RELEASABLE PLATELET PLASMINOGEN ACTIVATOR-INHIBITOR

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Venous thrombo-embolism and deep vein thrombophlebitis are major causes of post-surgical morbidity and mortality. For a variety of reasons, history and physical exam, intravenous phlebography, and I-125 iodine uptake are either not reliable enough or have too much risk-associated invasiveness to be used in the screening for DVT, especially in equivocal situations. Nor are there well-identified, specific risk factors one can determine as predisposing the surgical patient toward developing thrombotic complications. The long-term objectives of this study are to determine the possible roles of releasable platelet plasminogen activator-inhibitor (PA-inhibitor) in the post-surgical development of thrombosis and to develop a functional assay for the PA-inhibitor which could be used to follow the post-surgical changes in plasma PA-inhibitor levels. Specific aims toward meeting these objectives are to: 1) purify in a native form the releasable platelet PA-inhibitor using lectin affinity and HPLC column chromatography; 2) characterize the interaction of this purified PA-inhibitor with other platelet releasate proteins such as fibrinogen or thrombospondin by imunoprecipitation and SDS-gel electrophoresis and determine whether these interactions are important in modifying the kinetics of inhibition of plasminogen activators and/or activated protein C; and, 3) develop a functional assay of plasma PA-inhibitor levels based on ELISA plates coated with urokinase in place of antibodies and to use this assay to follow the post-surgical kinetics of PA-inhibitor levels. The results from this studies could provide the basis for a more extensive application to correlate elevated functional PA-inhibitor levels with post-surgical deep vein thrombosis.