Anti-platelet agents clopidogrel and aspirin inhibit expression of tissue factor procoagulant activity in patients with peripheral artery disease

Abstract number: P2014

Vaidyula^* V. R., Abdel-Hafiz^* E., Bagga^* S., Jalagadugula^* G., Wilhite† D., Comerota† A. J., Rao^* A. K.

†Department of Surgery, USA ^*Sol Sherry Thrombosis Research Center, USA;

Platelets play an important role in inflammation and in regulating monocyte expression of tissue factor (TF). We tested the hypothesis that platelet-inhibiting agents inhibit the expression of TF procoagulant activity (TF-PCA) in vivo. Twenty patients with lower extremity peripheral arterial disease (PAD), average age 67 ± 2 years (mean ± SE), were placed on the following sequential two-week regimens including aspirin (ASA, 325 mg daily), clopidogrel (Clop, 75 mg QD) and a phosphodiesterase inhibitor Cilostazol (Cilo, 100 mg BID), interspersed by washout periods: no platelet-inhibiting drugs (baseline), ASA alone, ASA + Cilo, washout, Cilo alone, Cilo + Clop, washout, Clop alone, Clop + ASA, and Clop + ASA + Cilo. After each regimen, we assessed TF-PCA in whole blood samples using a two-stage clotting assay (Key NS et al. Blood 1998; 91: 4216); and plasma factor VIIa (by clotting assay), and prothrombin fragment F1.2 and thrombin–antithrombin complexes (TAT) (both by ELISA). The data were analyzed by analysis of variance with Bonferroni correction. Baseline TF-PCA levels were elevated in patients (137 ± 30 U mL^-1, n = 16) compared to healthy controls (23 ± 2, n = 41, P = 0.0004). Compared to baseline (137 ± 30 U mL^-1) the TF-PCA was lower with ASA + Clop (57 ± 13 U mL^-1, P < 0.05) and ASA + Clop + Cilo (36 ± 6 U mL^-1, P < 0.001), but not with ASA, Clop or Cilo alone. These two Clop-containing combinations were not different from each other or from Clop alone (Table). TF-PCA with ASA + Cilo + Clop was significantly lower than with ASA or Cilo alone and with ASA + Cilo. Plasma FVIIa, TAT or F1.2 did not show significant change from the baseline or between groups. These studies provide evidence for the first time that a combination of anti-platelet agents Clopidogrel and ASA (with or without Cilostazol) inhibits not only platelet aggregation but also in vivo expression of TF-PCA, the physiologic initiating mechanism for blood coagulation. This effect may be related to an inhibition of platelet release of substances that stimulate TF expression by monocytes and important to the overall anti-thrombotic efficacy of these drugs in arterial diseases.

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