Figure 5
Figure 5. Location of VWF cleavage by ADAMTS13. Cartoon depicting the sites of VWF proteolysis by ADAMTS13. (UL)VWF is synthesized by the endothelium and stored within Weibel-Palade bodies (WPB; green). VWF multimers of various sizes, including UL-VWF, can be secreted directly into the circulation. (1) Alternatively, a proportion of UL-VWF may attach to the endothelial surface during exocytosis and unravel in response to shear forces. Under such circumstances, the VWF A2 domain unfolds to enable ADAMTS13 (red scissors) to cleave VWF and release the VWF string. Whether directly secreted or proteolytically released, VWF can adopt a globular fold in the plasma circulation. However, during passage through the microvasculature, globular UL-VWF in free circulation will probably unravel (at least partially/transiently). (2) Such unraveling permits the processing of the largest, most hemostatically active forms of VWF, resulting in their conversion to smaller plasma VWF multimers. Mutations in VWF that precipitate type 2A von Willebrand disease are particularly influenced by such proteolysis. This group of mutations enhances the propensity of VWF to unfold in free circulation, leading to excessive proteolysis and loss of hemostatically functional VWF. Conversely, ADAMTS13 deficiency results in the loss of such plasma processing. Under these circumstances, platelets (Pl) can become bound to transiently unraveled VWF, leading to the accumulation of VWF-platelet aggregates that occlude the microvasculature, as seen in patients presenting with TTP. At sites of vessel damage, endothelial damage results in exposure of subendothelial collagen. Plasma VWF binds to this, unravels, and, in turn, recruits platelets. The presence of collagen and thrombin induces rapid platelet activation, which consolidates the platelet plug. Thrombin further stabilizes this through the deposition of fibrin and the proteolytic inactivation of ADAMTS13. (3) Downstream of the site of injury (ie, in the absence of collagen and thrombin), VWF-platelet strings may still be proteolysed by ADAMTS13, which in turn limits/regulates platelet plug formation. Low or reduced ADAMTS13 levels may impair this process and consequently influence the pathophysiology of arterial thrombosis.

Location of VWF cleavage by ADAMTS13. Cartoon depicting the sites of VWF proteolysis by ADAMTS13. (UL)VWF is synthesized by the endothelium and stored within Weibel-Palade bodies (WPB; green). VWF multimers of various sizes, including UL-VWF, can be secreted directly into the circulation. (1) Alternatively, a proportion of UL-VWF may attach to the endothelial surface during exocytosis and unravel in response to shear forces. Under such circumstances, the VWF A2 domain unfolds to enable ADAMTS13 (red scissors) to cleave VWF and release the VWF string. Whether directly secreted or proteolytically released, VWF can adopt a globular fold in the plasma circulation. However, during passage through the microvasculature, globular UL-VWF in free circulation will probably unravel (at least partially/transiently). (2) Such unraveling permits the processing of the largest, most hemostatically active forms of VWF, resulting in their conversion to smaller plasma VWF multimers. Mutations in VWF that precipitate type 2A von Willebrand disease are particularly influenced by such proteolysis. This group of mutations enhances the propensity of VWF to unfold in free circulation, leading to excessive proteolysis and loss of hemostatically functional VWF. Conversely, ADAMTS13 deficiency results in the loss of such plasma processing. Under these circumstances, platelets (Pl) can become bound to transiently unraveled VWF, leading to the accumulation of VWF-platelet aggregates that occlude the microvasculature, as seen in patients presenting with TTP. At sites of vessel damage, endothelial damage results in exposure of subendothelial collagen. Plasma VWF binds to this, unravels, and, in turn, recruits platelets. The presence of collagen and thrombin induces rapid platelet activation, which consolidates the platelet plug. Thrombin further stabilizes this through the deposition of fibrin and the proteolytic inactivation of ADAMTS13. (3) Downstream of the site of injury (ie, in the absence of collagen and thrombin), VWF-platelet strings may still be proteolysed by ADAMTS13, which in turn limits/regulates platelet plug formation. Low or reduced ADAMTS13 levels may impair this process and consequently influence the pathophysiology of arterial thrombosis.

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