Functionally thrombasthenic state in normal platelets following the administration of ticlopidine.

Abstract

To elucidate the bleeding tendency that follows the administration of ticlopidine, we investigated the skin bleeding time and some ex vivo functions of platelets obtained from eight healthy volunteers before and 1 wk after daily administration of 500 mg of ticlopidine. We found the following: ticlopidine significantly (P < 0.001) prolonged the skin bleeding time and impaired the binding of radiolabeled fibrinogen and von Willebrand Factor, the clot retraction and the aggregation of platelets in response to ADP, epinephrine, thrombin, ionophore A23187, collagen, or arachidonic acid. In contrast, the administration of this drug did not affect intraplatelet levels of cAMP, agglutination and binding of von Willebrand Factor in response to ristocetin, shape change in response to ADP, collagen, thrombin, or arachidonic acid, or binding of prostaglandin El to resting platelets. Secretion of ATP in response to ADP or epinephrine was completely inhibited, whereas secretion as well as thromboxane synthesis in response to high concentrations of collagen, arachidonic acid, calcium ionophore A23187, or thrombin was unaffected. Studies with monoclonal antibodies showed that the glycoprotein IIb-IIIa complex (the putative receptor for fibrinogen and von Willebrand Factor on the surface of platelets exposed to naturally occurring aggregating agents) was quantitatively unaffected by ticlopidine. This observation was further confirmed by densitometric scannings of Periodic Acid-Schiff-stained gels of platelet suspensions. The onset, as well as the cessation of the inhibitory effect of ticlopidine on platelets was very slow, and reached a maximum after a 3-5-d administration. In addition, ticlopidine appeared to be a much more potent inhibitor when administered to subjects than when added in vitro to platelets. Finally, abnormalities comparable to those found in volunteers taking ticlopidine were observed when platelets from untreated subjects were incubated in the plasma of ticlopidine-treated subjects.We conclude that ticlopidine induces a thrombasthenic state in normal platelets without affecting the glycoprotein IlbIIIa complex quantitatively. Furthermore, our data suggest that one or more active metabolites rather than the native drug Portions of this work were presented at a symposium ("Ticlopidine: Quo vadis?") in Montpellier, France, 1983, and were published in abstract form in the proceedings of that symposium.Address reprint requests to Dr. Di Minno.

Antithrombotic Effects of KW-3635, a Thromboxane A2-Receptor Antagonist, in Guinea Pigs.

“…prevented by ticlopidine. Ticlopidine is a well-known anti platelet agent that inhibits platelet aggregation induced by various stimulators (23). In the present study, reduc tion of platelet count in the control group was observed, and ticlopidine inhibited the thrombus formation and tended to prevent the reduction of circulating platelets.…”

Protective Effects of Clopidogrel on Oxidant Damage in A Rat Model of Acute Ischemia

“…This antagonism is non-competitive, irreversible, and results in 50-70% inhibition of platelet fibrinogen binding. Clopidogrel has also been reported to prevent thrombocyte aggregation by inhibiting fibrinogen binding to activated fibrinogen receptors (GPllbllla complex) on the platelets (Dunn et al 1984;Di Minno et al 1985). Inhibition of platelet aggregation occurs 24-48 h following the oral intake of clopidogrel and reaches its maximum level in 3 to 5 days.…”

Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina Instabile Group.

“…26 The mechanism by which ticlopidine inhibits platelet aggregation is completely different from the mechanism of aspirin because it does not have any effects on cyclooxygenase.27 Recent studies indicate that ticlopidine inhibits ADP-mediated platelet aggregation15 and antagonizes the interaction of fibrogen with its platelet receptor, the membrane glycoprotein IIb-IIIa. 16 Ticlopidine has been given to patients with several clinical forms of atherosclerosis, such as transient ischemic attack, stroke, and peripheral vascular disease. In patients who have had stroke, ticlopidine decreased the incidence of such later vascular accidents as stroke, myocardial infarction, and vascular death by 23.3%.28 Ticlopidine was also effective in patients with peripheral vascular disease in a randomized, double-blind placebo-controlled study with a duration of 21 months.…”

“…Ticlopidine, unlike aspirin, does not block cyclooxygenase but appears to interfere with the ADP-mediated platelet activation mechanism15 and the platelet fibrinogen receptor. 16 The control group was not treated with aspirin because acetylsalicylic acid was not widely used for treatment of unstable angina in Italy in 1986, when the protocol was designed. Nowadays, aspirin is more widely used.…”