Thrombotic thrombocytopenic purpura (TTP) results from deficiency of ADAMTS13. ADAMTS13 normally cleaves which substrate, and at which site?

• A Fibrinogen alpha chain at the Arg-Gly cleavage site releasing fibrinopeptide A
• B Ultra-large von Willebrand factor (ULVWF) multimers at the A2 domain Tyr1605-Met1606 bond under shear stress ✓
• C Platelet GPIb receptor, reducing platelet adhesion to collagen
• D Thrombomodulin on endothelial cells, preventing protein C activation

Explanation

ADAMTS13 is a metalloprotease that specifically cleaves the Tyr1605-Met1606 bond within the A2 domain of VWF multimers. This cleavage requires shear stress to unfold the A2 domain and expose the cleavage site. ADAMTS13 deficiency (acquired autoantibody-mediated, as in acquired TTP, or congenital as in Upshaw-Schulman syndrome) causes accumulation of ULVWF multimers on endothelium that capture and aggregate platelets, forming microvascular thrombi characteristic of TTP.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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