A patient with thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal failure, and neurological symptoms is diagnosed with thrombotic thrombocytopenic purpura (TTP). The molecular defect in acquired TTP and its direct pathophysiological consequence is:

• A Complement dysregulation via anti-factor H antibodies leads to uncontrolled C5b-9 assembly on endothelial surfaces causing endothelial damage and platelet consumption
• B Shiga toxin-mediated endothelial injury triggers platelet thrombus formation in the renal microvasculature via direct GP1b binding
• C Acquired IgG autoantibodies inhibit ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs-13), causing accumulation of ultralarge vWF multimers that spontaneously capture and aggregate platelets in the microvasculature ✓
• D Heparin-induced thrombocytopenia (HIT) with anti-PF4 antibodies activating platelets via FcgammaRIIA receptors

Explanation

TTP is caused by severe deficiency (<10% activity) of ADAMTS13, a metalloprotease that cleaves ultralarge von Willebrand factor (ULvWF) multimers secreted from endothelial Weibel-Palade bodies into smaller, less adhesive fragments. In acquired TTP, IgG autoantibodies (typically IgG4) directed against the spacer domain of ADAMTS13 inhibit its cleavage activity, causing ULvWF multimer accumulation. These ULvWF strings spontaneously capture platelets via GpIb-IX-V interactions, forming platelet-rich microthrombi in small vessels — causing the pentad of MAHA, thrombocytopenia, neurological dysfunction, renal impairment, and fever. Complement dysregulation with anti-factor H antibodies causes atypical HUS, not TTP. Shiga toxin causes typical HUS (STEC-HUS). HIT involves PF4-heparin complexes.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.