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Aspirin and Aspirin Metabolites Inhibit Thrombin Activatable Fibrinolysis Inhibitor A Novel Mechanism To Explain the Profibrinolytic Effects Associated with Anti-Thrombotic Therapy



Aspirin and Aspirin Metabolites Inhibit Thrombin Activatable Fibrinolysis Inhibitor A Novel Mechanism To Explain the Profibrinolytic Effects Associated with Anti-Thrombotic Therapy



Blood 100(11): Abstract No 2771, November 16



The anti-thrombotic effect of aspirin (acetylsalicylic acid (ASA)) has long been recognized, and low doses of ASA are recommended for the prevention of ischemic events in patients with coronary artery disease (CAD). ASA was shown to significantly reduce both the occurrence of myocardial infarction and mortality rate in patients with unstable angina pectoris. The action of ASA as well as other non-steroidal anti-inflammatory drugs (NSAIDS) is thought to derive mostly from the selective and irreversible inhibitions of cyclooxygenases 1 and 2 (Cox 1 and 2) and thromboxane A2 (Tx-A2) synthesis at the platelet-vessel wall. However, the anti-platelet activity does not account all the biological effects associated with ASA therapy. Thrombin Activatable Fibrinolysis Inhibitor (TAFI), also called plasma procarboxypeptidase B or U, regulates the balance between fibrinolysis and coagulation. Activated TAFI(TAFIa) modulates fibrinolysis by removing C-ter arginine and lysine residues from partially degraded fibrin, which inhibits the binding of plasminogen to fibrin clots resulting in reduced rate of fibrinolysis. Changes in plasma TAFI levels have been reported in various pathological conditions including coronary artery disease, deep vein thrombosis, hemophilia, cancer, and liver disease. Inhibition of the TAFIa has been shown to modulate fibrinolysis in vivo and alter the hemostatic balance towards a profibrinolytic state. Here, we investigated whether aspirin and other NSAIDS including ibuprofen and acetaminophen can effect fibrinolysis through inhibition of TAFI. TAFI activity was measured using ActiFLUOR TAFI (874FX, American Diagnostica Inc.), a sensitive fluorometric in vitro assay. Aspirin and its two major metabolites salicylic acid (SA) and salicyluric acid (SU) was found to inhibit TAFI carboxypeptidase activity. SU was the most potent inhibitor (IC50= 1mM) of the salicilates. The concentrations of ASA, SA and SU required to inhibit TAFIa activity in vitro are consistent with plasma concentrations achieved following administration therapeutic doses of aspirin. Acetaminophen had a weak inhibitory effect on TAFI activity but ibuprofen did not inhibitory TAFI. Inhibition by ASA, SA and SU was specific for TAFI as none of the drugs inhibited plasma carboxypeptidase N. Additionally, the aspirin metabolites SU and to a lesser extent SA also blocked the activation of TAFI to TAFIa by thrombin/thrombomodulin complex. Thus, ASA administration may prevent TAFI function through blocking activation of TAFI and/or by direct inhibition of TAFIa activity. In summary, inhibition of TAFI represents a novel mechanism of action for ASA and may explain the enhanced fibrinolytic activity associated in plasma during ASA therapy. The important beneficial effects of ASA therapy in cardiovascular disease may be explained by a synergism between enhanced fibrinolysis due to inhibition of TAFI and the anti-thrombotic activity due to inhibition of COX enzymes. The hemorrhagic complications associated with aspirin therapy may also be enhanced by more rapid clot dissolution due to inhibition of TAFI. These results also suggest anti-inflammatory and anti-thrombotic drugs should be screened for anti-TAFI activity in order to fully assess the full therapeutic consequences of drug treatment.

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Accession: 034443601

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