The pathophysiology of thrombotic thrombocytopenic purpura

It has been hypothesised that thrombotic thrombocytopenic purpura (TTP) may be a disease of primary platelet aggregation mediated by the presence of ultra large von Willebrand factor (ULVWF) multimers. The principle aims of this thesis were to investigate platelet activation and VWF-cleaving protease activity in adult-onset and congenital TTP. There was evidence of significantly increased in vivo platelet activation in idiopathic TTP as detected by platelet degranulation using flow cytometric techniques. However other novel markers of platelet activation: platelet microparticles and platelet-leucocyte aggregates, were not elevated. This likely reflects the complex relationship between platelet activation and recruitment to areas of thrombus formation. Protease activity was significantly reduced at presentation of idiopathic TTP as compared to haemolytic uraemic syndrome (HUS) and healthy controls but was highly variable in secondary TTP. A significant positive correlation between clinical remission and recovery of protease activity was demonstrated in idiopathic TTP suggesting a pivotal pathogenic role for the latter. However persistently depressed activity did not preclude durable remission nor did it appear to confer an increased risk of relapse. Protease activity was uniformly significantly decreased in all congenital TTP samples despite variations in clinical severity. Correction studies were consistent with a constitutional deficiency. Unidentified factors may modulate phenotype since intrinsic protease activity of plasma products used in the management of congenital TTP correlated with clinical efficacy. In contrast, IgG with inhibitory protease activity was detected in some cases of idiopathic TTP both at presentation and in durable remission. The pathogenesis of TTP thus appears heterogeneous. Preliminary data is presented suggesting that this may explain in part the wide response to treatment seen in clinical practice. Since severe protease deficiency may not necessarily lead to clinical disease. it appears hitherto unidentified factors are also involved in the pathogenesis of TTP. Antiphospholipid antibodies were not implicated