CC BY-NC-ND 4.0 · Hamostaseologie 2023; 43(02): 110-121
DOI: 10.1055/a-1739-9351
Review Article

Platelets in Myocardial Ischemia/Reperfusion Injury

Nancy Schanze
1   Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
2   Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany
Muataz Ali Hamad
1   Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
3   Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
4   Faculty of Biology, University of Freiburg, Freiburg, Germany
Thomas Georg Nührenberg
5   Department of Cardiology and Angiology II, Heart Center, University of Freiburg, Freiburg, Germany
6   Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany
Christoph Bode
1   Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
Daniel Duerschmied
1   Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
2   Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany
7   European Center for AngioScience (ECAS) and German Center for Cardiovascular Research (DZHK) partner site Heidelberg/Mannheim, Mannheim, Germany
› Author Affiliations


Coronary artery disease, including myocardial infarction (MI), remains a leading cause of global mortality. Rapid reperfusion therapy is key to the improvement of patient outcome but contributes substantially to the final cardiac damage. This phenomenon is called “ischemia/reperfusion injury (IRI).” The underlying mechanisms of IRI are complex and not fully understood. Contributing cellular and molecular mechanisms involve the formation of microthrombi, alterations in ion concentrations, pH shifts, dysregulation of osmolality, and, importantly, inflammation. Beyond their known action as drivers of the development of coronary plaques leading to MI, platelets have been identified as important mediators in myocardial IRI. Circulating platelets are activated by the IRI-provoked damages in the vascular endothelium. This leads to platelet adherence to the reperfused endothelium, aggregation, and the formation of microthrombi. Furthermore, activated platelets release vasoconstrictive substances, act via surface molecules, and enhance leukocyte infiltration into post-IR tissue, that is, via platelet–leukocyte complexes. A better understanding of platelet contributions to myocardial IRI, including their interaction with other lesion-associated cells, is necessary to develop effective treatment strategies to prevent IRI and further improve the condition of the reperfused myocardium. In this review, we briefly summarize platelet properties that modulate IRI. We also describe the beneficial impacts of antiplatelet agents as well as their mechanisms of action in IRI beyond classic effects.

Publication History

Received: 15 June 2021

Accepted: 13 January 2022

Article published online:
29 July 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb Haemost 2014; 112 (04) 678-691
  • 2 Antczak AJ, Singh N, Gay SR, Worth RG. IgG-complex stimulated platelets: a source of sCD40L and RANTES in initiation of inflammatory cascade. Cell Immunol 2010; 263 (01) 129-133
  • 3 von Hundelshausen P, Koenen RR, Sack M. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005; 105 (03) 924-930
  • 4 von Hundelshausen P, Weber KS, Huo Y. et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 2001; 103 (13) 1772-1777
  • 5 Scheuerer B, Ernst M, Dürrbaum-Landmann I. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95 (04) 1158-1166
  • 6 Duerschmied D, Suidan GL, Demers M. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121 (06) 1008-1015
  • 7 Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008; 111 (11) 5271-5281
  • 8 Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 2007; 21 (02) 99-111
  • 9 Moore KL, Stults NL, Diaz S. et al. Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells. J Cell Biol 1992; 118 (02) 445-456
  • 10 Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res 2007; 100 (12) 1673-1685
  • 11 Coller BS, Peerschke EI, Scudder LE, Sullivan CA. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983; 72 (01) 325-338
  • 12 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell 1998; 94 (05) 657-666
  • 13 Ginsberg MH, Forsyth J, Lightsey A, Chediak J, Plow EF. Reduced surface expression and binding of fibronectin by thrombin-stimulated thrombasthenic platelets. J Clin Invest 1983; 71 (03) 619-624
  • 14 Wencel-Drake JD, Painter RG, Zimmerman TS, Ginsberg MH. Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin section. Blood 1985; 65 (04) 929-938
  • 15 Del Conde I, Crúz MA, Zhang H, López JA, Afshar-Kharghan V. Platelet activation leads to activation and propagation of the complement system. J Exp Med 2005; 201 (06) 871-879
  • 16 Roth GA, Mensah GA, Johnson CO. et al; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020; 76 (25) 2982-3021
  • 17 Prasad A, Stone GW, Holmes DR, Gersh B. Reperfusion injury, microvascular dysfunction, and cardioprotection: the “dark side” of reperfusion. Circulation 2009; 120 (21) 2105-2112
  • 18 Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123 (01) 92-100
  • 19 Fröhlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J 2013; 34 (23) 1714-1722
  • 20 Yang CF. Clinical manifestations and basic mechanisms of myocardial ischemia/reperfusion injury. Ci Ji Yi Xue Za Zhi 2018; 30 (04) 209-215
  • 21 Zhang W, Chen C, Wang J, Liu L, He Y, Chen Q. Mitophagy in cardiomyocytes and in platelets: a major mechanism of cardioprotection against ischemia/reperfusion injury. Physiology (Bethesda) 2018; 33 (02) 86-98
  • 22 Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, Inserte J, Barba I. Myocardial edema: a translational view. J Mol Cell Cardiol 2012; 52 (05) 931-939
  • 23 Hausenloy DJ, Chilian W, Crea F. et al. The coronary circulation in acute myocardial ischaemia/reperfusion injury: a target for cardioprotection. Cardiovasc Res 2019; 115 (07) 1143-1155
  • 24 Menger MD, Vollmar B. Pathomechanisms of ischemia-reperfusion injury as the basis for novel preventive strategies: is it time for the introduction of pleiotropic compounds?. Transplant Proc 2007; 39 (02) 485-488
  • 25 Bonaventura A, Montecucco F, Dallegri F. Cellular recruitment in myocardial ischaemia/reperfusion injury. Eur J Clin Invest 2016; 46 (06) 590-601
  • 26 Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 2014; 11 (05) 255-265
  • 27 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61 (03) 498-511
  • 28 Golebiewska EM, Poole AW. Platelet secretion: from haemostasis to wound healing and beyond. Blood Rev 2015; 29 (03) 153-162
  • 29 Barrabés JA, Inserte J, Agulló L, Alonso A, Mirabet M, Garcia-Dorado D. Microvascular thrombosis: an exciting but elusive therapeutic target in reperfused acute myocardial infarction. Cardiovasc Hematol Disord Drug Targets 2010; 10 (04) 273-283
  • 30 Köhler D, Straub A, Weissmüller T. et al. Phosphorylation of vasodilator-stimulated phosphoprotein prevents platelet-neutrophil complex formation and dampens myocardial ischemia-reperfusion injury. Circulation 2011; 123 (22) 2579-2590
  • 31 Cameron SJ, Mix DS, Ture SK. et al. Hypoxia and ischemia promote a maladaptive platelet phenotype. Arterioscler Thromb Vasc Biol 2018; 38 (07) 1594-1606
  • 32 Kiouptsi K, Gambaryan S, Walter E, Walter U, Jurk K, Reinhardt C. Hypoxia impairs agonist-induced integrin αIIbβ3 activation and platelet aggregation. Sci Rep 2017; 7 (01) 7621
  • 33 Braune S, Küpper JH, Jung F. Effect of prostanoids on human platelet function: an overview. Int J Mol Sci 2020; 21 (23) E9020
  • 34 Allencherril J, Alam M, Levine G. et al. Do we need potent intravenous antiplatelet inhibition at the time of reperfusion during ST-segment elevation myocardial infarction?. J Cardiovasc Pharmacol Ther 2019; 24 (03) 215-224
  • 35 Smyth EM. Thromboxane and the thromboxane receptor in cardiovascular disease. Clin Lipidol 2010; 5 (02) 209-219
  • 36 Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 2 (8607): 349-360
  • 37 d'Alessandro E, Becker C, Bergmeier W. et al; Scientific Reviewer Committee. Thrombo-inflammation in cardiovascular disease: an expert consensus document from the Third Maastricht Consensus Conference on Thrombosis. Thromb Haemost 2020; 120 (04) 538-564
  • 38 Loew D, Vinazzer H. Dose-dependent influence of acetylsalicyclic acid on platelet functions and plasmatic coagulation factors. Haemostasis 1976; 5 (04) 239-249
  • 39 Moroz LA. Increased blood fibrinolytic activity after aspirin ingestion. N Engl J Med 1977; 296 (10) 525-529
  • 40 Wu Z, Li X, Li X, Yu L. Effects of aspirin on myocardial ischemia-reperfusion injury in rats through STAT3 signaling pathway. BioMed Res Int 2021; 2021: 9931885
  • 41 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
  • 42 Chambers RC, Laurent GJ. Coagulation cascade proteases and tissue fibrosis. Biochem Soc Trans 2002; 30 (02) 194-200
  • 43 Berlioz BE, Sanghavi D. Bivalirudin. StatPearls; 2021
  • 44 Lund M, Macwan AS, Tunströmer K, Lindahl TL, Boknäs N. Effects of heparin and bivalirudin on thrombin-induced platelet activation: differential modulation of PAR signaling drives divergent prothrombotic responses. Front Cardiovasc Med 2021; 8: 717835
  • 45 Anand SX, Kim MC, Kamran M. et al. Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol 2007; 100 (03) 417-424
  • 46 Erlich JH, Boyle EM, Labriola J. et al. Inhibition of the tissue factor-thrombin pathway limits infarct size after myocardial ischemia-reperfusion injury by reducing inflammation. Am J Pathol 2000; 157 (06) 1849-1862
  • 47 Kolpakov MA, Rafiq K, Guo X. et al. Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury. J Mol Cell Cardiol 2016; 90: 21-29
  • 48 Kolpakov MA, Guo X, Rafiq K. et al. Loss of protease-activated receptor 4 prevents inflammation resolution and predisposes the heart to cardiac rupture after myocardial infarction. Circulation 2020; 142 (08) 758-775
  • 49 Chaudhary R, Mohananey A, Sharma SP, Singh S, Singh A, Kondur A. Improving outcomes in cardiovascular diseases: a review on vorapaxar. Cardiol Rev 2021; 19 DOI: 10.1097/CRD.0000000000000390.
  • 50 Heemskerk JW, Mattheij NJ, Cosemans JM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost 2013; 11 (01) 2-16
  • 51 Ten Cate H, Guzik TJ, Eikelboom J, Spronk HMH. Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment. Cardiovasc Res 2021; 117 (09) 2030-2044
  • 52 Rocha BML, da Cunha GJL, Aguiar CMT. A narrative review of low-dose rivaroxaban in patients with atherothrombotic cardiovascular disease: vascular protection beyond anticoagulation. Cardiovasc Diagn Ther 2021; 11 (01) 130-141
  • 53 Mega JL, Braunwald E, Wiviott SD. et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366 (01) 9-19
  • 54 Goto M, Miura S, Suematsu Y. et al. Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice. Int J Cardiol 2016; 220: 602-607
  • 55 Lorentz CU, Verbout NG, Cao Z. et al. Factor XI contributes to myocardial ischemia-reperfusion injury in mice. Blood Adv 2018; 2 (02) 85-88
  • 56
  • 57 Wang K, Zhou X, Huang Y. et al. Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. Thromb Haemost 2010; 104 (03) 609-617
  • 58 Barrabés JA, Inserte J, Mirabet M. et al. Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 2010; 104 (01) 128-135
  • 59 Penna C, Aragno M, Cento AS. et al. Ticagrelor conditioning effects are not additive to cardioprotection induced by direct NLRP3 inflammasome inhibition: role of RISK, NLRP3, and redox cascades. Oxid Med Cell Longev 2020; 2020: 9219825
  • 60 Yang XM, Liu Y, Cui L. et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther 2013; 18 (03) 251-262
  • 61 Patti G, Bárczi G, Orlic D. et al. Outcome comparison of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol 2011; 58 (15) 1592-1599
  • 62 Storey RF, Husted S, Harrington RA. et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 2007; 50 (19) 1852-1856
  • 63 Cannon CP, Husted S, Harrington RA. et al; DISPERSE-2 Investigators. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 2007; 50 (19) 1844-1851
  • 64 Cannon CP, Harrington RA, James S. et al; PLATelet inhibition and patient Outcomes Investigators. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375 (9711): 283-293
  • 65 van Leeuwen MAH, van der Hoeven NW, Janssens GN. et al. Evaluation of microvascular injury in revascularized patients with ST-segment-elevation myocardial infarction treated with ticagrelor versus prasugrel. Circulation 2019; 139 (05) 636-646
  • 66 Storey RF, Judge HM, Wilcox RG, Heptinstall S. Inhibition of ADP-induced P-selectin expression and platelet-leukocyte conjugate formation by clopidogrel and the P2Y12 receptor antagonist AR-C69931MX but not aspirin. Thromb Haemost 2002; 88 (03) 488-494
  • 67 Bonello L, Laine M, Kipson N. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014; 63 (09) 872-877
  • 68 Cattaneo M, Schulz R, Nylander S. Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol 2014; 63 (23) 2503-2509
  • 69 Vilahur G, Gutiérrez M, Casani L. et al. Protective effects of ticagrelor on myocardial injury after infarction. Circulation 2016; 134 (22) 1708-1719
  • 70 Ye Y, Birnbaum GD, Perez-Polo JR, Nanhwan MK, Nylander S, Birnbaum Y. Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. Arterioscler Thromb Vasc Biol 2015; 35 (08) 1805-1814
  • 71 Birnbaum Y, Birnbaum GD, Birnbaum I, Nylander S, Ye Y. Ticagrelor and rosuvastatin have additive cardioprotective effects via adenosine. Cardiovasc Drugs Ther 2016; 30 (06) 539-550
  • 72 Yang XM, Gadde S, Audia JP, Alvarez DF, Downey JM, Cohen MV. Ticagrelor does not protect isolated rat hearts, thus clouding its proposed cardioprotective role through ENT 1 in heart tissue. J Cardiovasc Pharmacol Ther 2019; 24 (04) 371-376
  • 73 Kleinbongard P, Andreadou I, Vilahur G. The platelet paradox of injury versus protection in myocardial infarction - Has it been overlooked?. Basic Res Cardiol 2021; 116 (01) 37
  • 74 Mastrocola R, Penna C, Tullio F. et al. Pharmacological inhibition of NLRP3 inflammasome attenuates myocardial ischemia/reperfusion injury by activation of RISK and mitochondrial pathways. Oxid Med Cell Longev 2016; 2016: 5271251
  • 75 Huang B, Qian Y, Xie S. et al. Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y12 signaling pathway. Cell Mol Immunol 2021; 18 (05) 1278-1289
  • 76 Davidson SM, Andreadou I, Barile L. et al. Circulating blood cells and extracellular vesicles in acute cardioprotection. Cardiovasc Res 2019; 115 (07) 1156-1166
  • 77 Neumann FJ, Zohlnhöfer D, Fakhoury L, Ott I, Gawaz M, Schömig A. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999; 34 (05) 1420-1426
  • 78 Tam SH, Sassoli PM, Jordan RE, Nakada MT. Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and alpha(v)beta3 integrins. Circulation 1998; 98 (11) 1085-1091
  • 79 Seligmann C, Simsek Y, Schimmer M, Leitsch T, Bock A, Schultheiss HP. Human thrombocytes are able to induce a myocardial dysfunction in the ischemic and reperfused guinea pig heart mediated by free radicals-role of the GPIIb/IIIa-blocker tirofiban. Life Sci 2002; 71 (19) 2319-2329
  • 80 Kingma JG. Inhibition of Na+/H+ exchanger with EMD 87580 does not confer greater cardioprotection beyond preconditioning on ischemia-reperfusion injury in normal dogs. J Cardiovasc Pharmacol Ther 2018; 23 (03) 254-269
  • 81 Chang ST, Yang YT, Chu CM. et al. Protein kinases are involved in the cardioprotective effects activated by platelet glycoprotein IIb/IIIa inhibitor tirofiban at reperfusion in rats in vivo. Eur J Pharmacol 2018; 832: 33-38
  • 82 Mammadova-Bach E, Ollivier V, Loyau S. et al. Platelet glycoprotein VI binds to polymerized fibrin and promotes thrombin generation. Blood 2015; 126 (05) 683-691
  • 83 Onselaer MB, Hardy AT, Wilson C. et al. Fibrin and D-dimer bind to monomeric GPVI. Blood Adv 2017; 1 (19) 1495-1504
  • 84 Jiang P, Jandrot-Perrus M. New advances in treating thrombotic diseases: GPVI as a platelet drug target. Drug Discov Today 2014; 19 (09) 1471-1475
  • 85 Stegner D, Nieswandt B. Platelet receptor signaling in thrombus formation. J Mol Med (Berl) 2011; 89 (02) 109-121
  • 86 Takaya N, Katoh Y, Iwabuchi K. et al. Platelets activated by collagen through the immunoreceptor tyrosine-based activation motif in the Fc receptor gamma-chain play a pivotal role in the development of myocardial ischemia-reperfusion injury. J Mol Cell Cardiol 2005; 39 (06) 856-864
  • 87 Pachel C, Mathes D, Arias-Loza AP. et al. Inhibition of platelet GPVI protects against myocardial ischemia-reperfusion injury. Arterioscler Thromb Vasc Biol 2016; 36 (04) 629-635
  • 88 Voors-Pette C, Lebozec K, Dogterom P. et al. Safety and tolerability, pharmacokinetics, and pharmacodynamics of ACT017, an antiplatelet GPVI (glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol 2019; 39 (05) 956-964
  • 89 Schönberger T, Ziegler M, Borst O. et al. The dimeric platelet collagen receptor GPVI-Fc reduces platelet adhesion to activated endothelium and preserves myocardial function after transient ischemia in mice. Am J Physiol Cell Physiol 2012; 303 (07) C757-C766
  • 90 Mayer K, Hein-Rothweiler R, Schüpke S. et al. Efficacy and safety of revacept, a novel lesion-directed competitive antagonist to platelet glycoprotein VI, in patients undergoing elective percutaneous coronary intervention for stable ischemic heart disease: the randomized, double-blind, placebo-controlled ISAR-PLASTER phase 2 trial. JAMA Cardiol 2021; 6 (07) 753-761
  • 91 Xu Y, Huo Y, Toufektsian MC. et al. Activated platelets contribute importantly to myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 2006; 290 (02) H692-H699
  • 92 Barrabés JA, Garcia-Dorado D, Mirabet M. et al. Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia. J Am Coll Cardiol 2005; 45 (02) 293-299
  • 93 Oostingh GJ, Pozgajova M, Ludwig RJ. et al. Diminished thrombus formation and alleviation of myocardial infarction and reperfusion injury through antibody- or small-molecule-mediated inhibition of selectin-dependent platelet functions. Haematologica 2007; 92 (04) 502-512
  • 94 Weyrich AS, Ma XY, Lefer DJ, Albertine KH, Lefer AM. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest 1993; 91 (06) 2620-2629
  • 95 Shimizu Y, Minatoguchi S, Hashimoto K. et al. The role of serotonin in ischemic cellular damage and the infarct size-reducing effect of sarpogrelate, a 5-hydroxytryptamine-2 receptor blocker, in rabbit hearts. J Am Coll Cardiol 2002; 40 (07) 1347-1355
  • 96 Mauler M, Herr N, Schoenichen C. et al. Platelet serotonin aggravates myocardial ischemia/reperfusion injury via neutrophil degranulation. Circulation 2019; 139 (07) 918-931
  • 97 Hohlfeld T, Braun M, Strobach H, Schrör K. Protection of reperfused ischemic pig myocardium by nexopamil, a new combined Ca2+ and serotonin antagonist. J Cardiovasc Pharmacol 1994; 23 (06) 922-931
  • 98 Bianchi P, Kunduzova O, Masini E. et al. Oxidative stress by monoamine oxidase mediates receptor-independent cardiomyocyte apoptosis by serotonin and postischemic myocardial injury. Circulation 2005; 112 (21) 3297-3305
  • 99 Jin L, Yan XW, Xu SH. [Platelet functions in patients with acute myocardial infarction]. Zhonghua Xin Xue Guan Bing Za Zhi 1989; 17 (05) 275-278, 317
  • 100 Ko YG, Jung JH, Park S. et al. Inflammatory and vasoactive factors in the aspirate from the culprit coronary artery of patients with acute myocardial infarction. Int J Cardiol 2006; 112 (01) 66-71
  • 101 Rieder M, Laumann R, Witsch T. et al. Evaluation of serum serotonin as a biomarker for myocardial infarction and ischemia/reperfusion injury. Appl Sci (Basel) 2020; 10 (18) 6379
  • 102 Aldosari S, Awad M, Harrington EO, Sellke FW, Abid MR. Subcellular reactive oxygen species (ROS) in cardiovascular pathophysiology. Antioxidants 2018; 7 (01) E14
  • 103 Seligmann C, Schimmer M, Leitsch T. et al. A thrombocyte-induced myocardial dysfunction in the ischemic and reperfused guinea pig heart is mediated by reactive oxygen species. Free Radic Biol Med 2000; 29 (12) 1244-1251
  • 104 Masselli E, Pozzi G, Vaccarezza M. et al. ROS in platelet biology: functional aspects and methodological insights. Int J Mol Sci 2020; 21 (14) E4866
  • 105 Leo R, Praticò D, Iuliano L. et al. Platelet activation by superoxide anion and hydroxyl radicals intrinsically generated by platelets that had undergone anoxia and then reoxygenated. Circulation 1997; 95 (04) 885-891
  • 106 Seligmann C, Prechtl G, Kusus-Seligmann M, Daniel WG. A myocardial ischemia- and reperfusion-induced injury is mediated by reactive oxygen species released from blood platelets. Platelets 2013; 24 (01) 37-43
  • 107 Sauter RJ, Sauter M, Reis ES. et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation 2018; 138 (16) 1720-1735
  • 108 Penna C, Bassino E, Alloatti G. Platelet activating factor: the good and the bad in the ischemic/reperfused heart. Exp Biol Med (Maywood) 2011; 236 (04) 390-401
  • 109 Montrucchio G, Alloatti G, Camussi G. Role of platelet-activating factor in cardiovascular pathophysiology. Physiol Rev 2000; 80 (04) 1669-1699
  • 110 Stangl V, Baumann G, Stangl K, Felix SB. Negative inotropic mediators released from the heart after myocardial ischaemia-reperfusion. Cardiovasc Res 2002; 53 (01) 12-30
  • 111 Wang EW, Han YY, Jia XS. PAFR-deficiency alleviates myocardial ischemia/reperfusion injury in mice via suppressing inflammation, oxidative stress and apoptosis. Biochem Biophys Res Commun 2018; 495 (04) 2475-2481
  • 112 Ko W, Lang D, Hawes AS, Zelano JA, Isom OW, Krieger KH. Platelet-activating factor antagonism attenuates platelet and neutrophil activation and reduces myocardial injury during coronary reperfusion. J Surg Res 1993; 55 (05) 504-515
  • 113 Rosskopf D. Sodium-hydrogen exchange and platelet function. J Thromb Thrombolysis 1999; 8 (01) 15-24
  • 114 Chang HB, Gao X, Nepomuceno R, Hu S, Sun D. Na(+)/H(+) exchanger in the regulation of platelet activation and paradoxical effects of cariporide. Exp Neurol 2015; 272: 11-16
  • 115 Roh HY, Jung IS, Park JW. et al. Cardioprotective effects of [5-(2-methyl-5-fluorophenyl)furan-2-ylcarbonyl]guanidine (KR-32568) in an anesthetized rat model of ischemia and reperfusion heart injury. Pharmacology 2005; 75 (01) 37-44
  • 116 Zeymer U, Suryapranata H, Monassier JP. et al; ESCAMI Investigators. The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial. J Am Coll Cardiol 2001; 38 (06) 1644-1650
  • 117 Penna C, Alloatti G, Cappello S. et al. Platelet-activating factor induces cardioprotection in isolated rat heart akin to ischemic preconditioning: role of phosphoinositide 3-kinase and protein kinase C activation. Am J Physiol Heart Circ Physiol 2005; 288 (05) H2512-H2520
  • 118 Ren F, Mu N, Zhang X. et al. Increased platelet-leukocyte aggregates are associated with myocardial no-reflow in patients with ST elevation myocardial infarction. Am J Med Sci 2016; 352 (03) 261-266
  • 119 Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002; 105 (18) 2166-2171
  • 120 Peters MJ, Dixon G, Kotowicz KT, Hatch DJ, Heyderman RS, Klein NJ. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Br J Haematol 1999; 106 (02) 391-399
  • 121 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9 (01) 61-67
  • 122 Maugeri N, Rovere-Querini P, Evangelista V. et al. An intense and short-lasting burst of neutrophil activation differentiates early acute myocardial infarction from systemic inflammatory syndromes. PLoS One 2012; 7 (06) e39484
  • 123 Page C, Pitchford S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int Immunopharmacol 2013; 17 (04) 1176-1184
  • 124 Lefer AM, Campbell B, Scalia R, Lefer DJ. Synergism between platelets and neutrophils in provoking cardiac dysfunction after ischemia and reperfusion: role of selectins. Circulation 1998; 98 (13) 1322-1328
  • 125 Götz AK, Zahler S, Stumpf P, Welsch U, Becker BF. Intracoronary formation and retention of micro aggregates of leukocytes and platelets contribute to postischemic myocardial dysfunction. Basic Res Cardiol 2005; 100 (05) 413-421
  • 126 Habazettl H, Hanusch P, Kupatt C. Effects of endothelium/leukocytes/platelet interaction on myocardial ischemia–reperfusion injury. Z Kardiol 2000; 89 (9, Suppl 9): IX, 92–95
  • 127 Théorêt JF, Bienvenu JG, Kumar A, Merhi Y. P-selectin antagonism with recombinant p-selectin glycoprotein ligand-1 (rPSGL-Ig) inhibits circulating activated platelet binding to neutrophils induced by damaged arterial surfaces. J Pharmacol Exp Ther 2001; 298 (02) 658-664
  • 128 Lefer DJ, Flynn DM, Buda AJ. Effects of a monoclonal antibody directed against P-selectin after myocardial ischemia and reperfusion. Am J Physiol 1996; 270 (1, Pt 2): H88-H98
  • 129 Seligmann C, Leitsch T, Kusus M. et al. PMN/platelets coinfused in guinea pig hearts Exposed to low-flow ischemia have no additive cardiodepressive effect. J Vasc Res 2003; 40 (06) 501-508
  • 130 Starz C, Härdtner C, Mauler M. et al. Platelet-leukocyte complex formation in myocardial infarction: a marker not a pathogen. Presented at the 87th European Atherosclerosis Society Congress. 2019 ; Maastricht, the Netherlands
  • 131 Henn V, Slupsky JR, Gräfe M. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391 (6667): 591-594
  • 132 Lakkis N, Dokainish H, Abuzahra M. et al. Reticulated platelets in acute coronary syndrome: a marker of platelet activity. J Am Coll Cardiol 2004; 44 (10) 2091-2093
  • 133 Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101 (01) 151-156
  • 134 Ts'ao CH. Rough endoplasmic reticulum and ribosomes in blood platelets. Scand J Haematol 1971; 8 (02) 134-140
  • 135 Hoffmann JJ. Reticulated platelets: analytical aspects and clinical utility. Clin Chem Lab Med 2014; 52 (08) 1107-1117
  • 136 Angénieux C, Maître B, Eckly A, Lanza F, Gachet C, de la Salle H. Time-dependent decay of mRNA and ribosomal RNA during platelet aging and its correlation with translation activity. PLoS One 2016; 11 (01) e0148064
  • 137 Stratz C, Bömicke T, Younas I. et al. Comparison of immature platelet count to established predictors of platelet reactivity during thienopyridine therapy. J Am Coll Cardiol 2016; 68 (03) 286-293
  • 138 Ibrahim H, Schutt RC, Hannawi B, DeLao T, Barker CM, Kleiman NS. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol 2014; 64 (20) 2122-2129
  • 139 Tscharre M, Farhan S, Bruno V. et al. Impact of platelet turnover on long-term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention. Eur J Clin Invest 2019; 49 (09) e13157
  • 140 Cesari F, Marcucci R, Gori AM. et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 2013; 109 (05) 846-853
  • 141 Stratz C, Nührenberg T, Amann M. et al. Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. Thromb Haemost 2016; 116 (05) 941-948
  • 142 Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2016; 119 (01) 91-112
  • 143 Walsh TG, Poole AW. Do platelets promote cardiac recovery after myocardial infarction: roles beyond occlusive ischemic damage. Am J Physiol Heart Circ Physiol 2018; 314 (05) H1043-H1048
  • 144 Rath D, Chatterjee M, Müller I. et al. Platelet expression of transforming growth factor beta 1 is enhanced and associated with cardiovascular prognosis in patients with acute coronary syndrome. Atherosclerosis 2014; 237 (02) 754-759
  • 145 Chatterjee M, Huang Z, Zhang W. et al. Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli. Blood 2011; 117 (14) 3907-3911
  • 146 Italiano Jr JE, Richardson JL, Patel-Hett S. et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 2008; 111 (03) 1227-1233
  • 147 Nording H, Baron L, Haberthür D. et al. The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets. Nat Commun 2021; 12 (01) 3352