Inactivation of plasminogen activator inhibitor type 1 by activated factor XII plays a role in the enhancement of fibrinolysis by contact factors in-vitro.
OBJECTIVE
Several activated coagulation factors have been reported to enhance fibrinolysis by inactivating plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor. We analyzed the interaction between PAI-1 and the three serine proteases generated during contact activation of plasma, activated factor XII (FXIIa), FXIa, and kallikrein, and evaluated their effects on fibrinolysis in-vitro.


METHODS
Effects of kaolin on euglobulin clot lysis time (ECLT) and behavior of PAI-1 in factor-depleted plasma were analyzed.


RESULTS
The ECLT of pooled plasma obtained from normal volunteers (designated as 100%) was shortened to 62.1+/-3.1% by Ca(2+) (5 mM) and 29.9+/-3.1% by kaolin. Activated protein C reversed the ECLT shortened by Ca(2+)-supplementation (86.3+/-17.4%), but did not affect the ECLT shortened by kaolin (31.4+/-2.1%). Thus, in contrary to Ca(2+)-supplementation, kaolin appeared to shorten the ECLT by a mechanism independent of thrombin generation. In three kinds of contact factor-depleted plasma, kaolin did not shorten ECLT only in FXII-depleted plasma. PAI-1 was cleaved to its inactive form in the Ca(2+) as well as the kaolin-supplemented euglobulin fraction in normal plasma, the latter of which, however, was not observed in FXII-depleted plasma. Similarly, a high molecular weight complex between FXIIa and PAI-1, as well as a cleaved form of PAI-1, was observed in kaolin-supplemented normal plasma, but neither was found in kaolin-supplemented FXII-depleted plasma.


CONCLUSIONS
PAI-1 inactivation by FXIIa appears to be a mechanism by which contact phase coagulation factors enhance fibrinolysis independently of thrombin generation.
Tanaka
Aki
A
Department of Physiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Suzuki
Yuko
Y
Sugihara
Kazuhiro
K
Kanayama
Naohiro
N
Urano
Tetsumei
T
D001780:Blood Coagulation Tests; D003029:Coagulants / Q000276:immunology / Q000378:metabolism; D015956:Factor XIIa / Q000502:physiology*; D015945:Factor XIa / Q000502:physiology; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D007610:Kallikreins / Q000502:physiology; D007616:Kaolin / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000276:immunology / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D012712:Serum Globulins / Q000187:drug effects; D013917:Thrombin / Q000187:drug effects / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000276:immunology / Q000378:metabolism
D003029:Coagulants; D017395:Plasminogen Activator Inhibitor 1; D015849:Plasminogen Inactivators; D015842:Serine Proteinase Inhibitors; D012712:Serum Globulins; D007616:Kaolin; D007610:Kallikreins; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin; D014568:Urokinase-Type Plasminogen Activator