A fine balance between fibrin generation and fibrin dissolution must be maintained in order to assure adequate hemostasis, while preventing thrombosis. An intricate fibrinolytic system is responsible for clot lysis. Recently, abnormalities of several components of this system resulting in thrombotic or hemorrhagic manifestations, have been identified in a small number of patients, supporting the physiological importance of the fibrinolytic system. The applicant proposes to examine individuals with idiopathic thrombosis for abnormalities of plasminogen, the key component of the fibrinolytic system. Over thirty patients with recurrent thrombosis or thrombosis occurring at a young age are now under investigation by the applicant. In addition to measurements of circulating plasminogen and plasmin inhibitor concentrationns, plasma-based chromogenic substrate assays are being utilized to assess plasminogen activation, catalytic activity of plasmin and the lysine binding capacity of plasminogen, as alterations of any of these could theoretically result in subphysiologic lysis. In preliminary studies we have identified five individuals with probable abnormalities. In patients with such findings, isolated plasminogen and/or plasminogen-depleted plasma will be examined utilizing a variety of biochemical techniques. Functional or structural defects in plasminogen will be defined. Investigations include electrophoretic studies of plasminogen, kinetics of its activation, analysis of kinetics of generated plasmin, and characterization of lysine binding by the plasminogen. The proposed studies will examine the participation of other plasma constituents in physiological fibrinolysis by identifying the basis for altered activity in those individuals where the isolated plasminogen is normal. Other groups of individuals, not overtly """"""""hypercoaguable"""""""" have been found to have alterations in fibrinolytic activity, e.g. women on combination oral contraceptives and patients in the period immediately following myocardial infarction. These two groups of patients will be studied in a similar manner to determine the basis for the variant plasminogen activity. Through these studies, the applicant hopes to clarify the role of plasminogen and associated components in the control of clot dissolution and maintenance of blood fluidity.
