FIBRIN AND FIBRINOLYSIS IN THROMBOTIC DISEASE

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Project 5 deals with translational research of laboratory observations to the patient, specifically regarding soluble fibrin (SF) measurements in vitro and in patients with hypercoagulable states and novel fibrinolytic and thromboprophylactic treatments. Aim 1 "to asses the in vitro foundation and the diagnostic and prognostic validity of soluble of fibrin measurement in acute and chronic pro-thrombotic states" includes three distinct sections. The first deals with the reactive of derivatives of fibrinogen and fibrin induced and fibrin induced by thrombin, factor XIIIa and plasmin, especially SF, using specific immunologic and functional approaches. The second utilizes this information to acute hypercoagulable syndromes (DIC) in patients with acute sepsis or with multi-trauma and in volunteers receiving endotoxin infusion. In the third part, the prognostic importance of SF will be assessed in patients with chronic hypercoagulable states, including those with breast malignancy who are prone to develop DVT and those with acute MI who are predisposed to recurrent MI or coronary death. Aim 2 "to critically evaluate new thromboprophylactic and fibrinolytic therapies" includes three randomized trials. The first extends our observations on central venous catheter thrombi to a clinical trial of low-dose warfarin prophylaxis. Fibrinolytic studies evaluate plasminogen amplification of UK therapy for peripheral arterial occlusion (PAO) and catheter-delivery of UK for DVT in comparison with UK administered intravenously. Some studies are well underway (plasminogen supplementation of UK for PAO), others have been recently initiated (SF structural investigations, prophylaxis of central venous catheter thrombosis, SF studies in patients with DIC, prognostic value of SF for recurrent coronary artery events, and SF as a marker of hypercoagulability in breast malignancy), and one study is in the pilot phase, with plans to initiate a prospective study (catheter versus IV administration of UK for DVT). These translational studies will critically evaluate the role of SF as a diagnostic and prognostic marker for microvascular, arterial and venous thrombotic disease and apply our prior observations to effective prevention of DVT associated with catheters and to thrombolytic management of PAO and DVT.