[Thrombotic microangiopathies: HUS/TTP. Physiopathological aspects].
In thrombotic thrombocytopenic purpura (TTP) and in the hemolytic uremic syndrome (HUS) fibrin-platelet thrombi occlude arterioles and capillaries. The mechanism of endothelial cell injury and the mechanism of thrombosis are the most important physiopathological events in this pathology and are largely unknown. In HUS due to the Shiga toxin, the lesion of the endothelial cells 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 the ribosomal level. Cytokines released during the inflammatory process, possibly enhance the endothelial damage. Genetic and immunologic predisposing factors for the development of HUS have also been postulated. In idiopathic, secondary and familial HUS/TTP the mechanism of endothelial lesion is unknown, but multiple responsible factors have been advocated such as infections, drugs, pregnancy, autoantibodies, apoptosis inducing molecules, etc. and other genetic, hormonal or immunologic predisposing factors may also be involved. Factor H deficiency has been blamed in familiar cases. The most important cause of microcirculation thrombosis is the thrombogenic capacity of endothelial cell "activation" or injury induced by multiple mechanisms. The predominant source of plasma vW factor multimers is apparent in the altered endothelial cell. The unusually large vWF multimers are more effective at binding to platelet glycoprotein Ib-IX and IIb-IIIa complexes and inducing aggregation, as also occurred with the low weight multimers formed with excessive proteolysis, as described in the acute phase of HUS/TTP. The recent report of congenital deficiency of a vWF protease in familial TTP and its functional inhibition by autoantibodies in acquired cases is characteristic of TTP. This protease inhibition has never been described in HUS and might 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 formation 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 stimulation secondary to the endothelial lesion or activation. Better knowledge of the endothelial physiology and the genetic polymorphism of the endothelial cell, the clonation of vWF-cleavage protease, etc., will provide valuable tools for the understanding of these fascinating entities.
Sánchez Avalos
J C
JC
Departamento de Hematología, Hospital de Clínicas José de San Martín, Facultad de Medicina, Universidad de Buenos Aires. asanchez@roche.com.ar
D004730:Endothelium, Vascular / Q000503:physiopathology; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D008833:Microcirculation; D011697:Purpura, Thrombotic Thrombocytopenic / Q000209:etiology / Q000503:physiopathology*