Microangiopathies: HUS/TPP. Physiopathologic aspects.

In thrombotic thrombocytopenic purpura (TTP) and in the hemolytic uremic sy ndrome (HUS) fibrin-platelet thrombi occlude arterioles and capillaries. Th e mechanism of endothelial cell injury and the mechanism of thrombosis are the most important physiopathological events in this pathology and are larg ely unknown. In HUS due to the Shiga toxin, the lesion of the endothelial c ells is due to penetration of the toxin into the cell via the Gb3 receptor. Endothelial cell death is a consequence of altered protein synthesis at th e ribosomal level: Cytokines released during the inflammatory process, poss ibly enhance the endothelial damage. Genetic and immunologic predisposing f actors for the development of HUS have also been postulated. in idiopathic, secondary and familial HUS/TTP the mechanism of endothelial lesion is unkn own, but multiple responsible factors have been advocated such as infection s, drugs, pregnancy, autoantibodies, apoptosis inducing molecules, etc. and other genetic, hormonal or immunologic predisposing factors may also be in volved. Factor H deficiency has been blamed in familiar cases. The most imp ortant cause of microcirculation thrombosis is the thrombogenic capacity of endothelial cell "activation" or injury induced by multiple mechanisms. Th e predominant source of plasma vW factor multimers is apparent in the alter ed endothelial cell. The unusually large vWF multimers are more effective a t binding to platelet glycoprotein Ib-IX and IIb-IIIa complexes and inducin g aggregation, as also occurred with the low weight multimers formed with e xcessive proteolysis, as described in the acute phase of HUS/TTP. The recen t report of congenital deficiency of a vWF protease in familial TTP and its functional inhibition by autoantibodies in acquired cases is characteristi c of TTP. This protease inhibition has never been described in HUS and migh t represent pathogenetic differences between TTP and HUS, and contribute to the differential diagnosis, but further confirmation of these findings is needed. We postulate that the abnormal cleavage of the vWF subunit, with fo rmation of different multimers with increased platelet aggregating capacity is an important mechanism to increase the microcirculatory thrombosis, but it is only a partial aspect in a more complex and unknown thrombogenic sti mulation secondary to the endothelial lesion or activation. Better knowledg e of the endothelial physiology and the genetic polymorphism of the endothe lial cell, the clonation of VWF-cleavage protease, etc., will provide valua ble tools for the understanding of these fascinating entities.