Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs

Foster, Carolyn; Prosser, Dina M.; Agans, Jacqueline; Zhai, Ying; Smith, Michelle; Lachowicz, Jean E.; Zhang, Fang L.; Gustafson, Eric L.; Monsma, Frederick J.; Wiekowski, Maria; Abbondanzo, Susan J.; Cook, Donald N.; Bayne, Marvin L.; Lira, Sérgio A.; Chintala, Madhu

doi:10.1172/jci12242

Cited by 380 publications

(273 citation statements)

References 29 publications

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“…ADP binds to the G‐protein‐coupled receptors P2Y 1 22 and P2Y 12 23, 24 located on the platelet surface membrane. For a normal ADP‐induced activation and aggregation, responses from both pathways are required 25, 26, 27. When a P2Y 12 ‐receptor antagonist such as ticagrelor has bound to the platelet receptor, the ADP‐induced activation of P2Y 12 is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

Singh

Malm

Ramström

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundTemporarily improved platelet reactivity may reduce the bleeding in patients on antiplatelet therapy who have ongoing bleeding or who are in need of acute surgery. Adrenaline can bind to adrenergic α2A‐receptors on platelets and potentially enhance platelet reactivity.ObjectiveTo assess if adrenaline can improve adenosine diphosphate (ADP)‐induced platelet aggregation and activation in blood samples from patients on dual antiplatelet therapy with acetylsalicylic acid (ASA) and the ADP‐receptor antagonist ticagrelor.MethodsBlood samples were collected from a total of forty acute coronary syndrome patients on dual antiplatelet therapy with ASA and ticagrelor. ADP‐induced platelet aggregation (by impedance aggregometry) and activation (by flow cytometry) were assessed before and after supplementation with adrenaline and/or platelet concentrate.ResultsAdrenaline supplementation (770 nmol L−1) increased median ADP‐induced aggregation from 15 (25‐75th percentiles: 10‐20) to 26 (18‐38) aggregation units. The effect was independent of concomitant platelet supplementation. Adrenaline also increased ADP‐induced platelet activation: from 40% (36‐54%) to 83% (74‐88%) platelets with active fibrinogen receptor (binding PAC‐1) and from 13% (7‐21%) to 35% (18‐50%) P‐selectin‐expressing platelets.ConclusionsAdrenaline potentiated ADP‐induced platelet aggregation and activation in blood samples from ticagrelor‐treated patients. Adrenaline infusion may be a new method to enhance platelet function in ticagrelor‐treated patients who are in need of acute surgery or have ongoing bleeding. In vivo studies are needed to confirm the present results.

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Section: Discussionmentioning

confidence: 99%

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

Singh

Malm

Ramström

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…A few other patients of this sort have been identified and Cattaneo [8] has described the molecular defects in the P2Y 12 receptor in these patients. In 2001, mice that are deficient in the P2Y 12 receptor were produced and found to have a prolonged bleeding time [127]. Their platelets aggregate weakly in response to ADP, but shape change and calcium mobilization are normal.…”

Section: The P2y 12 Receptormentioning

confidence: 99%

Historical perspective on ADP-induced platelet activation

Packham

Rand

2011

Purinergic Signalling

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“…P2Y12-mediated signaling is a major step during integrin α IIb β 3 activation [18, 19] and reduced ADP availability may account for the observed aggregation defect. 0.1 U mL −1 thrombin-evoked aggregation in the presence of a P2Y12 inhibitor (1 µM AR-C66096) decreased by 36.7 ± 8.2% and 51.2 ± 7.4% in the presence of 151 and 1 mM [Cl − ] o ( P < 0.01, Figure 2bi), respectively.…”

Section: Resultsmentioning

confidence: 99%

Extracellular chloride is required for efficient platelet aggregation

et al. 2017

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Anion channels perform a diverse range of functions and have been implicated in ATP release, volume regulation, and phosphatidylserine exposure. Platelets have been shown to express several anion channels but their function is incompletely understood. Due to a paucity of specific pharmacological blockers, we investigated the effect of extracellular chloride substitution on platelet activation using aggregometry and flow cytometry. In the absence of extracellular chloride, we observed a modest reduction of the maximum aggregation response to thrombin or collagen-related peptide. However, the rate of aggregation was substantially reduced in a manner that was dependent on the extracellular chloride concentration and aggregation in the absence of chloride was noticeably biphasic, indicative of impaired secondary signaling. This was further investigated by targeting secondary agonists with aspirin and apyrase or by blockade of the ADP receptor P2Y12. Under these conditions, the rates of aggregation were comparable to those recorded in the absence of extracellular chloride. Finally, we assessed platelet granule release by flow cytometry and report a chloride-dependent element of alpha, but not dense, granule secretion. Taken together these data support a role for anion channels in the efficient induction of platelet activation, likely via enhancement of secondary signaling pathways.

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Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs

Cited by 380 publications

References 29 publications

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor‐treated patients

Historical perspective on ADP-induced platelet activation

Extracellular chloride is required for efficient platelet aggregation

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