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Activated protein C attenuates coagulation‐associated over‐expression of fibrinolytic activity by suppressing the thrombin‐dependent inactivation of PAI‐1
Author(s) -
Urano T.,
Castellino F. J.,
Ihara H.,
Suzuki Y.,
Ohta M.,
Suzuki K.,
Mogami H.
Publication year - 2003
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1046/j.1538-7836.2003.00443.x
Subject(s) - thrombin , fibrinolysis , protein c , chemistry , plasminogen activator , coagulation , cleavage (geology) , biochemistry , activator (genetics) , microbiology and biotechnology , medicine , biology , endocrinology , immunology , gene , platelet , paleontology , fracture (geology)
Summary. Several activated coagulation factors have been reported to enhance fibrinolysis by neutralizing plasminogen activator inhibitor type 1 (PAI‐1) activity. We evaluated the physiological relevance of this mechanism using the euglobulin clot lysis time (ECLT) assay in the presence and absence of Ca 2+ , which is controlled by PAI‐1 and mimics physiological thrombolysis. We found that the ECLT (18.5 ± 0.6 h) was shortened by Ca 2+ (5 m m ) (6.6 ± 0.1 h). A significant difference was observed in thrombin generation by the presence of Ca 2+ in the euglobulin fraction. Prothrombin was almost fully converted to thrombin within 15 min in the presence of Ca 2+ , whereas essentially no conversion was observed without Ca 2+ . The presence of activated protein C (aPC) suppressed thrombin generation, and attenuated the shortening of ECLT in a dose‐dependent manner, an effect enhanced by phospholipid and protein S. In the absence of Ca 2+ , aPC did not prolong the ECLT. After addition of biotin‐labeled recombinant PAI‐1 to the euglobulin fraction, PAI‐1 was cleaved to lower molecular weight forms only in the presence of Ca 2+ . This cleavage did not occur in the presence of aPC, suggesting that thrombin was the catalyst for PAI‐1 cleavage. The cleavage and inactivation of PAI‐1 by generated thrombin is proposed to be responsible for the shortening of ECLT by Ca 2+ and for coagulation‐associated over‐expression of fibrinolysis. Under such conditions, aPC appeared to suppress thrombin generation and to normalize highly activated fibrinolysis.