We have found that the membrane requirements of the APC anti- coagulant complex differ markedly from those of the pro-coagulant complexes, These requirements mimic those of at least a population of autoantibodies found in thrombotic patients, providing both specificity and a link between the APC pathway, lupus anti-coagulant/anti- phospholipid antibodies and thrombosis. More recently, we have observed that phospholipid oxidation further enhances APC activity selectively. Oxidation is considered a central feature of many inflammatory diseases including lupus and cardiovascular disease. It is the goal of this application to determine the relationship between the different membrane structural requirements of the pro-thrombinase and APC complexes with an emphasis on the role of oxidation in these reaction. We will determine whether currently unknown plasma factors are involved in the oxidation, what the active products are and whether any modification to the proteins of the APC complex occur as a result of this oxidation. The lipophilic anti-oxidant, alpha-tocopherol is regarded as protective against oxidative damage in various diseases, including heart disease. We will determine whether incorporation of tocopherol derivatives in membranes differentially affects the pro- and anti- coagulant reactions which may have direct protective effects against thrombus formation. Patients have been identified whose immunoglobulin inhibits only the oxidation dependent anti-coagulant APC activity, while others inhibit the oxidation dependent and independent activity equivalently. It is not known whether these represent different risk groups. Immunoglobulin from thrombotic patients recruited during the first grant period will be screened for the prevalence of anti- APC activity and the binding specificities determined. A chimeric form of protein C whose membrane requirements more closely resemble those of the pro-coagulant complexes will also be used in these studies. We will attempt to correlate APC inhibition and binding patterns with the risk of rethrombosis in the study population to determine whether such classification is useful in the identification of pro-thrombotic antibodies for the diagnosis and/or treatment of thrombosis.
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