Thrombotic thrombocytopenic purpura (TTP) is caused by deficiency of ADAMTS13, a metalloprotease. What is the substrate of ADAMTS13 and how does its deficiency lead to TTP?
- A ADAMTS13 degrades fibrinogen; deficiency causes hyperfibrinogenaemia leading to sludging of red cells
- B ADAMTS13 cleaves ultra-large von Willebrand factor (UL-vWF) multimers; deficiency allows UL-vWF to accumulate on endothelium, causing platelet microthrombi in small vessels ✓
- C ADAMTS13 cleaves thrombomodulin, preventing protein C activation and causing thrombophilia
- D ADAMTS13 inactivates tissue factor pathway inhibitor, leading to unregulated coagulation cascade
Explanation
ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) is a plasma metalloprotease that cleaves ultra-large vWF multimers at the Tyr1605-Met1606 bond in the A2 domain. UL-vWF multimers are secreted by activated endothelial cells and normally cleaved immediately; in ADAMTS13 deficiency (autoimmune inhibitor in acquired TTP, or mutations in congenital Upshaw-Schulman syndrome), UL-vWF accumulates on endothelium and captures platelets under high shear stress, forming platelet-rich thrombi in microvasculature causing the classic pentad of TTP.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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