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DOI: 10.1160/TH09-09-0620
Activated monocytes capture platelets for heterotypic association in patients with severe carotid artery stenosis
Financial support: This study was supported by a grant from the Interdisciplinary Center for Clinical Research (IZKF), Muenster, Germany (projects Fo.01KS9604/0 and IZKF A6).Publication History
Received:
04 September 2009
Accepted after major revision:
24 January 2010
Publication Date:
22 November 2017 (online)
Summary
Inflammation and thrombosis, two processes influencing each other, are involved in the pathogenesis of cerebrovascular disease. We showed that in patients with acute ischaemic stroke circulating platelets are activated and exhausted. To identify whether activated haemostasis might be cause or effect, we investigated the role of leukocyte and platelet activation in patients with severe asymptomatic and symptomatic carotid artery disease. Flow cytometry analysis demonstrated that monocytes from symptomatic (acute stroke aetiology) and asymptomatic patients were highly activated, shown by significantly enhanced presentation of inflammatory markers CD11b and thrombospondin-1 (TSP-1) on the surface. Both correlated positively with monocyte-platelet association rate. However, increased monocyte activation and elevated levels of monocyte-platelet associates in asymptomatic patients were restricted to patients with echo-lucent plaques, providing a close link between monocyte activation and plaque morphology. Circulating single as well as monocyte-bound platelets from symptomatic patients showed significantly enhanced surface expression of P-selectin and TSP-1, whereas platelets from asymptomatic patients were not significantly activated. These results indicate that monocytes activated by inflammation rather than platelets might be the candidates to initiate platelet-monocyte rosetting during the pathogenesis of atherothrombotic cerebral ischaemia and that haemostasis might be activated secondarily by the first occurring inflammation.
Keywords
Cerebrovascular disease - inflammation - atherothrombosis - adhesion molecules - cell-cell interactions* KJ and MAR contributed equally to this study.
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References
- 1 Kochanek PM, Hallenbeck JM. Polymorphonuclear leukocytes and monocytes/ macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 1992; 23: 1367-1379.
- 2 Libby P. Vascular biology of atherosclerosis: overview and state of the art. Am J Cardiol 2003; 91: 3A-6A.
- 3 Meerschaert J, Furie MB. The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18, and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium. J Immunol 1995; 154: 4099-4112.
- 4 Wang Y, Sakuma M, Chen Z. et al. Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury. Circulation 2005; 112: 2993-3000.
- 5 Grau AJ, Ruf A, Vogt A. et al. Increased fraction of circulating activated platelets in acute and previous cerebrovascular ischemia. Thromb Haemost 1998; 80: 298-301.
- 6 Jurk K, Jahn UR, Van Aken H. et al. Platelets in patients with acute ischemic stroke are exhausted and refractory to thrombin, due to cleavage of the seven-trans-membrane thrombin receptor (PAR-1). Thromb Haemost 2004; 91: 334-344.
- 7 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
- 8 Schober A, Manka D, von Hundelshausen P. et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 2002; 106: 1523-1529.
- 9 Kuijper PH, Gallardo Torres HI. et al. P-selectin and MAC-1 mediate monocyte rolling and adhesion to ECM-bound platelets under flow conditions. J Leukoc Biol 1998; 64: 467-473.
- 10 Zirlik A, Maier C, Gerdes N. et al. CD40 ligand mediates inflammation independently of CD40 by interaction with Mac-1. Circulation 2007; 115: 1571-1580.
- 11 Li N, Hu H, Lindqvist M. et al. Platelet-leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol 2000; 20: 2702-2708.
- 12 Weyrich AS, Elstad MR, McEver RP. et al. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 1996; 97: 1525-1534.
- 13 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22: 1381-1389.
- 14 Jurk K, Clemetson KJ, de Groot PG. et al. Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor. FASEB J 2003; 17: 1490-1492.
- 15 Jaffe EA, Ruggiero JT, Falcone DJ. Monocytes and macrophages synthesize and secrete thrombospondin. Blood 1985; 65: 79-84.
- 16 Silverstein RL, Nachman RL. Thrombospondin binds to monocytes-macrophages and mediates platelet-monocyte adhesion. J Clin Invest 1987; 79: 867-874.
- 17 Gotis-Graham I, Hogg PJ, McNeil HP. Significant correlation between thrombospondin 1 and serine proteinase expression in rheumatoid synovium. Arthritis Rheum 1997; 40: 1780-1787.
- 18 Riessen R, Kearney M, Lawler J. et al. Immunolocalization of thrombospondin-1 in human atherosclerotic and restenotic arteries. Am Heart J 1998; 135: 357-364.
- 19 Kolominsky’Rabas PL, Weber M, Gefeller O. et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 2001; 32: 2735-2740.
- 20 Schulte-Altedorneburg G, Droste DW, Haas N. et al. Preoperative B-mode Ultra-sound appearence compared with carotid endarterectomy specimen histlogy. Acata Neurol Scand 2000; 101: 188-194.
- 21 Gawaz M, Fateh-Moghadam S, Pilz G. et al. Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure. Eur J Clin Invest 1995; 25: 843-851.
- 22 Furman MI, Benoit SE, Barnard MR. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31: 352-358.
- 23 Garlichs CD, Kozina S, Fateh-Moghadam S. et al. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia. Stroke 2003; 34: 1412-1418.
- 24 Pauletto P, Puato M, Faggin E. et al. Specific cellular features of atheroma associated with development of neointima after carotid endarterectomy: the carotid atherosclerosis and restenosis study. Circulation 2000; 102: 771-778.
- 25 Schillinger M, Exner M, Mlekusch W. et al. Inflammation and Carotid Artery--Risk for Atherosclerosis Study (ICARAS). Circulation 2005; 111: 2203-2209.
- 26 Pola R. Inflammatory markers for ischaemic stroke. Thromb Haemost 2009; 101: 800-801.
- 27 Schuett H, Luchtefeld M, Grothusen C. et al. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thromb Haemost 2009; 102: 215-222.
- 28 Spangenberg P, Redlich H, Bergmann I. et al. The platelet glycoprotein IIb/IIIa complex is involved in the adhesion of activated platelets to leukocytes. Thromb Haemost 1993; 70: 514-521.
- 29 Silverstein RL, Asch AS, Nachman RL. Glycoprotein IV mediates thrombospondin-dependent platelet-monocyte and platelet-U937 cell adhesion. J Clin Invest 1989; 84: 546-552.
- 30 Lievens D, Eijgelaar WJ, Biessen EA. et al. The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 2009; 102: 206-214.
- 31 Klinkhardt U, Bauersachs R, Adams J. et al. Copidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease. Clin Pharmacol Ther 2003; 73: 232-241.
- 32 Fateh-Moghadam S, Li Z, Ersel S. et al. Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type-2. Aterioscler Thromb Vasc Biol 2005; 25: 1299-1303.
- 33 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
- 34 Htun P, Fateh-Moghadam S, Tomandl B. et al. Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia. Stroke 2006; 37: 2283-2287.
- 35 Nicolaides AN. Asymptomatic carotid stenosis and risk of stroke. Identification of a high risk group (ACSRS). A natural history study. Int Angiol 1995; 14: 21-23.
- 36 O’Holleran LW, Kennelly MM, McClurken M. et al. Natural history of asymptomatic carotid plaque. Five year follow-up study. Am J Surg 1987; 154: 659-662.
- 37 Polak JF, Shemanski L, O’Leary DH. et al. Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. Radiology 1998; 208: 649-654.
- 38 Zalai CV, Kolodziejczyk MD, Pilarski L. et al. Increased circulating monocyte activation in patients with unstable coronary syndromes. J Am Coll Cardiol 2001; 38: 1340-1347.