Platelet-monocyte complex formation: effect of blocking PSGL-1 alone, and in combination with alphaIIbbeta3 and alphaMbeta2, in coronary stenting.

BACKGROUND: Binding of platelet P-selectin to P-selectin glycoprotein ligand 1 (PSGL-1) is an initial event in the interactions between platelets and monocytes. Platelet-monocyte complexes (PMCs) have been implicated in several vascular disease processes, including acute coronary syndromes (ACS) and complications after percutaneous coronary intervention (PCI). We investigated the effect of ex vivo blockade of PSGL-1, alone and in combination with blockade of the alphaMbeta(2) (Mac-1) and alpha(IIb)beta(3) (GP IIb/IIIa) integrins, on PMC formation. METHODS AND RESULTS: Dual-label flow cytometry was used to detect PMCs in the blood of 10 volunteers and 10 patients undergoing PCI who received intravenous GP IIb/IIIa antagonists. PSGL-1 blockade, both prior to and after platelet stimulation, markedly reduced the formation of PMCs. Concomitant ex vivo blockade of the alphaMbeta(2) and alpha(IIb)beta(3) integrins did not result in further decreases of PMCs compared to PSGL-1 blockade alone. Antagonism of PSGL-1 also led to near elimination of leukocyte-platelet interactions under flowing conditions. CONCLUSION: Blockade of PSGL-1 alone is sufficient to inhibit and reverse the formation of PMCs following platelet stimulation. Concurrent antagonism of PSGL-1 and the alpha(IIb)beta(3) and alphaMbeta(2) integrins was not more effective than inhibition of PSGL-1 alone. These results suggest that platelet-monocyte complex formation is mostly dependent on PSGL-1.

Pharmacodynamic profile of the direct thrombin antagonist bivalirudin given in combination with the glycoprotein IIb/IIIa antagonist eptifibatide.

BACKGROUND: Because of the adverse characteristics associated with heparin, direct antagonists of thrombin have been investigated as anticoagulants during percutaneous coronary interventions. However, the hematologic and clinical interactions between direct thrombin antagonists and inhibitors of platelet glycoprotein IIb-IIIa are incompletely explored. METHODS: Forty-two patients who underwent elective percutaneous coronary intervention were randomized to receive a bivalirudin 1.0 mg/kg bolus followed by a 4-hour infusion at 2.5 mg/kg/h; a bivalirudin 0.75 mg/kg bolus followed by a 4-hour infusion at 1.75 mg/kg; or a heparin 60 U/kg bolus. All the patients also received eptifibatide, given as 2 sequential boluses of 180 microg/kg followed by a 2 microg/kg/min infusion for 18 to 24 hours, and aspirin. RESULTS: After the bolus dose of the study drug, turbidimetric platelet aggregation in response to 5 micromol/L adenosine diphosphate increased in patients assigned to heparin but not those assigned to bivalirudin. After eptifibatide, platelet aggregation was eliminated in all 3 treatment groups. The effect of heparin and the effects of both bivalirudin regimens on the formation of thrombin antithrombin complexes and prothrombin fragment 1.2 were comparable. Neither agent affected the formation of platelet-monocyte complexes or expression of CD 63 lysosomal antigen. There were no major bleeding events, and a single non-Q-wave myocardial infarction (MI) occurred in a patient treated with bivalirudin. CONCLUSION: These findings show the feasibility of combining the direct thrombin antagonist bivalirudin with a potent antagonist of platelet glycoprotein IIb-IIIa. Clinical trials are needed to assess the safety and efficacy of this combination.