scholarly journals Inhibition of collagen-induced platelet activation by 5'-p- fluorosulfonylbenzoyl adenosine: evidence for an adenosine diphosphate requirement and synergistic influence of prostaglandin endoperoxides

Blood ◽  
1986 ◽  
Vol 68 (2) ◽  
pp. 565-570 ◽  
Author(s):  
RW Colman ◽  
WR Figures ◽  
LM Scearce ◽  
AM Strimpler ◽  
FX Zhou ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Shape Change ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Platelet Surface ◽  
Prostaglandin Endoperoxide ◽  
Fibrinogen Binding ◽  
Low Concentrations ◽  
Absolute Requirement

Abstract The relative roles of platelet autacoids such as adenosine diphosphate (ADP), prostaglandin endoperoxides, and thromboxane A2 (TXA2) in collagen-induced platelet activation are not fully understood. We reexamined this relationship using the ADP affinity analogue, 5'-p- fluorosulfonylbenzoyl adenosine (FSBA), which covalently modifies a receptor for ADP on the platelet surface, thereby inhibiting ADP- induced platelet activation. Collagen-induced shape change, aggregation, and fibrinogen binding were each fully inhibited under conditions in which FSBA is covalently incorporated and could not be overcome by raising the collagen used to supramaximal concentrations. In contrast, TXA2 synthesis stimulated by collagen under conditions that produced maximum aggregation was only minimally inhibited by FSBA. Since covalent incorporation of FSBA has been previously shown to specifically inhibit ADP-induced activation of platelets, the present study supports the contention that ADP is required for collagen-induced platelet activation. Under similar conditions, indomethacin, an inhibitor of cyclooxygenase, inhibited collagen-induced shape change, indicating that endoperoxides and/or TXA2 also play a role in this response. Shape change induced by low concentrations (10 nmol/L) of the stable prostaglandin endoperoxide, azo-PGH2, was also inhibited by FSBA. These observations indicate a role for ADP in responses elicited by low concentrations of endoperoxides. However, at higher concentrations of azo-PGH2 (100 nmol/L), inhibition by FSBA could be overcome. Thus, the effect of collagen apparently has an absolute requirement for ADP for aggregation and fibrinogen binding and for both ADP and prostaglandins for shape change. Aggregation and fibrinogen binding induced by prostaglandin endoperoxides also required ADP as a mediator, but ADP is not absolutely required at high endoperoxide concentration to induce shape change.

scholarly journals Inhibition of collagen-induced platelet activation by 5'-p- fluorosulfonylbenzoyl adenosine: evidence for an adenosine diphosphate requirement and synergistic influence of prostaglandin endoperoxides

Blood ◽  
1986 ◽  
Vol 68 (2) ◽  
pp. 565-570
Author(s):  
RW Colman ◽  
WR Figures ◽  
LM Scearce ◽  
AM Strimpler ◽  
FX Zhou ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Shape Change ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Platelet Surface ◽  
Prostaglandin Endoperoxide ◽  
Fibrinogen Binding ◽  
Low Concentrations ◽  
Absolute Requirement

The relative roles of platelet autacoids such as adenosine diphosphate (ADP), prostaglandin endoperoxides, and thromboxane A2 (TXA2) in collagen-induced platelet activation are not fully understood. We reexamined this relationship using the ADP affinity analogue, 5'-p- fluorosulfonylbenzoyl adenosine (FSBA), which covalently modifies a receptor for ADP on the platelet surface, thereby inhibiting ADP- induced platelet activation. Collagen-induced shape change, aggregation, and fibrinogen binding were each fully inhibited under conditions in which FSBA is covalently incorporated and could not be overcome by raising the collagen used to supramaximal concentrations. In contrast, TXA2 synthesis stimulated by collagen under conditions that produced maximum aggregation was only minimally inhibited by FSBA. Since covalent incorporation of FSBA has been previously shown to specifically inhibit ADP-induced activation of platelets, the present study supports the contention that ADP is required for collagen-induced platelet activation. Under similar conditions, indomethacin, an inhibitor of cyclooxygenase, inhibited collagen-induced shape change, indicating that endoperoxides and/or TXA2 also play a role in this response. Shape change induced by low concentrations (10 nmol/L) of the stable prostaglandin endoperoxide, azo-PGH2, was also inhibited by FSBA. These observations indicate a role for ADP in responses elicited by low concentrations of endoperoxides. However, at higher concentrations of azo-PGH2 (100 nmol/L), inhibition by FSBA could be overcome. Thus, the effect of collagen apparently has an absolute requirement for ADP for aggregation and fibrinogen binding and for both ADP and prostaglandins for shape change. Aggregation and fibrinogen binding induced by prostaglandin endoperoxides also required ADP as a mediator, but ADP is not absolutely required at high endoperoxide concentration to induce shape change.

scholarly journals Increased binding of fibrinogen to platelets in diabetes: the role of prostaglandins and thromboxane

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 156-162 ◽  
Author(s):  
G DiMinno ◽  
MJ Silver ◽  
AM Cerbone ◽  
G Riccardi ◽  
A Rivellese ◽  
...  
Keyword(s):  
Binding Sites ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Dienoic Acid ◽  
Platelet Glycoprotein ◽  
Platelet Surface ◽  
Prostaglandin Endoperoxide ◽  
Fibrinogen Binding ◽  
Before And After

Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than platelets from normal subjects. We compared fibrinogen binding to platelets from diabetic subjects with binding to platelets from normal subjects and determined whether aspirin (which inhibits the formation of prostaglandins and thromboxane) would inhibit the binding of fibrinogen to platelets from diabetic subjects and whether this correlated with its effects on platelet aggregation. We found the following: Aspirin suppressed thromboxane formation and rendered the platelets less sensitive to the induction of aggregation by adenosine diphosphate (ADP) or collagen. The amount of U-46619 [( 15s]-hydroxy-11-alpha, 9-alpha [epoxy-methano]- prosta[5Z,13E]-dienoic acid, a stable analog of prostaglandin endoperoxide/thromboxane A2) necessary to induce aggregation, was similar in normal and diabetic subjects and was unchanged after ingestion of aspirin. Binding of 125I-fibrinogen following stimulation of platelets by ADP or collagen was greater in diabetic (because more binding sites were exposed) than in normal subjects. However, following stimulation by U-46619, binding was similar in diabetic and normal subjects. Aspirin caused a reduction in the exposure of binding sites on both platelets from diabetic and normal subjects, so that (in this respect) platelets from diabetic subjects became more like those from normal subjects. Effects of the monoclonal antibody B59.2, which is specific for the platelet glycoprotein IIb-IIIa complex (the presumed receptor for fibrinogen on the platelet surface) were also studied. The amount of this antibody that bound to platelets was the same for normal and diabetic subjects both before and after aspirin and with or without stimulation by ADP or collagen. In addition, B59.2 inhibited aggregation and fibrinogen binding in both platelets from diabetic and normal subjects. The combined data suggest that the glycoprotein IIb- IIIa complex of platelets from diabetic subjects is similar to that of platelets from normal subjects and that the increased fibrinogen binding and aggregation of platelets from diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin endoperoxide or thromboxane A2, or both.

scholarly journals Increased binding of fibrinogen to platelets in diabetes: the role of prostaglandins and thromboxane

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 156-162 ◽  
Author(s):  
G DiMinno ◽  
MJ Silver ◽  
AM Cerbone ◽  
G Riccardi ◽  
A Rivellese ◽  
...  
Keyword(s):  
Binding Sites ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Dienoic Acid ◽  
Platelet Glycoprotein ◽  
Platelet Surface ◽  
Prostaglandin Endoperoxide ◽  
Fibrinogen Binding ◽  
Before And After

Abstract Previous studies suggested a role for prostaglandins or thromboxane A2, or both in the exposure of fibrinogen receptors on normal platelets in response to several aggregating agents. Platelets from diabetics are known to be more sensitive to aggregating agents and to produce more prostaglandins and thromboxane than platelets from normal subjects. We compared fibrinogen binding to platelets from diabetic subjects with binding to platelets from normal subjects and determined whether aspirin (which inhibits the formation of prostaglandins and thromboxane) would inhibit the binding of fibrinogen to platelets from diabetic subjects and whether this correlated with its effects on platelet aggregation. We found the following: Aspirin suppressed thromboxane formation and rendered the platelets less sensitive to the induction of aggregation by adenosine diphosphate (ADP) or collagen. The amount of U-46619 [( 15s]-hydroxy-11-alpha, 9-alpha [epoxy-methano]- prosta[5Z,13E]-dienoic acid, a stable analog of prostaglandin endoperoxide/thromboxane A2) necessary to induce aggregation, was similar in normal and diabetic subjects and was unchanged after ingestion of aspirin. Binding of 125I-fibrinogen following stimulation of platelets by ADP or collagen was greater in diabetic (because more binding sites were exposed) than in normal subjects. However, following stimulation by U-46619, binding was similar in diabetic and normal subjects. Aspirin caused a reduction in the exposure of binding sites on both platelets from diabetic and normal subjects, so that (in this respect) platelets from diabetic subjects became more like those from normal subjects. Effects of the monoclonal antibody B59.2, which is specific for the platelet glycoprotein IIb-IIIa complex (the presumed receptor for fibrinogen on the platelet surface) were also studied. The amount of this antibody that bound to platelets was the same for normal and diabetic subjects both before and after aspirin and with or without stimulation by ADP or collagen. In addition, B59.2 inhibited aggregation and fibrinogen binding in both platelets from diabetic and normal subjects. The combined data suggest that the glycoprotein IIb- IIIa complex of platelets from diabetic subjects is similar to that of platelets from normal subjects and that the increased fibrinogen binding and aggregation of platelets from diabetic subjects in response to ADP or collagen is mediated by increased formation of prostaglandin endoperoxide or thromboxane A2, or both.

Platelet ADP Receptors Stimulating Shape Change and Inhibiting Adenylate Cyclase

Physiology ◽  
1992 ◽  
Vol 7 (6) ◽  
pp. 274-278
Author(s):  
RW Colman
Keyword(s):  
Platelet Aggregation ◽  
Membrane Protein ◽  
Adenylate Cyclase ◽  
Shape Change ◽  
Surface Membrane ◽  
Thromboxane A2 ◽  
Platelet Surface ◽  
Fibrinogen Binding ◽  
Adp Receptors

Aggregin, a platelet surface membrane protein required for ADP-induced shape change, aggregation, and fibrinogen binding, is distinct from the receptor coupled to adenylate cyclase. Platelet aggregation by epinephrine, thromboxane A2, and collagen requires ADP binding to aggregin. Thrombin and plasmin are independent of ADP and activate platelet calpain, which cleaves aggregin.

scholarly journals Independent Induction of Platelet Aggregation and Secretion by Prostaglandin Endoperoxide Analogues and Thromboxane A2-Like Material

1977 ◽  
Author(s):  
I. F. Charo ◽  
R. D. Feinman ◽  
T. C. Detwiler ◽  
J. B. Smith
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Critical Concentration ◽  
Thromboxane A2 ◽  
Second Phase ◽  
Induce Platelet Aggregation ◽  
Prostaglandin Endoperoxide ◽  
Low Concentrations ◽  
New Instrument

We have investigated the mechanims of platelet activation by two prostaglandin endoperoxide analogues (U-46619 and U-44069) using a new instrument that simultaneously monitors platelet aggregation and secretion. Low concentrations of these compounds induce platelet aggregation without secretion (i. e., primary aggregation), while slightly higher concentrations induce biphasic aggregation with secretion paralleling the second phase. At still higher concentrations, aggregation and secretion begin simultaneously, and in the absence of stirring there is secretion but no aggregation. A critical concentration of endoperoxide analogues can often be found that will induce 2 waves of secretion, a phenomenon not seen with other stimuli. Similar results were obtained with thromboxane A2-like material that was generated by incubation of dog platelets with Na-arachidonate. In contrast, when platelets are stimulated with Na-arachidonate, the precursor of the endoperoxides and thromboxanes, we never observe significant aggregation without secretion, and even at the lowest concentrations secretion is independent of aggregation. We conclude that both the prostaglandin endoperoxide analogues and thromboxane A2-like material induce platelet aggregation independent of released ADP and only at higher concentrations can directly induce secretion, whereas Na-arachidonate induces aggregation and secretion in parallel.

THROMBOXANE-A2 MEDIATES THE ACTION OF INOSITOL (1.4.5) TRISPHOSPHATE (IP3) IN SAPONIN-PERMEABILISED PLATELETS

1987 ◽  
Author(s):  
K S Authi ◽  
B J Evenden ◽  
E J Hornby ◽  
N Crawford
Keyword(s):  
Phospholipase A2 ◽  
Shape Change ◽  
Thromboxane A2 ◽  
Thromboxane B2 ◽  
Cyclooxygenase Inhibitors ◽  
Storage Site ◽  
Platelet Surface ◽  
Surface Receptors ◽  
Thromboxane Receptor ◽  
Thromboxane Production

Inositol trisphosphate (IP3) has now been identified as an important intracellular second messenger that can initiate the release of Ca2+ from intracellular stores in a variety of cells, including platelets. We have studied the effects of IP3 on washed platelets permeabilised with saponin (12-14 μg/mi) which allows penetration into the cell of low M.Wt polar molecules. The permeabilised cells show normal responses to the agonists thrombin and collagen. The addition of IP (1-20 μM) after saponin treatment induces shape change, aggregation and secretion of preloaded [14C] 5HT. Concomitant with these responses, thromboxane is produced in a dose related manner. With 20 μM IP3 thromboxane B2 increases from basal levels of 5-4 ± 3-0 ng/ml to 140 ± 23 ng/ml. Both thromboxane production and the platelet responses induced by IP3 are inhibited by pretreatment with the cyclooxygenase inhibitors, indomethacin (EC50 50 μM) and aspirin (EC50 30 μM). Aggregation and secretion responses to IP3 are also inhibited by thromboxane B2 receptor agonists; EPO 92 (R. Jones, Edinburgh) and AH 23848 (Glaxo Ltd.). If Ca2+ EGTA buffers age used with permeabilised platelets to "lock" the cytosolic [Ca2+] at 0.1 μM, thromboxane production is reduced to the basal level. Intact platelets were labelled with Ca2+ (4h incubation) and after washing, resuspension and saponisation, IP3 induced the release of 20% of the cell associated Ca2+. The release was unaffected by pretreatment with antimycin and oligomycin indicating an gndoplasmic reticulum-lige storage site for the sequestered Ca2+. This IP3 -induced Ca2+ release was also not affected by pretreatment with either cyclooxygenase inhibitors or thromboxane receptor antagonists (EPO 92 and AH 23848). We believe these studies indicate that the action of IP3 in sagonised platelets involves release of intracellularly stored Ca2+, activation of phospholipase A2 and cyclooxygenase, and production of thromboxane A2. The release of thromboxane mediates and/or attenuates platelet responses by acting upon platelet surface receptors.

scholarly journals Effect of aspirin on platelet-von Willebrand factor surface expression on thrombin and ADP-stimulated platelets

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2016-2021 ◽  
Author(s):  
RI Parker ◽  
HR Gralnick
Keyword(s):  
Von Willebrand Factor ◽  
Shape Change ◽  
Adenosine Diphosphate ◽  
Surface Expression ◽  
Platelet Surface ◽  
Granule Secretion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Platelet Shape ◽  
Stimulation Of

Abstract Platelets contain a pool of endogenous platelet-von Willebrand factor (vWF) that becomes expressed on the platelet surface when platelets are stimulated by a variety of agonists. Maximal platelet-vWF expression occurs in concert with platelet alpha-granule secretion. Aspirin (ASA) is known to impair platelet activation and alpha-granule secretion by irreversible inhibition of platelet cyclo-oxygenase. We studied native and ASA-treated platelets for their ability to mobilize and to express platelet-vWF in response to adenosine diphosphate (ADP) or thrombin. We found that each agonist was effective in promoting increased platelet- vWF surface expression on native and ASA-treated platelets. ASA-treated platelets responded identically to native platelets to low (0.01 U/mL) and high (1.0 U/mL) concentrations of thrombin, while the ADP-induced increase in ASA-treated platelets was only 50% to 60% of that for control platelets. Measurement of secreted platelet-vWF and beta- thromboglobulin indicated that the increase seen with ADP was largely independent of alpha-granule secretion. Using monoclonal antibodies (MoAbs) against the platelet glycoproteins (GP) IIb/IIIa and Ib (MoAbs 10E5 and 6D1, respectively), we demonstrated that the ADP-induced increase in platelet-vWF expression on control platelets primarily involved the binding of secreted platelet-vWF to the platelet GPIIb/IIIa. In contrast, the increase in platelet-vWF that occurred following ADP stimulation of ASA-treated platelets was largely insensitive to GPIIb/IIIa blockade. No effect of GPIb blockade in platelet-vWf expression was noted for either control or ASA-treated platelets. When platelet shape change was prevented by the addition of cytochalasin D, ADP-induced platelet-vWf surface expression on ASA- treated platelets was reduced by more than 80%. Our data indicate that platelets in which the cyclooxygenase pathway is blocked by the action of aspirin can increase surface expression of platelet-vWf as a consequence of platelet shape change. We speculate that this process exposes platelet-vWf bound to GPIIb/IIIa, or possibly GPIb, within the surface connected canalicular system.

Aspirin-Dependent Effects on Purinergic P2Y1 Receptor Expression

2019 ◽  
Vol 119 (05) ◽  
pp. 726-734 ◽  
Author(s):  
Isabella Massimi ◽  
Laura Alemanno ◽  
Maria Guarino ◽  
Raffaella Guerriero ◽  
Massimo Mancone ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Receptor Expression ◽  
P2y1 Receptor ◽  
Biochemical Pathway ◽  
Thromboxane A2 Receptor ◽  
Induced Aggregation

AbstractChronic treatment with aspirin in healthy volunteers (HVs) is associated with recovery of adenosine diphosphate (ADP)-induced platelet activation. The purinergic P2Y1 receptor exerts its effects via a Gq-protein, which is the same biochemical pathway activated by thromboxane-A2 receptor. We hypothesized that recovery of ADP-induced platelet activation could be attributed to increased P2Y1 expression induced by chronic aspirin exposure. We performed a multi-phase investigation which embraced both in vitro and in vivo experiments conducted in (1) human megakaryoblastic DAMI cells, (2) human megakaryocytic progenitor cell cultures, (3) platelets obtained from HVs treated with aspirin and (4) platelets obtained from aspirin-treated patients. DAMI cells treated with aspirin or WY14643 (PPARα agonist) had a significant up-regulation of P2Y1 mRNA, which was shown to be a PPARα-dependent process. In human megakaryocytic progenitors, in the presence of aspirin or WY14643, P2Y1 mRNA expression was higher than in mock culture. P2Y1 expression increased in platelets obtained from HVs treated with aspirin for 8 weeks. Platelets obtained from patients who were on aspirin for more than 2 months had increased P2Y1 expression and ADP-induced aggregation compared with patients on aspirin treatment for less than a month. Overall, our results suggest that aspirin induces genomic changes in megakaryocytes leading to P2Y1 up-regulation and that PPARα is the nuclear receptor involved in this regulation. Since P2Y1 is coupled to the same Gq-protein of thromboxane-A2 receptor, platelet adaptation in response to pharmacological inhibition seems not to be receptor specific, but may involve other receptors with the same biochemical pathway.

scholarly journals Ultrastructural Studies of Platelet Aggregates From Human Subjects Receiving Clopidogrel and From a Patient With an Inherited Defect of an ADP-Dependent Pathway of Platelet Activation

1996 ◽  
Vol 16 (12) ◽  
pp. 1532-1543 ◽  
Author(s):  
Michel Humbert ◽  
Paquita Nurden ◽  
Claude Bihour ◽  
Jean-Max Pasquet ◽  
Joëlle Winckler ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Platelet Activation ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
High Dose ◽  
Platelet Response ◽  
Platelet Surface ◽  
Ultrastructural Studies ◽  
Contact Points ◽  
Platelet Aggregates

Our study investigated the effect of the antithrombotic drug clopidogrel (75 mg/d for 7 days) on the ultrastructure of platelet aggregates induced by ADP or 2-methylthio-ADP (2-MeS-ADP) in citrated platelet-rich plasma and examined the activation state of the GP IIb/IIIa complexes. Results were compared with those obtained for patient M.L., who has a congenital disorder characterized by a reduced and reversible platelet response to ADP. When untreated normal platelets were stimulated with high-dose ADP, electron microscopy revealed large and stable aggregates often surrounded by a layer of what appeared to be degranulated platelets. The reversible aggregates of platelets from subjects receiving clopidogrel or from patient M.L. did not show this layer. Electron microscopy showed that in both situations, the aggregates were composed of loosely bound platelets with few contact points. Immunogold labeling of ultrathin sections of Lowicryl-embedded aggregates formed by ADP or 2-MeS-ADP showed a much decreased platelet surface staining by (1) a polyclonal anti-fibrinogen antibody and (2) AP-6, a murine anti–ligand-induced binding site monoclonal antibody specific for GP IIb/IIIa complexes occupied with fibrinogen. Similar findings were seen after disaggregation, when many single platelets were present that showed no signs of secretion. Flow cytometry confirmed that the number of ligand-occupied GP IIb/IIIa complexes was much lower on platelets stimulated with ADP or 2-MeS-ADP after clopidogrel treatment. As expected from previous studies, ADP-induced platelet shape change and Ca 2+ influx were unaffected by clopidogrel. These results agree with the hypothesis that platelet activation by ADP is biphasic and highlight a receptor-induced activation pathway affected by clopidogrel (or congenitally impaired in patient M.L.) that is necessary for the full activation of GP IIb/IIIa and the formation of stable macroaggregates.

Ticlopidine Selectively Inhibits Human Platelet Responses to Adenosine Diphosphate

1991 ◽  
Vol 66 (06) ◽  
pp. 694-699 ◽  
Author(s):  
Marco Cattaneo ◽  
Benjaporn Akkawat ◽  
Anna Lecchi ◽  
Claudio Cimminiello ◽  
Anna M Capitanio ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Clot Retraction ◽  
Fibrinogen Binding ◽  
Low Concentrations ◽  
Binding Inhibition ◽  
High Concentrations ◽  
Formalin Fixed

SummaryPlatelet aggregation and fibrinogen binding were studied in 15 individuals before and 7 days after the oral administration of ticlopidine (250 mg b.i.d.). Ticlopidine significantly inhibited platelet aggregation induced by adenosine diphosphate (ADP), the endoperoxide analogue U46619, collagen or low concentrations of thrombin, but did not inhibit platelet aggregation induced by epinephrine or high concentrations of thrombin. Ticlopidine inhibited 125I-fibrinogen binding induced by ADP, U46619 or thrombin (1 U/ml). The ADP scavengers apyrase or CP/CPK, added in vitro to platelet suspensions obtained before ticlopidine, caused the same pattern of aggregation and 125I-fibrihogen binding inhibition as did ticlopidine. Ticlopidine did not inhibit further platelet aggregation and 125I-fibrinogen binding induced in the presence of ADP scavengers. After ticlopidine administration, thrombin or U46619, but not ADP, increased the binding rate of the anti-GPIIb/IIIa monoclonal antibody 7E3 to platelets. Ticlopidine inhibited clot retraction induced by reptilase plus ADP, but not that induced by thrombin or by reptilase plus epinephrine, and prevented the inhibitory effect of ADP, but not that of epinephrine, on the PGE1-induced increase in platelet cyclic AMP. The number of high- and low-affinity binding sites for 3H-ADP on formalin-fixed platelets and their K d were not modified by ticlopidine. These findings indicate that ticlopidine selectively inhibits platelet responses to ADP.

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