The hypothesis guiding this study is that microvascular endothelial cell (MVEC) apoptosis plays a key role in the pathophysiology of idiopathic and HIV-associated thrombotic thrombocytopenic purpura (TTP). It is also proposed that apoptosis is initiated by plasma factors up regulated in HIV and certain other infections, particularly soluble tumor necrosis factor-related ligand (TRAIL). It is furthermore proposed that these factors lead to alterations in MVEC-extracellular matrix (ECM) interactions and production of cytokines and vasoactive substances such as nitric oxide, all critical to MVEC survival. These concepts are supported by observations that: plasmas from HIV+ and HIV- patients with idiopathic and ticlopidine-linked TTP induce apoptosis in restricted lineages of MVEC, paralleling the EC tissue restriction of TTP lesions in vivo; plasma from patients with TTP or hemolytic-uremic syndromes related to cancer, marrow transplantation or other drugs, diseases distinct pathologically from idiopathic TTP, do not have these effects in vitro; apoptotic MVEC are present in splenic and marrow biopsies of idiopathic, HIV, and ticlopidine-linked TTP, accompanied by down regulation of ECM; and ticlopidine and HIV can directly affect ECM deposition and/or production. An additional recent finding is that MVEC-soluble HIV gp120-monocyte interactions up regulate TRAIL, TRAIL receptors, capsases 1 and 3, and suppress bcl-2-related molecules. Up regulation of bcl-2, anti-TRAIL antibody, or over expression of TRAIL decoys blocked TTP plasma-mediated apoptosis. The underlying hypothesis provides a basis for the clinical efficacy of anti-apoptotic agents and the nitric oxide precursor L-arginine in pilot trials for refractory TTP. The model presented could also enable exploration of new therapeutic modalities for TTP, based upon modulation of specific apoptotic pathways.
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