The acquired immunodeficiency syndrome frequently manifests abnormalities of hemostasis. Of obscure etiology, they include i) significant, sustained thrombocytopenia, ii) prolongation in vitro of clotting via the intrinsic pathway, and iii) irregularities of individual factors. Some may follow opportunistic infection, but the correlation is not absolute. In advanced disease, syndromes that resemble DIC or liver failure and deplete the clotting factors overall may be superimposed on the already compromised patient and cause life-threatening bleeding. This proposal seeks to dissect out the mechanisms that lead to the defects and to establish any links between them. In part, this entails the systematic collection over long periods, by standard coagulation screening tests, of data that describe the onset and development of each clotting defect during progression from the AIDS-related complex to AIDS itself. In addition, sensitive immunochemical and radiochemical methods will be used to look for evidence of platelet abnormalities, thrombin generation, activation of factor VIII and activation of factor VII (by factor Xa), hallmarks of low levels of stimulation in vivo, and to trace any fluctuations in individual factors by both immunological and functional activity. We will also test the hypothesis that stimulation results in part from the expression of tissue factor and proteases by monocytes, either themselves infected with HIV or responding to stimulation by other infected cells. Regarding mechanisms of thrombocytopenia, the hypothesis is advanced that the platelets of patients with AIDs are coated both specifically and non- specifically (via their Fc receptors) by IgG and IgM antibodies of the """"""""lupus-anticoagulant"""""""" type, after exposure of membrane phospholipid epitopes not usually available on resting cells. The nature and source of the original antigen (platelet or otherwise) will be probed with monoclonal antibodies from human hybridomas in which one fusion partner is the B cell population from selected patients at different stages of their disease. The role of these epitopes on endothelial cells, where there exists a possible mechanisms of thrombogenesis in which the lipid-dependent activation of protein C is prevented, will also be examined. The project is undertaken with a view to developing more rational means of allaying the hemostatic disorders in AIDs, to introducing better diagnostic methods for platelet-associated antibody, and to understanding the impact of a profound immune disorder on the coagulation system.
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