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Platelet-Leukocyte Interaction in Atherosclerosis and Atherothrombosis: What We Have Learnt From Human Studies and Animal Models

Ying Wang, Zhen-Yuan Li, Wei Wang

Ying Wang, Wei Wang, Departments of Medicine, Division of Molecular Medicine, Columbia University, New York, the United States
Zhen-Yuan Li, Renal Division, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

Correspondence to: Wei Wang, Ying Wang, Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, 630 West 168th Street, New York, the United States.
Email: ww2351@columbia.edu, yw2323@columbia.com
Telephone: +1-212-305-5789
Received: February 27, 2014
Revised: April 30, 2014
Accepted: May 6, 2014
Published online: June 10, 2014

ABSTRACT

Platelets, the cellular fragments of their precursor megakaryocytes, play an important role in hemostasis and other pathophysiological circumstances including atherothrombosis and atherosclerosis. Activated platelet not only can aggregate with each other to form the thrombi, but also can interact with leukocytes in the circulation to form the platelet-leukocyte aggregates (PLAs). Increased number of PLAs has been reported in patients with atherosclerosis or atherothrombosis, and animal models using different knock-out mice have unraveled the molecular mechanisms underlying the platelet leukocyte interaction. This review describes the platelet leukocyte interaction in atherosclerosis and atherothrombosis by integrating our knowledge of basic mechanisms of platelet leukocyte interaction from animal studies with the clinical studies illustrating the platelet leukocyte interaction in patients with atherosclerosis.

Key words: Platelets; Platelet leukocyte interaction; Platelet leukocyte aggregation; Atherosclerosis; Atherothrombosi

© 2014 The Author. Published by ACT Group Ltd.

Wang Y, Li ZY, Wang W. Platelet-Leukocyte Interaction in Atherosclerosis and Atherothrombosis: What We Have Learnt From Human Studies and Animal Models. Journal of Cardiology and Therapy 2014; 1(5): 92-97 Available from: URL: http://www.ghrnet.org/index.php/jct/article/view/710

INTRODUCTION

Platelets, the cellular fragment of their precursor megakaryocytes, play an important role not only in hemostasis and thrombosis[1], but also in others physiological and pathophysiological conditions including inflammation, tumor metastasis, fibrosis and atherosclerosis[1-4]. Atherosclerosis is a chronic inflammatory process in which endothelial cells dysfunction, mononuclear cell recruitment and intrusion, and lipid dysfunction are all involved[5-7]. Activated platelets are present in circulation of patients with unstable and stable coronary artery disease[8,9]and has been reported to be actively involved in the pathogenesis of atherosclerosis through the inflammatory processes[10]. Depleting platelets in circulation was able to dramatically decrease the atherosclerotic lesion size in mouse model through the mechanism of interrupting the adhesion of activated platelets to endothelium[11]. When the atherosclerotic plaque ruptures, exposed collagen under the injured endothelium initiates the activation and aggregation of platelets to the injured endothelial cells and facilitates the thrombus formation[10]. Therefore, platelet activation is one of the major characteristics present throughout the atherosclerotic and atherothrombosis processes.

Leukocytes, another important cellular type in circulation, are also actively involved in the pathogenesis of atherosclerosis through mechanisms including leukocytosis, leukocyte infiltration and foam cell formation[12]. Blocking leukocyte recruitment or depleting leukocytes from circulation, particularly monocytes and neutrophils infiltration, could also successfully protect atherosclerotic lesion formation in mouse model[13,14]. However, platelets and leukocytes do not act separately in atherogenesis. Activate platelets are not only able to conjugate with leukocytes but also able to further regulate the function of these leukocytes to facilitate atherogenesis. This review will describe the platelet leukocyte interaction in atherosclerosis and atherothrombosis by integrating our knowledge of basic mechanisms of platelet leukocyte interaction from animal studies with the clinical studies illustrating the platelet leukocyte interaction in patients with atherosclerosis.

PLATELETS ARE ACTIVATED IN ATHEROSCLEROSIS AND ATHEROTHROMBOSIS

Platelets remain in their original, inactivated state when circulating in vessels with intact endothelium, while being activated when these anucleate cells encountered with the exposed collagen under the injured endothelium. Study has shown that platelets adhere to the injured vascular endothelium before the development of atherosclerotic lesion in mice and inhibiting platelet adhesion reduced atherosclerotic lesion formation, indicating an important role of platelets in atherogenesis[10,11]. Once the vulnerable atherosclerotic plaque ruptures, platelets are immediately activated at the site of the injured vessels and form the thrombi. Platelets from patients with hypercholesterolemic or diabetic conditions are hyper-reactive and much easier to be activated and faster in forming the thrombosis, leading to the much more severe symptoms and diffused atherothrombosis under such circumstances compared with those patients without these risk factors[9,15-17].

PLATELET-LEUKOCYTE INTERACTION IN PATHOGENESIS OF ATHEROSCLEROSIS AND ATHEROTHROMBOSIS

Apart from aggregating with each other which is regarded as homogenous aggregation, platelets had also been reported to conjugate with leukocytes in circulation once activated, defined as a heterogenous aggregation[18]. However, the role of these aggregates in cardiovascular diseases especially atherosclerosis was not fully understood until more than ten years after the report of increased platelet-leukocyte aggregates in circulation of patients with stroke, cardiopulmonary bypass and hemodialysis from several studies[19-21]. The first study linking PLAs to atherosclerosis was reported by Ott et al showing that patients of unstable angina had increased number of PLAs in circulation compared with patients with stable angina, indicating platelet activation under the condition of a potential acute cardiovascular event[22]. Afterward, several other studies added more evidence showing the association of the propensity of thrombosis with increased platelet leukocyte interaction in cardiovascular diseases including stable angina, unstable angina and myocardial infarction (Table 1)[23-28]. In animal models, depleting neutrophils or platelets have been able to reduce the atherosclerotic lesion size in atherosclerosis-prone mice[11,14], and the adhesion and infiltration of these neutrophils are mediated by the platelet-derived chemokines CCL5[14]. Therefore, both the human and mice data indicated an important but not fully unraveled role of platelet leukocyte interaction in atherosclerosis and atherothrombosis. PLAs are also proposed as a reliable and sensitive marker of a pro-thrombotic condition in patients with stable angina or atherosclerosis.

MOLECULES UNDERLYING PLATELET-LEUKOCYTE INTERACTION

Thanks to the studies of platelet-leukocyte interaction in other diseases using different animal models, the molecular mechanism mediating platelet leukocyte interaction has been illustrated. Platelet-leukocyte interaction can be briefly divided into three stages, namely initiation of the interaction, stabilization of the aggregates and amplification of leukocyte activation. Binding of P-selectin (CD62P) on the membrane of activated platelets to the P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes is believed to be the most important molecule to initiate the platelet leukocyte interaction[10,29-33]. P-selectin is a protein stored in α-granules of inactivated platelets and quickly translocates to membrane from granules upon platelet activation. Cross-linking of PSGL-1 by P-selectin also primes leukocytes intracellularly for cytokine and chemoattractant-induced integrin β2 activation to firm adhesion of leukocytes through regulating the Scr family tyrosine kinase activity[30]. The increased integrin β2 further facilitates the interaction between leukocyte surface Mac-1 (also known as integrin αMβ2 and CD11b/CD18) and platelet surface glycoprotein Ib (GPIb)[30,34], which is an important step to stabilize the initial PLAs formation. The initial interaction between αMβ2 and GPIb led to the generation of an outside-in, SFK-Pyk2–mediated signal to stabilize the integrin-ligand binding or induce the activity of Scr family tyrosine kinase Lyn[14,17]. The PLAs will be further stabilized through several other pairs of ligand-receptor interaction including the binding of leukocyte surface Mac-1 to the platelet surface integrin αIIbβ3 and/or to platelet surface adhesion molecule 3 (JAM-3)[35-38], the binding of ligand on platelet surface to the triggering receptor expressed on myeloid cells 1 (TREM-1[39], binding of ICAM-2 on platelets to LFA-1 (CD11a/CD18) on neutrophils[40,41], interaction between CD40L on platelets and CD40 on monocytes[42], and also between GpIbα on platelet and ICAM-1 on neutrophils[43,44]. Detailed molecules mediating the platelet leukocyte interaction and their role in atherosclerosis and atherothrombosis are summarized in table 2.

CONSEQUENCES OF PLATELET-LEUKOCYTE INTERACTION IN ATHEROSCLEROSIS AND ATHEROTHROMBOSIS

About 5-10% of leukocytes are aggregated with platelets in human whole blood reported in healthy controls[45,46] and PLAs number in animal models varies from different studies and models, ranging from 5% to 60%[29,47]. However, platelet leukocyte interaction is a transient process which would be dissociated by various anti-platelet activation molecules in circulation like nitro oxidase (NO), matrix metalloproteinases and prostaglandin[48], and are highly regulated by shear stress[49]. On the other side, those leukocytes firmly aggregated with platelets will gain a more active phenotype in being recruited to the injured endotheilum, and contribute to the atherosclerotic plaque formation. This step is defined as the amplification of leukocyte activation. There are many studies have demonstratde the mechanisms of how the behavior of leukocytes change once aggregated with platelets and how the activated leukocyte further activate and recruit platelets in circulation.

In human studies, platelet monocyte interaction could induce an expansion of the pool of circulating CD14highCD16+ monocytes, a subpopulation of monocytes in human which is similar to Ly-6Chigh monocytes in mouse[50]. These monocytes are the major leukocyte population that enters the atherosclerotic lesion and forms foam cells. The most important evidence from mice model supporting the role of platelet leukocyte interaction in atherogensis was provided the study carried out by Huo et al[32]. The study showed that following a single injection of activated platelets, monocytes disappear from the circulation and increased monocyte adhesion was observed on atherosclerotic lesions in carotid arteries, indicating that platelet-monocyte aggregation is one of the ways in which circulating activated platelets may participate in the formation of atherosclerotic lesions[32].

Besides regulating monocytosis and the interaction with monocyte to facilitate the atherosclerosis development, platelets could also reprogram the leukocytes to gain pro-atherosclerotic phenotype. For example, monocytes attached with platelets have increased cell surface CD11b or vascular cell adhesion molecule-1 (VCAM-1) levels. These adhesions molecule facilitate the monocyte interaction with injured endothelium and further infiltration[32,37]. Activated platelets can also deliver the chemokines or pro-inflammatory factors including RANTES (CCL5) and PF4 (CXC motif ligand 4, CXCL4) to leukocytes/monocytes which further facilitates the adhesion of leukocytes to atherosclerotic lesions[32]. Platelet-monocyte aggregates could further support the monocyte adhesion to endothelium by enhancing the secondary tethering and cluster formation through up-regulating L-selectin and P-selectin[51]. When platelets are aggregated with neutrophils, these neutrophils could gain enhanced ability of transmigration in response to oxidized low-density lipoprotein (oxLDL) in a PI3K-dependent manner[52]. As an important factor in atherosclerosis, oxLDL could also increase the interaction between platelet and monocyte, in a process that involved platelet CD36-OxLDL interaction, release of chemokines such as CXCL4, direct platelet-monocyte interaction, and phagocytosis of platelets[53]. In summary, the aggregation between platelets and monocyte promotes leukocytosis, leukocyte infiltration and extravasation, and enhanced foam cell formation, indicate a role of PLA in atherosclerotic plaque development and plaque destabilization[53].

As the plaque ruptures, not only platelets are recruited to the injured endothelium to form the thrombi, leukocytes also actively participate in the thrombi formation through their interaction with platelets. Activated leukocytes attached with platelets can recruit circulating activated platelets through P-selectin/PSGL-1 interactions and contribute to further platelet activation through cathepsin G and fibrin deposition, which helps to form the firm atherosclerotic thrombi[44]. On the other side, activated platelets which have already attached on the injured endothelial will attract more leukocytes and the fibrin-collagen matrix would trap red blood cells from circulation to completely block the vessel lumen[11,14].

CHALLENGES IN EVALUATING PLAS IN CIRCULATION OF PATIENTS WITH CORONARY ARTERY DISEASES

Based on the observation of increased PLAs in circulation of patients with cardiovascular diseases including stable angina, unstable angina and myocardial infarction, as well as the supporting mechanistic studies from animal models, PLAs could be a promising and sensitive marker to screen the patients with potential risk of developing athrothrombosis. Therefore, accurately measuring the PLAs in circulation is of vital importance which requires careful sample handling and standard protocols since factors including how long the blood sample is process after collection, the anticoagulant used, the way to lyse and fix the samples, the flow cytometer used all contribute to the final result of the PLAs[45,46]. Compared with EDTA, sodium citrate and PPACK, heparin has the least artificial effect on the PLAs[46]. Lysing red blood cell and fixation do not impact the final PLAs count in circulation a lot[45,46]. However, samples should be processed as soon as possible, preferentially within 12-24 hour after the collection since the longer the sample is sitting on the bench, the higher the PLAs number would be[45]. Sample processing should be always kept on ice or centrifuged at 4℃ to avoid the unnecessary activation of leukocytes.

Cost-effectiveness of this flow cytometry-based test including the cost of experimental reagent, the flow cytometer and operator training, might be another challenge. However, with careful experimental design to titrate the concentration of commercial available antibodies, the cost of reagent especially antibodies could be reduced by more than 50% according to our experience. The cost of flow cytometer which was earlier an experimental device in general might be another consideration of clinicians to choose such a test or not. However, technological advances have enabled widespread applications for the use of flow cytometer in clinical purposes especially in large hospital and institutes with basic research facilities. With sharing the instrumental and expertise sources, the cost-effectiveness of such a test could be dramatically decreased and more practical to be performed.

SUMMARY

As two major cell types that contribute to the pathogenesis of atherosclerosis and atherothrombosis, interaction between platelets and leukocytes are of great interesting not only because that increased number of PLAs have been found in circulation of patients with atherosclerosis and its complications, but also because of the increased number of animal studies unraveling the mechanisms underlying the interaction. Although a great effort is still needed to clarify the mechanisms of PLAs in atherosclerosis and atherothrombisis, using PLA as a marker for platelet and/or leukocyte activation and for evaluating the risk of developing atherothrombosis holds great promise. Since several small scale human studies have pointed out a potential benefit of using commercially available anti-platelet medicines in reducing platelet leukocyte interaction[24, 38] and the role of PLA in atherosclerosis development and atherothrobosis has been gradually unraveled, PLA would also be an interesting therapeutic target to reduce the atherosclerosis development and atherothrobosis.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

REFERENCES

1 Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 2003; 23: 2131-2137

2 Meyer A, Wang W, Qu J, Croft L, Degen JL, Coller BS, Ahamed J. Platelet tgf-beta1 contributions to plasma tgf-beta1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood 2012; 119: 1064-1074

3 von Hundelshausen P, Weber C. Platelets as immune cells: Bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40

4 Karpatkin S, Pearlstein E. Role of platelets in tumor cell metastases. Ann Intern Med 1981; 95: 636-641

5 Wang W, Peng W, Zhang X, Lu L, Zhang R, Zhang Q, Wang L, Chen Q, Shen W. Chromosome 9p21.3 polymorphism in a chinese han population is associated with angiographic coronary plaque progression in non-diabetic but not in type 2 diabetic patients. Cardiovasc Diabetol 2010; 9: 33

6 Wang Y, Wang GZ, Rabinovitch PS, Tabas I. Macrophage mitochondrial oxidative stress promotes atherosclerosis and nuclear factor-kappab-mediated inflammation in macrophages. Circ Res 2014; 114: 421-433

7 Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab 2012; 15: 545-553

8 Fitzgerald DJ, Roy L, Catella F, FitzGerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989

9 Ferroni P, Basili S, Falco A, Davi G. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2: 1282-1291

10 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494

11 Massberg S, Brand K, Gruner S, Page S, Muller E, Muller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896

12 Westerterp M, Bochem AE, Yvan-Charvet L, Murphy AJ, Wang N, Tall AR. Atp-binding cassette transporters, atherosclerosis, and inflammation. Circ Res 2014; 114: 157-170

13 Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, Welch CL, Wang N, Randolph GJ, Snoeck HW, Tall AR. Atp-binding cassette transporters and hdl suppress hematopoietic stem cell proliferation. Science 2010; 328: 1689-1693

14 Drechsler M, Megens RT, van Zandvoort M, Weber C, Soehnlein O. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122: 1837-1845

15 Broijersen A, Hamsten A, Eriksson M, Angelin B, Hjemdahl P. Platelet activity in vivo in hyperlipoproteinemia--importance of combined hyperlipidemia. Thromb Haemost 1998; 79: 268-275

16 Sener A, Ozsavci D, Oba R, Demirel GY, Uras F, Yardimci KT. Do platelet apoptosis, activation, aggregation, lipid peroxidation and platelet-leukocyte aggregate formation occur simultaneously in hyperlipidemia? Clin Biochem 2005; 38: 1081-1087

17 Bornfeldt KE. 2013 russell ross memorial lecture in vascular biology: Cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 2014; 34: 705-714

18 Jungi TW, Spycher MO, Nydegger UE, Barandun S. Platelet-leukocyte interaction: Selective binding of thrombin-stimulated platelets to human monocytes, polymorphonuclear leukocytes, and related cell lines. Blood 1986; 67: 629-636

19 Marquardt L, Anders C, Buggle F, Palm F, Hellstern P, Grau AJ. Leukocyte-platelet aggregates in acute and subacute ischemic stroke. Cerebrovasc Dis 2009; 28: 276-282

20 Gawaz MP, Mujais SK, Schmidt B, Gurland HJ. Platelet-leukocyte aggregation during hemodialysis. Kidney Int 1994; 46: 489-495

21 Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte-platelet adhesion. Blood 1992; 79: 1201-1205

22 Ott I, Neumann FJ, Gawaz M, Schmitt M, Schomig A. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation 1996; 94: 1239-1246

23 Jensen MK, de Nully Brown P, Lund BV, Nielsen OJ, Hasselbalch HC. Increased circulating platelet-leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet count. Eur J Haematol 2001; 66: 143-151

24 Xiao Z, Theroux P. Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome. J Am Coll Cardiol 2004; 43: 1982-1988

25 Tuttle HA, Davis-Gorman G, Goldman S, Copeland JG, McDonagh PF. Platelet-neutrophil conjugate formation is increased in diabetic women with cardiovascular disease. Cardiovasc Diabetol 2003; 2: 12

26 Mickelson JK, Lakkis NM, Villarreal-Levy G, Hughes BJ, Smith CW. Leukocyte activation with platelet adhesion after coronary angioplasty: A mechanism for recurrent disease? J Am Coll Cardiol. 1996;28:345-353

27. Furman MI, Benoit SE, Barnard MR, Valeri CR, Borbone ML, Becker RC, Hechtman HB, Michelson AD. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358

28 Furman MI, Barnard MR, Krueger LA, Fox ML, Shilale EA, Lessard DM, Marchese P, Frelinger AL, 3rd, Goldberg RJ, Michelson AD. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38: 1002-1006

29 Yokoyama S, Ikeda H, Haramaki N, Yasukawa H, Murohara T, Imaizumi T. Platelet p-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates. J Am Coll Cardiol 2005; 45: 1280-1286

30 Evangelista V, Manarini S, Coller BS, Smyth SS. Role of p-selectin, beta2-integrins, and src tyrosine kinases in mouse neutrophil-platelet adhesion. J Thromb Haemost 2003; 1: 1048-1054

31 Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by p-selectin on adherent platelets. Nature 1992; 359: 848-851

32 Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein e. Nat Med 2003; 9: 61-67

33 Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 1994; 91: 8767-8771

34 Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC, Lopez JA. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin mac-1 (cd11b/cd18). J Exp Med 2000; 192: 193-204

35 Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, Chavakis T. The junctional adhesion molecule 3 (jam-3) on human platelets is a counterreceptor for the leukocyte integrin mac-1. J Exp Med 2002; 196: 679-691

36 Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK. 7e3 monoclonal antibody directed against the platelet glycoprotein iib/iiia cross-reacts with the leukocyte integrin mac-1 and blocks adhesion to fibrinogen and icam-1. Arterioscler Thromb Vasc Biol 1997; 17: 528-535

37 Patko Z, Csaszar A, Acsady G, Peter K, Schwarz M. Roles of mac-1 and glycoprotein iib/iiia integrins in leukocyte-platelet aggregate formation: Stabilization by mac-1 and inhibition by gpiib/iiia blockers. Platelets 2012; 23: 368-375

38 Neumann FJ, Zohlnhofer D, Fakhoury L, Ott I, Gawaz M, Schomig 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: 1420-1426

39 Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP. Trem-1 ligand expression on platelets enhances neutrophil activation. Blood 2007; 110: 1029-1035

40 Diacovo TG, deFougerolles AR, Bainton DF, Springer TA. A functional integrin ligand on the surface of platelets: Intercellular adhesion molecule-2. J Clin Invest 1994; 94: 1243-1251

41 Issekutz AC, Rowter D, Springer TA. Role of icam-1 and icam-2 and alternate cd11/cd18 ligands in neutrophil transendothelial migration. J Leukoc Biol 1999; 65: 117-126

42 Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, Wijnands E, Goossens P, van Kruchten R, Thevissen L, Boon L, Flavell RA, Noelle RJ, Gerdes N, Biessen EA, Daemen MJ, Heemskerk JW, Weber C, Lutgens E. Platelet cd40l mediates thrombotic and inflammatory processes in atherosclerosis. Blood 2010; 116: 4317-4327

43 Cerletti C, Evangelista V, de Gaetano G. P-selectin-beta 2-integrin cross-talk: A molecular mechanism for polymorphonuclear leukocyte recruitment at the site of vascular damage. Thromb Haemost 1999; 82: 787-793

44 Cerletti C, Evangelista V, de Gaetano G. Platelet-polymorphonuclear leukocyte functional interactions: Role of adhesive molecules. Haemostasis 1996; 26 Suppl 4: 20-27

45 Li N, Goodall AH, Hjemdahl P. Efficient flow cytometric assay for platelet-leukocyte aggregates in whole blood using fluorescence signal triggering. Cytometry 1999; 35: 154-161

46 Harding SA, Din JN, Sarma J, Jessop A, Weatherall M, Fox KA, Newby DE. Flow cytometric analysis of circulating platelet-monocyte aggregates in whole blood: Methodological considerations. Thromb Haemost 2007; 98: 451-456

47 Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, Gear AR, Linden J. P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arterioscler Thromb Vasc Biol 2010; 30: 2392-2399

48 Chung AW, Radomski A, Alonso-Escolano D, Jurasz P, Stewart MW, Malinski T, Radomski MW. Platelet-leukocyte aggregation induced by par agonists: Regulation by nitric oxide and matrix metalloproteinases. Br J Pharmacol 2004; 143: 845-855

49 Hu H, Varon D, Hjemdahl P, Savion N, Schulman S, Li N. Platelet-leukocyte aggregation under shear stress: Differential involvement of selectins and integrins. Thromb Haemost 2003; 90: 679-687

50 Passacquale G, Vamadevan P, Pereira L, Hamid C, Corrigall V, Ferro A. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PLoS One 2011; 6: e25595

51 da Costa Martins P, van den Berk N, Ulfman LH, Koenderman L, Hordijk PL, Zwaginga JJ. Platelet-monocyte complexes support monocyte adhesion to endothelium by enhancing secondary tethering and cluster formation. Arterioscler Thromb Vasc Biol 2004; 24: 193-199

52 Badrnya S, Butler LM, Soderberg-Naucler C, Volf I, Assinger A. Platelets directly enhance neutrophil transmigration in response to oxidised low-density lipoprotein. Thromb Haemost 2012; 108: 719-729

53 Badrnya S, Schrottmaier WC, Kral JB, Yaiw KC, Volf I, Schabbauer G, Soderberg-Naucler C, Assinger A. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol 2014; 34: 571-580

Peer reviewer: Jung-Sun, Kim, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, South Korea.

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