HYDROLYTIC ENZYMES OF BLOOD IN HEALTH AND DISEASE

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To explore interrelated functions of hemostatic, kinin-releasing and complement systems in plasma we will examine certain functions of: 1) the serum inhibitor of the activated first component of complement (Cl-Inhibitor), 2) high molecular weight kininogen (HMW-K), 3) Hageman factor and fragments cleaved from Hageman factor (HFf) in the following approaches: 1) The capacity of dysmorphic C1-Inhibitor proteins isolated from plasma of certain persons with hereditary angioneurotic edema to inhibit activated Hageman factor, plasma kallikrein, and plasmin will be tested. Normal C1-Inhibitor blocks these hemostatic enzymes, as well as Cl, but dysmorphic C1-Inhibitors do not inhibit C1. Fragments released from normal and dysmorphic C1-Inhibitors during cyanogen bromide cleavage will be compared as to their inhibitory and binding properties with respect to each enzyme. 2) Monoclonal antibody to light chain of HMW-K will be prepared, fluorescinated and used to locate HMW-K in tissues and cells of blood and endothelial cells. The effect of anti-HMW-K upon platelet functions will be tested, if HMW-K is present on platelet membranes. Anti-HMW-K will be tested for its effect on directed mobility of polymorphonuclear cells in a modified Boyden Chamber. If HMW-K is found on endothelial cells, the possibility that it may affect the morphology of these cells, or play a role in the release of coagulant activity from the cells will be examined. 3) With antibody to Hageman factor fragments (HFf), we will examine plasma from individuals susceptible to thromboembolism, as well as normal persons, to see if HFf in plasma may be associated with a thromboembolic tendency. The possibility that the initial step in the activation of Hageman factor may involve non-enzymatic cleavage of an internal thioester bond in the single-chain Hageman factor molecule will be examined.