Thrombotic microangiopathies: from animal models to human disease and cure

Abstract

Thrombotic microangiopathies are a group of microvascular disorders, with reduced organ perfusion and hemolytic anemia. The two most relevant conditions characterized by thrombotic microangiopathic anemia (TMA) are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). In TTP, systemic microvascular aggregation of platelets causes ischemia in the brain and other organs. In HUS, platelet-fibrin thrombi predominantly occlude the renal circulation. TTP can be inherited due to deficiencies in the activity of von Willebrand factor cleaving protease (ADAMTS13) or acquired due to the presence of autoantibodies directed against ADAMTS13. The majority of HUS cases are secondary to infections by strains of Escherichia coli that produce Shiga-like toxins (Stx-HUS), while about 5- 10% of all cases are classified as atypical HUS (aHUS). Genetically derived impaired regulation of the complement system is associated with aHUS. Infusion or the exchange of fresh frozen plasma have ameliorated the prognosis of TMA; however, no specific therapies aimed at preventing or limiting the microangiopathic process have been proven to affect the course of TMA. Large mammals, small animal models, knockout and transgenic mouse models of TTP and both Stx-HUS and aHUS have been developed and have provided outstanding contributions to nearly all areas of TMA research. A better understanding of the key clinical features of the diseases and of the importance of genetic and/or environmental factors involved in the pathogenesis of the diseases have been obtained. These animal models have also allowed the set up of protocols aimed at ameliorating the clinical approach to patients and for the development of new drugs and vaccines.