| Summary: | 碩士 === 長庚大學 === 生物醫學研究所 === 105 === Clinical thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is associated with significant limitations, including resistance to recanalization, prolonged time to achieve reperfusion, acute thrombotic reocclusion in a high percentage of treated patients, and increased risks for bleeding. It has been hypothesized that conjunctive administration of antiplatelet or anticoagulant agents with rtPA could potentially enhance thrombolysis and prevent reocclusion. In this study, we examined the effects of conjunctive administration of Kinexins (Kunitz inhibitor-Annexin V fusion proteins) with rtPA on thrombolysis. Thromboelastometry indicated that both A-6L15 (an inhibitor of tissue factor/FVIIa) and TAP-A (an inhibitor of FXa and prothrombinase) exerted concentration-dependent (10 to 100 nM) effects on clot formation. At 100 nM, TAP-A and A-6L15 prolonged clotting time (CT) by 4- and 11-fold (n=9-17; p<0.05), increased clot formation time (CFT) by 4- and 16-fold (n=9-17; p<0.05), decreased α-angle by 22% and 71%, respectively. TAP-A reduced maximal clot firmness (MCF) by 43%; whereas A-6L15 did not alter MCF, suggesting that TAP-A several-fold more potent than A-6L15 in whole blood. Combination of A-6L15 or TAP-A with rtPA (1 μg/ml) led to decrease in lysis index, suggesting that A-6L15 or TAP-A enhanced rtPA-induced clot lysis. In a rat cremaster muscle model, photochemical injury by rose bengal plus laser irradiation reduced tissue blood flow to ~20% of basal level within 15 min which remained at this level for 55 min as measured with laser speckle contrast imaging. Administration of rtPA or TAP-A alone during induction of injury delayed the decrease of blood flow and restored the flow from ~20% to 30-35%; conjunctive administration of TAP-A with rtPA further restored the blood flow to 56%. In conclusion, the results suggested that conjunctive administration of A-6L15 or TAP-A with rtPA enhanced thrombolysis and suppressed re-thrombosis. A-6L15 and TAP-A were potentially useful adjunctive agents for rtPA thrombolytic therapy.
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