Molecular basis of ADAMTS13 dysfunction in thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathic disorder characterized by thrombocytopenia, hemolytic anemia, neurological and renal manifestations, and fever. It is associated with dysfunctional von Willebrand factor (VWF) proteolysis and the occurrence of VWF- and platelet-rich thrombi in the microcirculation of multiple organs, including the kidneys. Von Willebrand factor is a large glycoprotein that circulates in plasma as a series of multimers, and it plays a major role in primary hemostasis by inducing the formation of platelet plugs at sites of vascular injury and high-shear stress. Its activity is dependent on the sizes of the multimers, with ultra-large (UL) VWF multimers being biologically very potent. The ULVWF multimers are rapidly degraded upon their secretion from endothelial cells in normal individuals but not in the circulation of TTP patients, causing the formation of disseminated thrombi in the latter. The defective breakdown of VWF is attributed to a severely deficient activity of the VWF-cleaving protease ADAMTS13, a plasma metalloprotease synthesized in the liver, kidneys, and endothelium. This protease rapidly degrades VWF-platelet strings under flow by proteolytic cleavage of the VWF subunit, thereby regulating the size of the platelet thrombus. Congenital TTP occurs due to ADAMTS13 mutations, with the usual debut occurring during the first years of life, while acquired TTP is associated with auto-antibodies against ADAMTS13.