Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model
Mark R Thomas, Samuel N Outteridge, Ramzi A Ajjan, Fladia Phoenix, Gurpreet K Sangha, Rachael E Faulkner, Rosemary Ecob, Heather M Judge, Haroon Khan, Laura E West, David H Dockrell, Ian Sabroe, Robert F Storey, Mark R Thomas, Samuel N Outteridge, Ramzi A Ajjan, Fladia Phoenix, Gurpreet K Sangha, Rachael E Faulkner, Rosemary Ecob, Heather M Judge, Haroon Khan, Laura E West, David H Dockrell, Ian Sabroe, Robert F Storey
Abstract
Objective: Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model.
Approach and results: We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 inhibitors significantly reduced platelet-monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor α, interleukin-6, and chemokine (C-C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony-stimulating factor and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y12 inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure.
Conclusions: Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y12 inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y12 inhibitors in patients with sepsis in clinical studies.
Trial registration: ClinicalTrials.gov NCT01846559.
Keywords: antiplatelet agents; clopidogrel; fibrin; infection; sepsis; thrombosis; ticagrelor.
© 2015 American Heart Association, Inc.
Figures
![Figure 1. Levels of pro-inflammatory cytokines TNFα…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0001.jpg)
Figure 2. Platelet-monocyte (A) and platelet-neutrophil (B)…
Figure 2. Platelet-monocyte (A) and platelet-neutrophil (B) aggregate formation and platelet P-selectin expression (C) at…
Figure 3. Leukocyte (A), neutrophil (B), monocyte…
Figure 3. Leukocyte (A), neutrophil (B), monocyte (C) and platelet (D) counts before and after…
Figure 4. Levels of D-dimer (A) and…
Figure 4. Levels of D-dimer (A) and fibrin clot maximum absorbance (B) (a measure of…
Figure 5. Representative electron microscope images of…
Figure 5. Representative electron microscope images of fibrin clots formed from plasma ex vivo in…
Figure 6. Fibrin fiber diameter (A) and…
Figure 6. Fibrin fiber diameter (A) and fibrin network density (B) (determined by electron microscopy)…
- Effect of P2Y12 inhibitors on inflammation and immunity.Thomas MR, Storey RF. Thomas MR, et al. Thromb Haemost. 2015 Aug 31;114(3):490-7. doi: 10.1160/TH14-12-1068. Epub 2015 Jul 9. Thromb Haemost. 2015. PMID: 26156883 Review.
- Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry.Olivier CB, Diehl P, Schnabel K, Weik P, Zhou Q, Bode C, Moser M. Olivier CB, et al. Thromb Haemost. 2014 Feb;111(2):266-72. doi: 10.1160/TH13-06-0508. Epub 2013 Oct 31. Thromb Haemost. 2014. PMID: 24172891
- A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia.Kiers D, van der Heijden WA, van Ede L, Gerretsen J, de Mast Q, van der Ven AJ, El Messaoudi S, Rongen GA, Gomes M, Kox M, Pickkers P, Riksen NP. Kiers D, et al. Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6. Thromb Haemost. 2017. PMID: 28692111 Clinical Trial.
- Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.Traby L, Kollars M, Kaider A, Eichinger S, Wolzt M, Kyrle PA. Traby L, et al. J Thromb Haemost. 2016 Feb;14(2):273-81. doi: 10.1111/jth.13216. Epub 2016 Jan 30. J Thromb Haemost. 2016. PMID: 26663880 Clinical Trial.
- Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes.Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Schrottmaier WC, et al. Thromb Haemost. 2015 Aug 31;114(3):478-89. doi: 10.1160/TH14-11-0943. Epub 2015 Apr 23. Thromb Haemost. 2015. PMID: 25904241 Review.
- Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.Jain N, Corken A, Arthur JM, Ware J, Arulprakash N, Dai J, Phadnis MA, Davis O, Rahmatallah Y, Mehta JL, Hedayati SS, Smyth S. Jain N, et al. Vascul Pharmacol. 2023 Feb;148:107143. doi: 10.1016/j.vph.2023.107143. Epub 2023 Jan 20. Vascul Pharmacol. 2023. PMID: 36682595 Clinical Trial.
- Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches.Gauer JS, Ajjan RA, Ariëns RAS. Gauer JS, et al. J Am Heart Assoc. 2022 Oct 18;11(20):e027071. doi: 10.1161/JAHA.122.027071. Epub 2022 Oct 17. J Am Heart Assoc. 2022. PMID: 36250653 Free PMC article. Review.
- Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response.Chen Z, Wang G, Xie X, Liu H, Liao J, Shi H, Chen M, Lai S, Wang Z, Wu X. Chen Z, et al. Front Immunol. 2022 Aug 12;13:918476. doi: 10.3389/fimmu.2022.918476. eCollection 2022. Front Immunol. 2022. PMID: 36032109 Free PMC article.
- An Insight into Recent Advances on Platelet Function in Health and Disease.Chaudhary PK, Kim S, Kim S. Chaudhary PK, et al. Int J Mol Sci. 2022 May 27;23(11):6022. doi: 10.3390/ijms23116022. Int J Mol Sci. 2022. PMID: 35682700 Free PMC article. Review.
- Pleiotropic effects of clopidogrel.Kuszynski DS, Lauver DA. Kuszynski DS, et al. Purinergic Signal. 2022 Sep;18(3):253-265. doi: 10.1007/s11302-022-09876-0. Epub 2022 Jun 9. Purinergic Signal. 2022. PMID: 35678974 Free PMC article. Review.
- Comparative Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adenosine / analogs & derivatives*
- Adenosine / therapeutic use
- Anti-Inflammatory Agents / therapeutic use*
- Biomarkers / blood
- Blood Platelets / drug effects*
- Blood Platelets / metabolism
- Chemotaxis, Leukocyte / drug effects
- Clopidogrel
- Cytokines / blood
- Endotoxins
- England
- Female
- Fibrin Fibrinogen Degradation Products / metabolism
- Humans
- Inflammation / blood
- Inflammation / chemically induced
- Inflammation / drug therapy*
- Inflammation Mediators / blood
- Male
- Platelet Adhesiveness / drug effects
- Platelet Aggregation Inhibitors / therapeutic use*
- Prospective Studies
- Purinergic P2Y Receptor Antagonists / therapeutic use*
- Receptors, Purinergic P2Y12 / blood*
- Thrombosis / blood
- Thrombosis / chemically induced
- Thrombosis / drug therapy*
- Ticagrelor
- Ticlopidine / analogs & derivatives*
- Ticlopidine / therapeutic use
- Time Factors
- Treatment Outcome
- Young Adult
- Anti-Inflammatory Agents
- Biomarkers
- Cytokines
- Endotoxins
- Fibrin Fibrinogen Degradation Products
- Inflammation Mediators
- P2RY12 protein, human
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Receptors, Purinergic P2Y12
- fibrin fragment D
- endotoxin, Escherichia coli
- Clopidogrel
- Ticagrelor
- Adenosine
- Ticlopidine
- ClinicalTrials.gov/NCT01846559
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2. Platelet-monocyte (A) and platelet-neutrophil (B)…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0002.jpg)
Figure 3. Leukocyte (A), neutrophil (B), monocyte…
Figure 3. Leukocyte (A), neutrophil (B), monocyte (C) and platelet (D) counts before and after…
Figure 4. Levels of D-dimer (A) and…
Figure 4. Levels of D-dimer (A) and fibrin clot maximum absorbance (B) (a measure of…
Figure 5. Representative electron microscope images of…
Figure 5. Representative electron microscope images of fibrin clots formed from plasma ex vivo in…
Figure 6. Fibrin fiber diameter (A) and…
Figure 6. Fibrin fiber diameter (A) and fibrin network density (B) (determined by electron microscopy)…
- Effect of P2Y12 inhibitors on inflammation and immunity.Thomas MR, Storey RF. Thomas MR, et al. Thromb Haemost. 2015 Aug 31;114(3):490-7. doi: 10.1160/TH14-12-1068. Epub 2015 Jul 9. Thromb Haemost. 2015. PMID: 26156883 Review.
- Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry.Olivier CB, Diehl P, Schnabel K, Weik P, Zhou Q, Bode C, Moser M. Olivier CB, et al. Thromb Haemost. 2014 Feb;111(2):266-72. doi: 10.1160/TH13-06-0508. Epub 2013 Oct 31. Thromb Haemost. 2014. PMID: 24172891
- A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia.Kiers D, van der Heijden WA, van Ede L, Gerretsen J, de Mast Q, van der Ven AJ, El Messaoudi S, Rongen GA, Gomes M, Kox M, Pickkers P, Riksen NP. Kiers D, et al. Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6. Thromb Haemost. 2017. PMID: 28692111 Clinical Trial.
- Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.Traby L, Kollars M, Kaider A, Eichinger S, Wolzt M, Kyrle PA. Traby L, et al. J Thromb Haemost. 2016 Feb;14(2):273-81. doi: 10.1111/jth.13216. Epub 2016 Jan 30. J Thromb Haemost. 2016. PMID: 26663880 Clinical Trial.
- Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes.Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Schrottmaier WC, et al. Thromb Haemost. 2015 Aug 31;114(3):478-89. doi: 10.1160/TH14-11-0943. Epub 2015 Apr 23. Thromb Haemost. 2015. PMID: 25904241 Review.
- Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.Jain N, Corken A, Arthur JM, Ware J, Arulprakash N, Dai J, Phadnis MA, Davis O, Rahmatallah Y, Mehta JL, Hedayati SS, Smyth S. Jain N, et al. Vascul Pharmacol. 2023 Feb;148:107143. doi: 10.1016/j.vph.2023.107143. Epub 2023 Jan 20. Vascul Pharmacol. 2023. PMID: 36682595 Clinical Trial.
- Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches.Gauer JS, Ajjan RA, Ariëns RAS. Gauer JS, et al. J Am Heart Assoc. 2022 Oct 18;11(20):e027071. doi: 10.1161/JAHA.122.027071. Epub 2022 Oct 17. J Am Heart Assoc. 2022. PMID: 36250653 Free PMC article. Review.
- Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response.Chen Z, Wang G, Xie X, Liu H, Liao J, Shi H, Chen M, Lai S, Wang Z, Wu X. Chen Z, et al. Front Immunol. 2022 Aug 12;13:918476. doi: 10.3389/fimmu.2022.918476. eCollection 2022. Front Immunol. 2022. PMID: 36032109 Free PMC article.
- An Insight into Recent Advances on Platelet Function in Health and Disease.Chaudhary PK, Kim S, Kim S. Chaudhary PK, et al. Int J Mol Sci. 2022 May 27;23(11):6022. doi: 10.3390/ijms23116022. Int J Mol Sci. 2022. PMID: 35682700 Free PMC article. Review.
- Pleiotropic effects of clopidogrel.Kuszynski DS, Lauver DA. Kuszynski DS, et al. Purinergic Signal. 2022 Sep;18(3):253-265. doi: 10.1007/s11302-022-09876-0. Epub 2022 Jun 9. Purinergic Signal. 2022. PMID: 35678974 Free PMC article. Review.
- Comparative Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adenosine / analogs & derivatives*
- Adenosine / therapeutic use
- Anti-Inflammatory Agents / therapeutic use*
- Biomarkers / blood
- Blood Platelets / drug effects*
- Blood Platelets / metabolism
- Chemotaxis, Leukocyte / drug effects
- Clopidogrel
- Cytokines / blood
- Endotoxins
- England
- Female
- Fibrin Fibrinogen Degradation Products / metabolism
- Humans
- Inflammation / blood
- Inflammation / chemically induced
- Inflammation / drug therapy*
- Inflammation Mediators / blood
- Male
- Platelet Adhesiveness / drug effects
- Platelet Aggregation Inhibitors / therapeutic use*
- Prospective Studies
- Purinergic P2Y Receptor Antagonists / therapeutic use*
- Receptors, Purinergic P2Y12 / blood*
- Thrombosis / blood
- Thrombosis / chemically induced
- Thrombosis / drug therapy*
- Ticagrelor
- Ticlopidine / analogs & derivatives*
- Ticlopidine / therapeutic use
- Time Factors
- Treatment Outcome
- Young Adult
- Anti-Inflammatory Agents
- Biomarkers
- Cytokines
- Endotoxins
- Fibrin Fibrinogen Degradation Products
- Inflammation Mediators
- P2RY12 protein, human
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Receptors, Purinergic P2Y12
- fibrin fragment D
- endotoxin, Escherichia coli
- Clopidogrel
- Ticagrelor
- Adenosine
- Ticlopidine
- ClinicalTrials.gov/NCT01846559
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 3. Leukocyte (A), neutrophil (B), monocyte…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0003.jpg)
Figure 4. Levels of D-dimer (A) and…
Figure 4. Levels of D-dimer (A) and fibrin clot maximum absorbance (B) (a measure of…
Figure 5. Representative electron microscope images of…
Figure 5. Representative electron microscope images of fibrin clots formed from plasma ex vivo in…
Figure 6. Fibrin fiber diameter (A) and…
Figure 6. Fibrin fiber diameter (A) and fibrin network density (B) (determined by electron microscopy)…
- Effect of P2Y12 inhibitors on inflammation and immunity.Thomas MR, Storey RF. Thomas MR, et al. Thromb Haemost. 2015 Aug 31;114(3):490-7. doi: 10.1160/TH14-12-1068. Epub 2015 Jul 9. Thromb Haemost. 2015. PMID: 26156883 Review.
- Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry.Olivier CB, Diehl P, Schnabel K, Weik P, Zhou Q, Bode C, Moser M. Olivier CB, et al. Thromb Haemost. 2014 Feb;111(2):266-72. doi: 10.1160/TH13-06-0508. Epub 2013 Oct 31. Thromb Haemost. 2014. PMID: 24172891
- A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia.Kiers D, van der Heijden WA, van Ede L, Gerretsen J, de Mast Q, van der Ven AJ, El Messaoudi S, Rongen GA, Gomes M, Kox M, Pickkers P, Riksen NP. Kiers D, et al. Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6. Thromb Haemost. 2017. PMID: 28692111 Clinical Trial.
- Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.Traby L, Kollars M, Kaider A, Eichinger S, Wolzt M, Kyrle PA. Traby L, et al. J Thromb Haemost. 2016 Feb;14(2):273-81. doi: 10.1111/jth.13216. Epub 2016 Jan 30. J Thromb Haemost. 2016. PMID: 26663880 Clinical Trial.
- Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes.Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Schrottmaier WC, et al. Thromb Haemost. 2015 Aug 31;114(3):478-89. doi: 10.1160/TH14-11-0943. Epub 2015 Apr 23. Thromb Haemost. 2015. PMID: 25904241 Review.
- Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.Jain N, Corken A, Arthur JM, Ware J, Arulprakash N, Dai J, Phadnis MA, Davis O, Rahmatallah Y, Mehta JL, Hedayati SS, Smyth S. Jain N, et al. Vascul Pharmacol. 2023 Feb;148:107143. doi: 10.1016/j.vph.2023.107143. Epub 2023 Jan 20. Vascul Pharmacol. 2023. PMID: 36682595 Clinical Trial.
- Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches.Gauer JS, Ajjan RA, Ariëns RAS. Gauer JS, et al. J Am Heart Assoc. 2022 Oct 18;11(20):e027071. doi: 10.1161/JAHA.122.027071. Epub 2022 Oct 17. J Am Heart Assoc. 2022. PMID: 36250653 Free PMC article. Review.
- Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response.Chen Z, Wang G, Xie X, Liu H, Liao J, Shi H, Chen M, Lai S, Wang Z, Wu X. Chen Z, et al. Front Immunol. 2022 Aug 12;13:918476. doi: 10.3389/fimmu.2022.918476. eCollection 2022. Front Immunol. 2022. PMID: 36032109 Free PMC article.
- An Insight into Recent Advances on Platelet Function in Health and Disease.Chaudhary PK, Kim S, Kim S. Chaudhary PK, et al. Int J Mol Sci. 2022 May 27;23(11):6022. doi: 10.3390/ijms23116022. Int J Mol Sci. 2022. PMID: 35682700 Free PMC article. Review.
- Pleiotropic effects of clopidogrel.Kuszynski DS, Lauver DA. Kuszynski DS, et al. Purinergic Signal. 2022 Sep;18(3):253-265. doi: 10.1007/s11302-022-09876-0. Epub 2022 Jun 9. Purinergic Signal. 2022. PMID: 35678974 Free PMC article. Review.
- Comparative Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adenosine / analogs & derivatives*
- Adenosine / therapeutic use
- Anti-Inflammatory Agents / therapeutic use*
- Biomarkers / blood
- Blood Platelets / drug effects*
- Blood Platelets / metabolism
- Chemotaxis, Leukocyte / drug effects
- Clopidogrel
- Cytokines / blood
- Endotoxins
- England
- Female
- Fibrin Fibrinogen Degradation Products / metabolism
- Humans
- Inflammation / blood
- Inflammation / chemically induced
- Inflammation / drug therapy*
- Inflammation Mediators / blood
- Male
- Platelet Adhesiveness / drug effects
- Platelet Aggregation Inhibitors / therapeutic use*
- Prospective Studies
- Purinergic P2Y Receptor Antagonists / therapeutic use*
- Receptors, Purinergic P2Y12 / blood*
- Thrombosis / blood
- Thrombosis / chemically induced
- Thrombosis / drug therapy*
- Ticagrelor
- Ticlopidine / analogs & derivatives*
- Ticlopidine / therapeutic use
- Time Factors
- Treatment Outcome
- Young Adult
- Anti-Inflammatory Agents
- Biomarkers
- Cytokines
- Endotoxins
- Fibrin Fibrinogen Degradation Products
- Inflammation Mediators
- P2RY12 protein, human
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Receptors, Purinergic P2Y12
- fibrin fragment D
- endotoxin, Escherichia coli
- Clopidogrel
- Ticagrelor
- Adenosine
- Ticlopidine
- ClinicalTrials.gov/NCT01846559
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4. Levels of D-dimer (A) and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0004.jpg)
Figure 5. Representative electron microscope images of…
Figure 5. Representative electron microscope images of fibrin clots formed from plasma ex vivo in…
Figure 6. Fibrin fiber diameter (A) and…
Figure 6. Fibrin fiber diameter (A) and fibrin network density (B) (determined by electron microscopy)…
- Effect of P2Y12 inhibitors on inflammation and immunity.Thomas MR, Storey RF. Thomas MR, et al. Thromb Haemost. 2015 Aug 31;114(3):490-7. doi: 10.1160/TH14-12-1068. Epub 2015 Jul 9. Thromb Haemost. 2015. PMID: 26156883 Review.
- Third generation P2Y12 antagonists inhibit platelet aggregation more effectively than clopidogrel in a myocardial infarction registry.Olivier CB, Diehl P, Schnabel K, Weik P, Zhou Q, Bode C, Moser M. Olivier CB, et al. Thromb Haemost. 2014 Feb;111(2):266-72. doi: 10.1160/TH13-06-0508. Epub 2013 Oct 31. Thromb Haemost. 2014. PMID: 24172891
- A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia.Kiers D, van der Heijden WA, van Ede L, Gerretsen J, de Mast Q, van der Ven AJ, El Messaoudi S, Rongen GA, Gomes M, Kox M, Pickkers P, Riksen NP. Kiers D, et al. Thromb Haemost. 2017 Aug 30;117(9):1798-1807. doi: 10.1160/TH16-10-0799. Epub 2017 Jul 6. Thromb Haemost. 2017. PMID: 28692111 Clinical Trial.
- Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects.Traby L, Kollars M, Kaider A, Eichinger S, Wolzt M, Kyrle PA. Traby L, et al. J Thromb Haemost. 2016 Feb;14(2):273-81. doi: 10.1111/jth.13216. Epub 2016 Jan 30. J Thromb Haemost. 2016. PMID: 26663880 Clinical Trial.
- Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes.Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Schrottmaier WC, et al. Thromb Haemost. 2015 Aug 31;114(3):478-89. doi: 10.1160/TH14-11-0943. Epub 2015 Apr 23. Thromb Haemost. 2015. PMID: 25904241 Review.
- Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.Jain N, Corken A, Arthur JM, Ware J, Arulprakash N, Dai J, Phadnis MA, Davis O, Rahmatallah Y, Mehta JL, Hedayati SS, Smyth S. Jain N, et al. Vascul Pharmacol. 2023 Feb;148:107143. doi: 10.1016/j.vph.2023.107143. Epub 2023 Jan 20. Vascul Pharmacol. 2023. PMID: 36682595 Clinical Trial.
- Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches.Gauer JS, Ajjan RA, Ariëns RAS. Gauer JS, et al. J Am Heart Assoc. 2022 Oct 18;11(20):e027071. doi: 10.1161/JAHA.122.027071. Epub 2022 Oct 17. J Am Heart Assoc. 2022. PMID: 36250653 Free PMC article. Review.
- Ginsenoside Rg5 allosterically interacts with P2RY12 and ameliorates deep venous thrombosis by counteracting neutrophil NETosis and inflammatory response.Chen Z, Wang G, Xie X, Liu H, Liao J, Shi H, Chen M, Lai S, Wang Z, Wu X. Chen Z, et al. Front Immunol. 2022 Aug 12;13:918476. doi: 10.3389/fimmu.2022.918476. eCollection 2022. Front Immunol. 2022. PMID: 36032109 Free PMC article.
- An Insight into Recent Advances on Platelet Function in Health and Disease.Chaudhary PK, Kim S, Kim S. Chaudhary PK, et al. Int J Mol Sci. 2022 May 27;23(11):6022. doi: 10.3390/ijms23116022. Int J Mol Sci. 2022. PMID: 35682700 Free PMC article. Review.
- Pleiotropic effects of clopidogrel.Kuszynski DS, Lauver DA. Kuszynski DS, et al. Purinergic Signal. 2022 Sep;18(3):253-265. doi: 10.1007/s11302-022-09876-0. Epub 2022 Jun 9. Purinergic Signal. 2022. PMID: 35678974 Free PMC article. Review.
- Comparative Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adenosine / analogs & derivatives*
- Adenosine / therapeutic use
- Anti-Inflammatory Agents / therapeutic use*
- Biomarkers / blood
- Blood Platelets / drug effects*
- Blood Platelets / metabolism
- Chemotaxis, Leukocyte / drug effects
- Clopidogrel
- Cytokines / blood
- Endotoxins
- England
- Female
- Fibrin Fibrinogen Degradation Products / metabolism
- Humans
- Inflammation / blood
- Inflammation / chemically induced
- Inflammation / drug therapy*
- Inflammation Mediators / blood
- Male
- Platelet Adhesiveness / drug effects
- Platelet Aggregation Inhibitors / therapeutic use*
- Prospective Studies
- Purinergic P2Y Receptor Antagonists / therapeutic use*
- Receptors, Purinergic P2Y12 / blood*
- Thrombosis / blood
- Thrombosis / chemically induced
- Thrombosis / drug therapy*
- Ticagrelor
- Ticlopidine / analogs & derivatives*
- Ticlopidine / therapeutic use
- Time Factors
- Treatment Outcome
- Young Adult
- Anti-Inflammatory Agents
- Biomarkers
- Cytokines
- Endotoxins
- Fibrin Fibrinogen Degradation Products
- Inflammation Mediators
- P2RY12 protein, human
- Platelet Aggregation Inhibitors
- Purinergic P2Y Receptor Antagonists
- Receptors, Purinergic P2Y12
- fibrin fragment D
- endotoxin, Escherichia coli
- Clopidogrel
- Ticagrelor
- Adenosine
- Ticlopidine
- ClinicalTrials.gov/NCT01846559
![Figure 5. Representative electron microscope images of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0005.jpg)
![Figure 6. Fibrin fiber diameter (A) and…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4663676/bin/emss-65643-f0006.jpg)
Source: PubMed