Signaling via P2Y12 may be critical for early stabilization of platelet aggregates

Henry E. Speich, Vinay Bhal, Kourtney H. Houser, Alex T. Caughran, Lindsey T. Lands, Aiilyan K. Houng, Jonas Bäckstrom, Malin Enerbäck, Guy Reed, Lisa K. Jennings

Research output: Contribution to journalArticle

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Abstract

P2Y12 receptor antagonism inhibits platelet aggregation by preventing adenosine diphosphate (ADP)-mediated amplification of activation pathways downstream of primary agonists, such as thrombin and collagen. However, the role of ADP signaling in maintaining aggregate stability and the effects of P2Y12 antagonists on preestablished aggregates in vitro and arterial thrombus in vivo are not well understood. This study evaluated the impact of P2Y12 signaling on platelet aggregate stability and early thrombotic occlusion using a reversible P2Y12 antagonist, ticagrelor. There were 2 study objectives: (1) to determine if there was a time-dependent factor on the capacity of a P2Y12 antagonist to affect human platelet aggregate stability in vitro using light transmission aggregometry and (2) to evaluate the extent of arterial thrombus reversal in a preclinical model upon administration of ticagrelor in vivo. Platelet aggregates were exposed to ticagrelor after ADP or collagen activation, monitored for stability by aggregometry, and visualized by microscopy. Freshly formed ADP- and collagen-induced platelet aggregates were more rapidly dispersed by a P2Y12 antagonist than drug carrier control at clinically relevant concentrations (P < 0.05). However, stable aggregates were not noticeably affected. A murine arterial thrombosis model was used to evaluate thrombus stability in an in vivo mouse model. Thrombotic occlusion was induced by FeCl3, followed by a bolus intravenous administration of ticagrelor or vehicle control. Doppler blood flow was monitored before injury and 30 minutes after bolus administration. Arteries were retrieved for inspection for residual thrombus. Early arterial thrombotic occlusion in vivo was partially reversed by ticagrelor administration. Blood flow through the injured artery increased, and thrombus size within the artery decreased (P < 0.05, n = 3). In conclusion, P2Y12 antagonism disrupts the stability of newly formed platelet aggregates, promoting disaggregation, and reverses thrombotic vascular occlusion. Thus, in addition to activating platelets, signaling via P2Y12 seems to be required for stabilizing platelet thrombi.

Original languageEnglish (US)
Pages (from-to)520-527
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume63
Issue number6
DOIs
StatePublished - Jan 1 2014

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Thrombosis
Blood Platelets
Adenosine Diphosphate
Collagen
Arteries
Drug Carriers
Drug and Narcotic Control
Platelet Aggregation
Thrombin
Intravenous Administration
Blood Vessels
Microscopy
Ticagrelor
Light
Wounds and Injuries
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Speich, H. E., Bhal, V., Houser, K. H., Caughran, A. T., Lands, L. T., Houng, A. K., ... Jennings, L. K. (2014). Signaling via P2Y12 may be critical for early stabilization of platelet aggregates. Journal of Cardiovascular Pharmacology, 63(6), 520-527. https://doi.org/10.1097/FJC.0000000000000076

Signaling via P2Y12 may be critical for early stabilization of platelet aggregates. / Speich, Henry E.; Bhal, Vinay; Houser, Kourtney H.; Caughran, Alex T.; Lands, Lindsey T.; Houng, Aiilyan K.; Bäckstrom, Jonas; Enerbäck, Malin; Reed, Guy; Jennings, Lisa K.

In: Journal of Cardiovascular Pharmacology, Vol. 63, No. 6, 01.01.2014, p. 520-527.

Research output: Contribution to journalArticle

Speich, HE, Bhal, V, Houser, KH, Caughran, AT, Lands, LT, Houng, AK, Bäckstrom, J, Enerbäck, M, Reed, G & Jennings, LK 2014, 'Signaling via P2Y12 may be critical for early stabilization of platelet aggregates', Journal of Cardiovascular Pharmacology, vol. 63, no. 6, pp. 520-527. https://doi.org/10.1097/FJC.0000000000000076
Speich, Henry E. ; Bhal, Vinay ; Houser, Kourtney H. ; Caughran, Alex T. ; Lands, Lindsey T. ; Houng, Aiilyan K. ; Bäckstrom, Jonas ; Enerbäck, Malin ; Reed, Guy ; Jennings, Lisa K. / Signaling via P2Y12 may be critical for early stabilization of platelet aggregates. In: Journal of Cardiovascular Pharmacology. 2014 ; Vol. 63, No. 6. pp. 520-527.
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