A novel approach to arterial thrombolysis.
Achieving early, complete, and sustained reperfusion after acute myocardial infarction does not occur in approximately 50% of patients, even with the most potent established thrombolytic therapy. Bleeding is observed with increased concentrations of thrombolytics as well as with adjunctive antithrombotic and antiplatelet agents. A novel approach to enhance thrombolytic therapy is to inhibit the activated form of thrombin-activatable fibrinolysis inhibitor (TAFI), which attenuates fibrinolysis in clots formed from human plasma. Identification of TAFI in rabbit plasma facilitated the development of a rabbit arterial thrombolysis model to compare the thrombolytic efficacy of tissue-plasminogen activator (tPA) alone or with an inhibitor, isolated from the potato tuber (PTI), of activated TAFI (TAFIa). Efficacy was assessed by determining the time to patency, the time the vessel remained patent, the maximal blood flow achieved during therapy, the percentage of the original thrombus, which lysed, the percentage change in clot weight, the net clot accreted, and the release of radioactive fibrin degradation products into the circulation. The results indicate that coadministration of PTI and tPA significantly improved tPA-induced thrombolysis without adversely affecting blood pressure, activated partial thromboplastin time, thrombin clotting time, fibrinogen, or alpha-2-antiplasmin concentrations. The data indicate that inhibitors of TAFIa may comprise novel and very effective adjuncts to tPA and improve thrombolytic therapy to achieve both clot lysis and vessel patency.
Klement
P
P
Hamilton Civic Hospitals Research Centre and McMaster University, Hamilton, Ontario, Canada.
Liao
P
P
Bajzar
L
L
D000818:Animals; D025901:Carboxypeptidase B2; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005337:Fibrin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology; D010314:Partial Thromboplastin Time; D010940:Plant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D013047:Specific Pathogen-Free Organisms; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
D010940:Plant Proteins; D011480:Protease Inhibitors; D005337:Fibrin; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2; D010959:Tissue Plasminogen Activator