Ticlopidine Facilitates the Deaggregation of Human Platelets Aggregated by Thrombin

Abstract

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

Inhibition of the platelet P2Y12 receptor for adenosine diphosphate potentiates the antiplatelet effect of prostacyclin

“…Activation of the G q pathway through P2Y 1 leads to platelet shape change and rapidly reversible aggregation, while activation of the G i pathway through P2Y 12 elicits a slowly progressive and sustained PA not preceded by shape change. In addition to its role in ADP-induced PA, P2Y 12 mediates (i) the potentiation of platelet secretion by ADP, which is independent of the formation of large aggregates and thromboxane A 2 synthesis [3,4] and (ii) the stabilization of thrombin-induced platelet aggregates [5][6][7].…”

P2Y12 receptors: structure and function

“…This effect was independent of the concentrations of extracellular Ca 2+ and of the formation of large platelet aggregates and was not inhibited by acetylsalicylic acid [4,40,41]. P2Y 12 plays an essential role in the stabilization of platelet aggregates induced by thrombin [5][6][7] or TXA 2 [42]. P2Y 12 R is an important cofactor of platelet aggregation and secretion induced by several agonists (Fig.…”

“…When ADP is secreted by platelet dense granules upon stimulation by secretioninducing agonists, it amplifies the platelet responses [3,4], stabilizes platelet aggregates [5][6][7], and contributes to the procoagulant activity of platelets [8]. The secretion of platelet dense granules constituents and the ensuing secondary aggregation that are sometimes observed following stimulation with ADP of normal platelet-rich plasma (PRP) are triggered by thromboxane (Tx) A 2 , whose synthesis is stimulated by platelet aggregation and not by ADP [9,10].…”

The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects

“…27 This effect, which is probably mediated by PI3K, 18,28 was observed both at physiologic and micromolar concentrations of extracellular Ca 2ϩ , in the presence of acetylsalicylic acid (ASA), and independently of the formation of large platelet aggregates, demonstrating that it is a direct effect of P2Y 12 , rather than secondary to P2Y 12 -mediated amplification of aggregation. [24][25][26] P2Y 12 plays an essential role in the stabilization of platelet aggregates induced by thrombin [3][4][5] or thromboxane A 2 (Figure 2), 29 which is mediated by PI3K. 14 Studies of human platelets congenitally lacking P2Y 12 and of P2Y 12 knockout mice demonstrated that platelet aggregation and secretion induced by a range of platelet agonists were impaired.…”