Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents.
3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration-dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl-glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2-antiplasmin and Cl inhibitor.
D001777:Blood Coagulation; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism*; D005174:Factor XII / Q000037:antagonists & inhibitors; D005337:Fibrin / Q000037:antagonists & inhibitors; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005439:Flufenamic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D012995:Solubility; D000979:alpha-2-Antiplasmin / Q000378:metabolism*
D003174:Complement C1 Inactivator Proteins; D005343:Fibrinolytic Agents; D011412:Propanolamines; D000979:alpha-2-Antiplasmin; C017315:flufenamic acid hydroxypropylamide; D005439:Flufenamic Acid; D005174:Factor XII; D005337:Fibrin; D010958:Plasminogen; D007610:Kallikreins; D005341:Fibrinolysin