The genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura

Abstract

In recent years there has been a substantial increase in the understanding of the genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. In diarrhoeal associated haemolytic uraemic syndrome it has been established that the virulence of Escherichia coli O157 is related to intimin adhesion and the transport of verocytotoxin on polymorphonuclear cells. It has been shown that early changes in the coagulation pathway predate the onset of diarrhoeal haemolytic uraemic syndrome. Mutations in factor H, a fluid-phase regulator of the alternative complement pathway, have been identified in 10-20% of patients with both familial and sporadic (non-diarrhoeal-associated) haemolytic uraemic syndrome. The mutations mainly cluster in the C terminal part of factor H, a region that is important for both binding to C3b and also polyanionic structures on cell surfaces. The identification of antibodies against a plasma metalloproteinase responsible for cleaving ultralarge von Willebrand factor multimers in thrombotic thrombocytopenic purpura has been followed by the elucidation of the identity of the proteinase. It has been shown to be a member of the ADAMTS family, and mutations have been identified in the gene in families with inherited thrombotic thrombocytopenic purpura. The molecular pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura is an exciting and rapidly evolving field. These recent advances will lead to logical, targetted changes in the management of these conditions.