ADMINISTRATION OF TICLOPIDINE IMPEDES ADP-INDUCED ACTIVATION BUT DOES NOT INDUCE A THROMBASTHENIC STATE

The aim of this study was to reassess the pattern of aggregation and to investigate the platelet-fibrinogen interaction, in response to various agonists, following T. treatment: 250 mg b.i.d. for at least 1 week. Platelets were obtained from healthy volunteers (n=8) as well as from patients with cerebro-vascular disease (n=5). The regimen was able to induce the well-known and expected alterations of platelet behaviour in citrated PRP. Washed platelets were prepared according to MUSTARD et al. (1972). (1) In a first set of experiments it was shown that these alterations persisted after resuspension of twice-washed platelets, in the presence of fibrinogen (3.7 μM); with ADP there was a marked impairment of aggregation, quantified either as maximal change in light transmission (DTLmax), or as maximal velocity; after stimulation with 100 μM ADP there was still a 40% decrease in DTL max and an about 50-fold faster de-aggregation as compared to values obtained without T. treatment. PAF-acether (0.1 to 3 μM): decreased DTLmax mainly with the higher doses, persistent de-aggregation but unimpaired velocity. Collagen (from Stago, μg.ml⁻¹ ): DTLmax was decreased in response to low concentrations only (0.3 and 0.6). Arachidonic acid (20, 50, 100 μM) -induced aggregation remained unchanged, but the concentrations of U 46,619 able to induce an at least 50% DTLmax was shifted from 0.05 to 0.1 or 1.0 μM. (2) The association of human fibrinogen with stimulated platelets was quantified by plotting velocity against concentration of exogenous fibrinogen (0.06, 0.23, 0.92, 3.7 μM). The dose-response curves were modified in the presence of ADP (5 μM) but not PAF (0.5 μM) . With selected low concentrations of collagen or arachidonic acid addition of fibrinogen is a prerequisite for aggregation; under these experimental conditions T. treatment only induced slight modifications of the responses. Fibrinogen-dependent aggregation (DTLmax) of platelets from T. treated patients in response to ADP (10 μM) or after pretreatment with alpha-chymotrypsin was 1/3 and 2/3 of control values respectively. Taken together our results do not support the induction of a functionally thrombasthenic-like state, but rather suggest a selective impairment of ADP-mediated platelet activation. Accordingly, the pattern of platelet behaviour observed under T. treatment can be mimicked by adding ATP (as ADP-antagonist) to normal platelets.