A kinetic analysis of fibrinogenolysis during plasminogen activator therapy

A mathematic model of the systemic fibrinogenolysis that accompanies coronary thrombolysis with recombinant tissue plasminogen activator (rt-PA) has been devised. The kinetic parameters of the model were estimated by nonlinear regression analysis with data from a clinical trial of rt-PA. The plasma elimination rate constant for rt-PA was estimated to be 10.0 hr-1, the second-order catalytic rate constant for the in vivo rt-PA-mediated conversion of plasminogen to plasmin 0.0078 (microgram rt-PA/kg body weight)-1 hr-1, the plasma elimination rate constant for plasmin 2.33 hr-1, and the second-order catalytic rate constant for the in vivo plasmin-catalyzed degradation of fibrinogen 0.466 (mg plasmin/dl)-1 hr-1. Computer simulation studies based on these parameter estimates show that the magnitude of fibrinogenolysis induced by rt-PA is related to the dose in a curvilinear fashion, showing diminishing increments in the effect at increasing doses. The degree of fibrinogenolysis induced by rt-PA administration is nearly independent of the dosing schedule.