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 inc
reased concentrations of thrombolytics as well as with adjunctive antithrom
botic and antiplatelet agents. A novel approach to enhance thrombolytic the
rapy 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 effica
cy of tissue-plasminogen activator (tPA) alone or with an inhibitor, isolat
ed from the potato tuber (PTI), of activated TAFI (TAFIa). Efficacy was ass
essed by determining the time to patency, the time the vessel remained pate
nt, the maximal blood flow achieved during therapy, the percentage of the o
riginal thrombus, which lysed, the percentage change in clot weight, the ne
t clot accreted, and the release of radioactive fibrin degradation products
into the circulation. The results indicate that coadministration of PTI an
d tPA significantly improved tPA-induced thrombolysis without adversely aff
ecting blood pressure, activated partial thromboplastin time, thrombin clot
ting time, fibrinogen, or alpha-2-antiplasmin concentrations, The data indi
cate that inhibitors of TAFIa may comprise novel and very effective adjunct
s to tPA and improve thrombolytic therapy to achieve both clot lysis and ve
ssel patency. (C) 1999 by The American Society of Hematology.