EFFICACY OF LOCAL INHIBITION OF PROCOAGULANT ACTIVITY ASSOCIATED WITHSMALL-DIAMETER PROSTHETIC VASCULAR GRAFTS

Purpose: Graft procoagulant activity is determined by thrombin (IIa) a nd activated factor X (Xa) that binds to thrombus. Thrombus-associated factor Xa and thrombin are resistant to antithrombin III-dependent th erapy (heparin). To avoid complications and costs associated with syst emic administration, we evaluated whether locally applied antithrombot ic agents inhibit prosthetic graft procoagulant activity under no-flow and low-flow conditions. Methods: Four-millimeter-diameter collagen-c oated grafts were preclotted in recalcified human plasma, washed, imme rsed in antithrombotic agents (either 100 nm hirudin, 20 mu m D-Phe-L- Pro-L-Arg chloromethylketone, 5 mu m tick anticoagulant peptide or 5 o r 10 mu g/ml tissue factor pathway inhibitor) or saline solution, and extensively rewashed. Grafts were exposed to recalcified plasma either in multiwell plates or underwent perfusion at 1 ml/min flow rate. Fib rinopeptide A, which reflects fibrin elaboration, was measured as a ma rker of thrombin activity. Results: Inhibitors reduced fibrinopeptide generation at 8 minutes by 55% (tissue factor pathway inhibitor), 57% (hirudin), or 63% (tick anticoagulant peptide and D-Phe-L-Pro-L-Argchl oromethylketone) compared with the control agents (p < 0.05). Under lo w-flow conditions tissue factor pathway inhibitor and hirudin reduced fibrinopeptide generation at 13 minutes by 61% and 49%, respectively, when compared with control agents (p < 0.05). Conclusions: Graft-assoc iated inhibitors targeted at factors IIa, Xa, or tissue factor/VIIa/Xa complex effectively reduce procoagulant activity on prosthetic grafts . The success of local application of antithrombotic agents in attenua ting; early fibrin formation suggests that this strategy could favorab ly influence acute graft patency, and me speculate these agents may im prove long-term graft patency as well.