title: Effect of antiplatelet agents clopidogrel, aspirin, and cilostazol on circulating tissue factor procoagulant activity in patients with peripheral arterial disease.
abstract: Tissue factor (TF) is the physiological initiating mechanism for blood coagulation. Platelets play an important role in monocyte TF expression, thrombosis and inflammation. Aspirin, clopidogrel and cilostazol, which inhibit platelet responses by different mechanisms, are widely used in patients with arterial diseases. We tested the hypothesis that platelet-inhibiting agents inhibit the levels of circulating TF procoagulant activity (TF-PCA) in patients with peripheral arterial disease (PAD). Twenty-six patients with lower extremity PAD, average age 65.9 +/- 8.4 years (mean +/- SEM), were studied at baseline and following sequential two-week treatment regimens with aspirin (325 mg daily), clopidogrel (75 mg daily) or a phosphodiesterase inhibitor cilostazol (100 mg twice daily) singly, and with each possible combination of these agents. Circulating TF-PCA in whole blood, and plasma factor VIIa, prothrombin fragment F1.2, thrombin-antithrombin complexes (TAT), and P-selectin were measured. Baseline TF-PCA levels in the patients were elevated (131 +/- 19 U/ml) compared to control subjects (23 +/- 2, p < 0.0001). TF-PCA levels declined following treatment with clopidogrel alone, and with combinations of clopidogrel with aspirin or cilostazol, with the lowest levels being with the triple-drug combination. Plasma P-selectin declined in all treatment groups. No changes were noted in plasma factor VIIa, F1.2 or TAT. In conclusion, treatment of PAD patients with antiplatelet agents decreases circulating TF, a molecule with prothrombotic and proinflammatory effects. These findings suggest an unrecognized mechanism, beyond inhibiting aggregation responses, for the efficacy of antiplatelet drugs in patients with arterial diseases.
authors.affiliation: Division of Hematology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 N Broad St, OMS 300, Philadelphia, PA 19140, USA. koneti.rao@temple.edu
authors.forename: A Koneti
authors.initials: AK
authors.lastname: Rao
authors.forename: Vijender R
authors.initials: VR
authors.lastname: Vaidyula
authors.forename: Shagun
authors.initials: S
authors.lastname: Bagga
authors.forename: Gauthami
authors.initials: G
authors.lastname: Jalagadugula
authors.forename: John
authors.initials: J
authors.lastname: Gaughan
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Wilhite
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Comerota
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000990:Antithrombin III; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000077407:Cilostazol; D000077144:Clopidogrel; D015536:Down-Regulation / Q000187:drug effects; D004359:Drug Therapy, Combination; D015942:Factor VIIa / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000188:drug therapy*; D010865:Pilot Projects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D011516:Prothrombin; D013777:Tetrazoles / Q000627:therapeutic use*; D013925:Thromboplastin / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D019007:P-Selectin; D010446:Peptide Fragments; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; C046193:antithrombin III-protease complex; C045879:prothrombin fragment 1.2; D023201:CD40 Ligand; D000990:Antithrombin III; D011516:Prothrombin; D002097:C-Reactive Protein; D013925:Thromboplastin; D000077144:Clopidogrel; D010447:Peptide Hydrolases; D015942:Factor VIIa; D000077407:Cilostazol; D013988:Ticlopidine; D001241:Aspirin