Short-term intravenous eptifibatide infusion combined with reduced dose recombinant tissue plasminogen activator inhibits platelet recruitment at sites of coronary artery injury.

OBJECTIVES: This study was designed to determine in a dog model of coronary thrombosis whether short-term eptifibatide (Ep) combined with low-dose plasminogen activator (rt-PA) inhibits platelet recruitment at sites of endothelial damage after normalization of platelet function. BACKGROUND: Ep plus reduced-dose rt-PA has not previously been shown to render a recanalized coronary artery resistant to platelet recruitment after normalization of platelet function. METHOD: Inhibition of platelet recruitment was studied by scanning electron microscopy (SEM) in a canine model of left anterior descending (LAD) thrombosis. In phase I treatment groups were: 1) Ep (n = 6); 2) Ep + rt-PA (n = 6); 3) rt-PA (n = 6); and 4) placebo (n = 4). Coronary blood flow was monitored and LAD segments excised for SEM after 90-min infusion of study drug. In phase II, dogs were randomized to Ep alone (n = 5) or to Ep + rt-PA (n = 5). Coronary blood flow was monitored during and 120 min after cessation of drug when platelet function had returned to normal and LAD segments were excised. RESULTS: All animals except placebo showed reflow. In phase I, SEM showed an absence of platelet aggregates with Ep alone and with Ep + rt-PA, but not with rt-PA alone. In phase II, SEM showed an intimal surface devoid of mural thrombus and platelet aggregates only in Ep + rt-PA treated arteries. Ep-alone treated arteries showed new platelet aggregates at sites of residual mural thrombus. CONCLUSIONS: Short-term infusion Ep plus low-dose rt-PA acutely neutralizes the ability of damaged endothelial surfaces to recruit new platelets by inhibiting platelet aggregation and eliminating residual mural thrombus.

Cardiopulmonary bypass induces release of soluble CD40 ligand.

BACKGROUND: Cardiopulmonary bypass (CPB) is known to induce platelet activation, thrombosis, thrombocytopenia, and a systemic inflammatory response. It is known that CD40 ligand (CD40L) exists in platelets, that a soluble form of this protein (sCD40L) is released on platelet activation, that platelets are the primary source of sCD40L in blood, and that sCD40L is involved in thrombosis and inflammation. The present study was designed to determine whether sCD40L is released during CPB. Methods and Results- Blood was obtained from patients undergoing CPB-requiring surgery and analyzed for sCD40L, interleukin-6, and platelet factor 4 and beta-thromboglobulin (markers of platelet activation). Platelets were also isolated and analyzed for their levels of CD40L. Plasma levels of sCD40L increased >1.7-fold (from 0.29 to 0.51 ng/mL, P=0.001) within 1 hour on CPB and increased further to 3.7-fold (to 1.08 ng/mL, P=0.03) 2 hours after the procedure. Half of the released sCD40L was cleared in 2 hours, which allowed the sCD40L to return to approximately baseline levels 8 hours after the procedure. The platelet content of CD40L was decreased by 40% (2.675 to 1.64 ng/10(8) platelets, P=0.001) 1 hour after initiation of CPB and was similar to that observed for platelet factor 4 and beta-thromboglobulin. Interleukin-6, a marker of inflammation, also increased during CPB. CONCLUSIONS: The present study demonstrates that CPB causes an increase in the concentration of plasma sCD40L. The corresponding decrease in platelet CD40L suggests that this prothrombotic and proinflammatory protein was derived primarily from platelets and may contribute to the thrombotic and inflammatory complications associated with CPB.