AUTOIMMUNE MECHANISMS OF THROMBOSIS

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DESCRIPTION (provided by applicant): The Antiphospholipid Syndrome (APS) represents an interface between the immune system and blood coagulation. In APS, an abnormal immune response leads to the production of autoantibodies with an apparent specificity for anionic phospholipids. These autoantibodies are strongly associated with both arterial and venous thrombosis. New insights into the pathophysiology of APS have been provided by the discovery that most of the autoantibodies associated with the syndrome are directed against a number of phospholipid-binding plasma proteins, such as beta2-glycoprotein I (beta2GPI), rather than phospholipids alone. A growing body of evidence supports the view that autoantibodies directly contribute to the thrombotic diathesis in APS. Recent data suggest that an important mechanism of autoantibody-mediated thrombosis is upregulation of the tissue factor (TF) pathway, the physiological trigger of normal coagulation and an important trigger in thrombosis. These observations lead us to hypothesize that increased TF activity on blood monocytes is an important cause of hypercoagulability in APS. This hypothesis will be tested through the following specific aims. Aim 1 is to identify and characterize the particular autoantibodies that increase TF activity on normal monocytes in vitro, focusing on anti-beta2GPI autoantibodies and autoantibodies to tissue factor pathway inhibitor (TFPI), a critical inhibitor of both factor VIIa/TF and factor Xa. Whole blood TF activity in APS patients will be measured to determine if certain autoantibodies are associated with increased TF on circulating monocytes in vivo. Aims 2 and 3 will determine the general mechanisms by which autoantibodies increase monocyte TF activity. Aim 2 is to determine the effects of antibodies on a) the quantitative expression of TF mRNA and protein and b) the qualitative functional status of TF molecules on the monocyte surface. Experiments in this aim will also examine whether certain pharmacological agents that block monocyte TF expression in response to other stimuli are also capable of inhibiting monocyte TF expression induced by APS autoantibodies. Aim 3 is to determine whether autoantibodies enhance TF activity by blocking the effects of TFPI. Together, the proposed experiments will identify autoantibodies capable of inducing monocyte TF activity and the general mechanisms that are involved. These data will be useful in focusing future research efforts on specific pathways of antibody-mediated monocyte activation and hypercoagulability and in designing new therapeutic strategies.