vWF metalloprotease
Summary
vWF metalloprotease, also known as ADAMTS13, cleaves large von Willebrand factor (vWF) multimers into smaller, less active forms. Deficiency or inhibition of ADAMTS13 leads to accumulation of ultra-large vWF multimers, causing excessive platelet aggregation and microthrombi formation, classically seen in thrombotic thrombocytopenic purpura (TTP).
Detail
ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13) is a plasma metalloprotease synthesized primarily by hepatic stellate cells. Its main function is to cleave ultra-large von Willebrand factor (ULvWF) multimers released from endothelial cells into smaller, functionally less adhesive multimers, thereby regulating platelet adhesion and aggregation. Deficiency of ADAMTS13 activity—either due to inherited mutations (Upshaw-Schulman syndrome) or acquired autoantibodies against ADAMTS13 (most common cause)—results in persistence of ULvWF multimers. These multimers spontaneously bind platelets, causing widespread microvascular platelet thrombi, leading to the clinical syndrome of thrombotic thrombocytopenic purpura (TTP). TTP classically presents with the pentad: fever, microangiopathic hemolytic anemia (schistocytes on peripheral smear), thrombocytopenia, renal dysfunction, and neurologic symptoms, though all five features are not always present. Diagnosis is supported by markedly reduced ADAMTS13 activity (<10%) and presence of inhibitory autoantibodies in acquired cases. Treatment involves plasma exchange (to remove autoantibodies and replenish ADAMTS13) and immunosuppression (e.g., corticosteroids, rituximab) for autoimmune TTP. This contrasts with hemolytic uremic syndrome (HUS), which is caused by Shiga toxin-mediated endothelial damage and has normal ADAMTS13 activity, important for distinguishing the two thrombotic microangiopathies on exams.
Sources
- First Aid for the USMLE Step 1 (2023)
- Robbins and Cotran Pathologic Basis of Disease, 10th ed.
- UpToDate: Thrombotic Thrombocytopenic Purpura
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