Thrombotic thrombocytopenic purpura (TTP) is caused by deficiency of ADAMTS13. The substrate of ADAMTS13 and the mechanism of thrombosis are:

• A ADAMTS13 degrades thrombin, and its deficiency leads to uncontrolled fibrin formation in the microvasculature
• B ADAMTS13 cleaves VWF at the Tyr1605-Met1606 bond in the A2 domain; deficiency causes ultra-large VWF multimers to accumulate and cause platelet agglutination in microvessels ✓
• C ADAMTS13 inactivates complement factor H, and its deficiency leads to complement-mediated platelet lysis
• D ADAMTS13 cleaves PCSK9, increasing LDL uptake and platelet membrane cholesterol causing hyperreactivity

Explanation

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) is a metalloprotease that cleaves von Willebrand factor (VWF) at the Tyr1605-Met1606 peptide bond within the A2 domain. This cleavage requires tensile force unfolding the A2 domain (shear stress-dependent). In TTP (immune or congenital ADAMTS13 deficiency), ultra-large VWF multimers (UL-VWF) — which are normally secreted from Weibel-Palade bodies as 'UL-VWF strings' — accumulate on endothelium and in plasma. UL-VWF has enhanced platelet-binding affinity via GPIbα (especially in high shear conditions in small vessels), causing spontaneous platelet agglutination, microvascular thrombi, MAHA, and thrombocytopenia.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.