Pathogenesis of Thrombotic Thrombocytopenic Purpura: ADAMTS13 Deficiency and Beyond

Abstract

Thrombotic thrombocytopenic purpura (TTP) is characterized by the systemic deposition of platelet thrombi with abundance of von Willebrand factor (vWF) in the arterioles and capillaries. Recently, vWF protease (ADAMTS13) activity was found to be severely deficient in hereditary TTP as well as acquired idiopathic TTP. Homozygous or compound heterozygous mutations of ADAMTS13 gene were demonstrated in hereditary TTP. Autoantibodies against ADAMTS13 were present in majority of patients with idiopathic TTP and ticlopidine- and clopidogrel-associated TTP. The deficiency of ADAMTS13 leaves unchecked the hyperadhesive vWF unfolded under high shear stress in the microvessels, resulting in the formation of platelet thrombi, which in turn causes TTP. ADAMTS13 activity is usually normal in hemolytic uremic syndrome. Approximately 0 to 67% of idiopathic TTP patients reported may not be severely deficient of ADAMTS13. Therefore, acquired TTP is not caused by ADAMTS13 deficiency alone and may be triggered by certain stimuli that possibly cause autoimmune reactivity to ADAMTS13, and also induce platelet aggregation either dependent on or independent of vWF, and/or vascular injury, to account for variable clinical and laboratory presentations. Plasma samples from TTP patients have been shown to induce endothelial cell apoptosis and activation. Platelet aggregating factors independent of vWF purified from the plasma of a subset of TTP patients have been reported and shown to be inhibited by normal plasma and immunoglobulin G purified from normal plasma. Defective fibrinolysis and abnormal natural coagulation inhibitors may enhance the thrombi formation in the microcirculation.

A second national questionnaire survey of TMA

“…This is further supported by our finding that the frequency of positivity for antinuclear antibodies was high in patients with ADAMTS13 TMA. In contrast, auto-antibodies against ADAMTS13 were rarely detected in patients with malignant diseases or infections, and those that were post-surgery or posttransplantation, all of which may cause TMA via vascular endothelial injuries and inflammation [23]. Neurological symptoms tended to be high in patients with ADAMTS13 TMA, and the frequency of renal dysfunction was high in those with other TMA, suggesting that ADAMTS13 TMA might be suitable for a typical TTP, while the other TMA might be suitable for typical HUS.…”

National questionnaire survey of TMA

“…Indeed, the frequency of positive antinuclear antibody was higher in ADAMTS13 TMA than in other TMA. While the detection of auto-antibodies for ADAMTS13 is rare in malignant diseases, post-operation, post-transplantation, infections etc., these conditions may cause TMA via vascular endothelial injuries and inflammation [20]. The frequency of several symptoms of TMA such as neurological symptoms, renal dysfunction, and fever were different in each type of TMA, but may depend on the sensitivity of diagnosis of TMA.…”

Elevated Von Willebrand factor propeptide for the diagnosis of thrombotic microangiopathy and for predicting a poor outcome

“…Severe infection often is associated with vascular endothelial cell injury and multiple organ failure. Auto-antibodies against ADAM-TS13 were rarely detected in patients with malignant diseases or infections, and in those that were post-surgery or post-transplantation, all of which may cause TMA via vascular endothelial injuries and inflammation [21,22].…”