The Action of Ticlopidine on Human Platelets

Summary

The effects on platelet function of a 5-day course of Ticlopidine (Tel) have been studied in two groups of volunteers receiving different dosage schedules. Tel had a relatively greater inhibitory effect on aggregation induced by ADP than by other agonists, and a greater effect, in contrast to that of an ADP receptor antagonist, on the second phase than on the initial rate of aggregation. Tel inhibited ATP secretion in response to ADP and 0.05 u/ml thrombin, but not to higher concentrations of thrombin or to calcium ionophores. No inhibitory effect was observed on Ca²⁺ influx or intracellular mobilization, on the binding of monoclonal antibodies to the glycoprotein IIb-IIIa complex or on the state of association of the complex. We suggest that Tel neither inhibits the binding of ADP to its receptor nor acts directly on the fibrinogen binding site, but that it may inhibit a step in signal transduction between these two events.

• References

• 1 Thebault JJ, Blatrix CE, Blanchard JF, Panak EA. Effects of ticlopidine, a new platelet aggregation inhibitor in man. Clin Pharmacol Ther 1975; 18: 485-490
• 2 O’Brien JR, Etherington MD, Shuttleworth RD. Ticlopidine. An antiplatelet drug: effects in human volunteers. Thromb Res 1978; 13: 245-254
• 3 Dunn FW, Soria J, Soria C, Thomaidis A, Lee H, Caen JP. In vivo effect of ticlopidine on fibrinogen-platelet cofactor activity and binding of fibrinogen to platelets. Agents Actions Suppl 1984; 15: 97-104
• 4 Di MinnoG, Cerbone AM, Mattiolo PL, Turco S, Iovine C, Mancini M. Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest 1985; 75: 328-338
• 5 Panak E, Maffrand JP, Picard-Fraire C, Vallee E, Blanchard J, Roncucci R. Ticlopidine: a promise for the prevention and treatment of thrombosis and its complications. Haemostasis 1983; 13 (Suppl. 01) 1-54
• 6 Lips J PM, Sixma JJ, Schiphorst ME. The effect of ticlopidine administration to humans on the binding of adenosine diphosphate to blood platelets. Thromb Res 1980; 17: 19-27
• 7 Hallam TJ, Rink TJ. Responses to adenosine diphosphate in human platelets loaded with the fluorescent calcium indicator quin 2. J Physiol 1985; 368: 131-146
• 8 Jones D, Fritschy J, Garson J, Nokes T JC, Kemshead J, Hardisty RM. A monoclonal antibody binding to human medulloblastoma cells and to the platelet glycoprotein IIb-IIIa complex. Br J Haematol 1984; 57: 621-631
• 9 Thorsen LI, Gaudemack G, Brosstad F, Pedersen TM, Solum NO. Identification of platelet antigens by monoclonal antibodies using crossed immunoelectrophoresis with immunoblotting of the monoclonal antibody. Thromb Haemostas 1987; 57: 212-216
• 10 Cheeseman JE, Mills SP, Hardisty RM. Platelet aggregometry on whole blood: the use of the ELT8/ds blood cell counter in the investigation of bleeding disorders. Clin Lab Haematol 1984; 6: 265-272
• 11 Hallam TJ, Sanchez A, Rink TJ. Stimulus-response coupling in human platelets. Changes evoked by platelet activating factor in cytoplasmic free calcium monitored with the fluorescent calcium indicator quin 2. Biochem J 1984; 218: 819-827
• 12 Johnston GI, Heptinstall S, Robins RA, Price MR. The expression of glycoproteins on single blood platelets from healthy individuals and from patients with congenital bleeding disorders. Biochem Biophys Res Commun 1984; 123: 1091-1098
• 13 Bom G VR, Foulks JG. Inhibition by a stable analogue of adenosine triphosphate of platelet aggregation by adenosine diphosphate. Br J Pharmacol 1977; 61: 87-89
• 14 Rink TJ, Smith SW, Tsien RY. Cytoplasmic free Ca²⁺ in human platelets: Ca²⁺ thresholds and Ca-independent activation for shape-change and secretion. FEBS Lett 1982; 148: 21-26
• 15 Pidard D, Montgomery RR, Bennett JS, Kunicki TJ. Interaction of AP-2, a monoclonal antibody specific for the human platelet glycoprotein IIb-IIIa complex, with intact platelets. J Biol Chem 1983; 258: 12582-12586
• 16 Newman PJ, Allen RW, Kahn RA, Kunicki TJ. Quantitation of membrane glycoprotein Ilia on intact human platelets using the monoclonal antibody, AP-3. Blood 1985; 65: 227-232
• 17 McMichael AJ, Rust NA, Pilch JR, Sochynsky R, Morton J, Mason DY, Ruan C, Tobelem G, Caen J. Monoclonal antibody to human platelet glycoprotein 1.1. Immunological studies. Br J Haematol 1981; 49: 501-509
• 18 Pidard D, Didry D, Kunicki TJ, Nurden AT. Temperature-dependent effects of EDTA on the membrane glycoprotein IIb-IIIa complex and platelet aggregability. Blood 1986; 67: 604-611
• 19 David JL, Monfort F, Herion F, Raskinet R. Compared effects of three dose-levels of ticlopidine on platelet function in normal subjects. Thromb Res 1979; 14: 35-49
• 20 Conard J, Lecrubier C, Scarabin PY, Horellou MH, Samama M, Bousser MG. Effects of long term administration of ticlopidine on platelet function and hemostatic variables. Thromb Res 1980; 20: 143-148
• 21 Powling MJ, Cox AD, Goodall AH, Hardisty RM. Functional and phenotypic heterogeneity of CDw41 and CDw42 antibodies. In: Leucocyte Typing IV Knapp W. (ed) Oxford University Press; Oxford: 1989
• 22 Gachet C, Bouloux C, Maffrand J-P, Cazenave J-P. Ticlopidine selectively prevents the inhibitory effect of ADP but not of adrenaline on cAMP levels raised by stimulation of human platelets by PGE₁ . Circulation 1988; 78 Suppl. II 517
• 23 Derian CK, Friedman PA. Effect of ticlopidine ex vivo on platelet intracellular calcium mobilization. Thromb Res 1988; 50: 65-76