still be proteolyzed by ADAMTS13, which in turn limits/regulates platelet plug formation. ADAMTS13 deficiency either through anti-ADAMTS13 antibodies or through inherited deficiency in the ADAMTS13 gene results in the loss of VWF processing. Under these circumstances, platelets (Pl) can bind unraveled VWF, leading to the accumulation of VWF-platelet aggregates that occlude the microvasculature, as seen in patients presenting with TTP.