Thrombotic microangiopathies: new insights and new challenges

Abstract

Thrombotic microangiopathies (TMAs) manifest as a spectrum of related disorders in the form of thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). New data on both diseases support more and more the relatedness of the disorders and reveal related pathomechanisms, which, however, manifest in different organs. TTP develops primarily at neurological sites, and also in the kidney, and HUS is a kidney disease. In TTP thrombi formation occurs subsequently to the release of multimers of von Willebrand factor (vWF), and in HUS endothelial cell damage is considered the reason for complement and platelet activation leading to thrombus formation. Genetic mutations are associated with both disorders: in TTP the ADAMTS13 gene, the vWF cleaving protease, is affected, and in HUS several complement genes are mutated. In addition autoimmune forms, with acquired, de-novo generated inhibitors in the form of autoantibodies exist for both disorders, affecting ADAMTS13 in TTP or the central complement inhibitor factor H in HUS. In HUS autoantibodies can develop in the context of a specific mostly homozygous chromosomal deletion that represents a new subform of the disease, which is termed DEAP-HUS (deficient for CFHR proteins and autoantibody positive HUS). As the underlying disease mechanisms of TMA are now being better understood new options for a more precise diagnosis, improved therapy and prognosis for kidney transplantation become available for the benefit of patients. Here we summarize the recent developments in this rapidly progressing field.