Renal and hepatic handling of endogenous tissue-type plasminogen activator (t-PA) and its inhibitor in man

In eight male patients with normal liver and kidney function fibrinolytic components were measured in arterial blood and in renal and hepatic vein blood, obtained during catheterization for analysis of hypertension. Blood samples were collected simultaneously from veins und corresponding arteries before and 5 minutes after the completion of intravenous injection of desmopressin (DDAVP), 0.4 μg/kg body weight over a 10 minute period. DDAVP induced a rise in t-PA antigen and activity, and in von Willebrand factor, accompanied by a decrease in free PA-inhibitor level. We failed to detect a significant rise in plasma urokinase activity. The concentrations of fibrinogen, plasminogen, α2-antiplasmin, antithrombin III and coeruloplasmin did not change either. Renal production of t-PA under basal conditions was inferred from a negative arterio-venous (A-V) difference in t-PA-activity and in t-PA-antigen levels but this could not be confirmed by orthogonal regression analysis of the same data. A-V differences of other fibrinolytic factors were negligible. In the hepatic vessels a significant positive A-V difference of t-PA-activity and of t-PA-antigen levels was a uniform finding. After DDAVP, when plasma levels were elevated, the mean A-V difference was proportionally higher, consistent with a constant fractional elimination rate. Free PA-inhibitor was virtually absent from arterial blood after DDAVP, but appeared in hepatic vein blood, indicating either production of the inhibitor by the liver or dissociation of a circulating complex of t-PA and its inhibitor in the liver. The blood levels of the other investigated components did not show any change upon passage through the liver. Plotting of individual venous versus arterial levels of t-PA activity and of t-PA-antigen both before and after DDAVP injection yielded straight lines which in orthogonal regression analysis showed a slope significantly lower than unity; this was interpreted as net clearance of the activator. Clearance rate was not changed by DDAVP. Assuming a normal blood volume and hepatic blood flow in these subjects, the t 1/2 of the disappearance of endogenous plasminogen activator over the liver can be calculated: t-PA-activity: 3.1 min, t-PA-antigen: 4.1 min. Since these figures are close to those found by others for the half-disappearance time of t-PA from the entire circulation, it is concluded that t-PA is eliminated from the blood mainly by the liver. The t 1/2 of disappearance of endogenous, free PA-inhibitor is about 3 times longer, in our example 10.4 minutes. Chemicals/CAS: desmopressin, 16679-58-6; plasminogen activator inhibitor, 105844-41-5; tissue plasminogen activator, 105913-11-9; Blood Coagulation Factors; Desmopressin, 16679-58-6; Glycoproteins; Plasminogen Activators, EC 3.4.21.-; Plasminogen Inactivators; Tissue Plasminogen Activator, EC 3.4.21.68