Platelet density per monocyte predicts adverse events in patients after percutaneous coronary intervention

Summary

Monocyte recruitment to damaged endothelium is enhanced by platelet binding to monocytes and contributes to vascular repair. Therefore, we studied whether the number of platelets per monocyte affects the recurrence of adverse events in patients after percutaneous coronary intervention (PCI). Platelet-monocytes complexes with high and low median fluorescence intensities (MFI) of the platelet marker CD42b were isolated using cell sorting. Microscopic analysis revealed that a high platelet marker MFI on monocytes corresponded with a high platelet density per monocyte while a low platelet marker MFI corresponded with a low platelet density per monocyte (3.4 ± 0.7 vs 1.4 ± 0.1 platelets per monocyte, P=0.01). Using real-time video microscopy, we observed increased recruitment of high platelet density monocytes to endothelial cells as compared with low platelet density monocytes (P=0.01). Next, we classified PCI scheduled patients (N=263) into groups with high, medium and low platelet densities per monocyte and assessed the recurrence of adverse events. After multivariate adjustment for potential confounders, we observed a 2.5-fold reduction in the recurrence of adverse events in patients with a high platelet density per monocyte as compared with a low platelet density per monocyte [hazard ratio=0.4 (95 % confidence interval, 0.2–0.8), P=0.01]. We show that a high platelet density per monocyte increases monocyte recruitment to endothelial cells and predicts a reduction in the recurrence of adverse events in patients after PCI. These findings may imply that a high platelet density per monocyte protects against recurrence of adverse events.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Monocytes - platelets - adverse events - percutaneous coronary intervention

^# Prof. P.G. de Groot and Dr. I.E. Hoefer contributed equally to this study.

• References

• 1 Cuculi F, Lim C, Banning A. Periprocedural myocardial injury during elective percutaneous coronary intervention: is it important and how can it be prevented?. Heart 2010; 96: 736-740.
• 2 Ganesha Babu G, Malcolm Walker J, Yellon D. et al. Peri-procedural myocardial injury during percutaneous coronary intervention: an important target for car-dioprotection. Eur Heart J 2010; 32: 23-31.
• 3 Lansky A, Stone G. Periprocedural Myocardial Infarction: Prevalence, Prognosis, and Prevention. Circulation Cardiovasc Interven 2010; 03: 602-610.
• 4 Levitsky S. Protecting the Myocardial Cell During Coronary Revascularisation. Circulation 2006; 114: I-339-I-343.
• 5 Murray P, Wynn T. Protective and pathogenic functions of macrophage subsets. Nature Rev Immunol 2011; 11: 723-737.
• 6 Fujiyama S. Bone Marrow Monocyte Lineage Cells Adhere on Injured Endothe-lium in a Monocyte Chemoattractant Protein-1-Dependent Manner and Accelerate Reendothelialisation as Endothelial Progenitor Cells. Circulation Res 2003; 93: 980-989.
• 7 Moldovan N, Goldschmidt-Clermont P, Parker-Thornburg J. et al. Contribution of Monocytes/Macrophages to Compensatory Neovascularisation: The Drilling of Metalloelastase-Positive Tunnels in Ischaemic Myocardium. Circulation Res 2000; 87: 378-384.
• 8 Asahara T, Bauters C, Pastore C. et al. Local Delivery of Vascular Endothelial Growth Factor Accelerates Reendothelialisation and Attenuates Intimal Hyper-plasia in Balloon-Injured Rat Carotid Artery. Circulation 1995; 91: 2793-2801.
• 9 Nahrendorf M, Pittet M, Swirski F. Monocytes: Protagonists of Infarct Inflammation and Repair After Myocardial Infarction. Circulation 2010; 121: 2437-2445.
• 10 Nahrendorf M, Swirski F, Aikawa E. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204: 3037-3047.
• 11 Rehman J. Peripheral Blood “Endothelial Progenitor Cells” Are Derived From Monocyte/Macrophages and Secrete Angiogenic Growth Factors. Circulation 2003; 107: 1164-1169.
• 12 Urbich C. Relevance of Monocytic Features for Neovascularisation Capacity of Circulating Endothelial Progenitor Cells. Circulation 2003; 108: 2511-2516.
• 13 Kalka C, Masuda H, Takahashi T. et al. Transplantation of ex vivo expanded en-dothelial progenitor cells for therapeutic neovascularisation. Pro Natl Acad Sci 2000; 97: 3422-3427.
• 14 Rookmaaker M. Endothelial Progenitor Cells: Mainly Derived From the Mono-cyte/Macrophage-Containing CD34- Mononuclear Cell Population and Only in Part From the Hematopoietic Stem Cell-Containing CD34+ Mononuclear Cell Population * Response. Circulation 2003; 108: 150e-150.
• 15 Davis C, Fischer J, Ley K. et al. The role of inflammation in vascular injury and repair. J Thromb Haemost 2003; 01: 1699-1709.
• 16 Morrell C, Aggrey A, Chapman L. et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123: 2759-2767.
• 17 Leppanen A, Yago T, Otto V. et al. Model Glycosulfopeptides from P-selectin Glycoprotein Ligand-1 Require Tyrosine Sulfation and a Core 2-branched O-Glycan to Bind to L-selectin. J Biol Chem 2003; 278: 26391-26400.
• 18 Huo Y, Ley K. Role of Platelets in the Development of Atherosclerosis. Trends Cardiovasc Med 2004; 14: 18-22.
• 19 Huo Y, Schober A, Forlow S. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2002; 09: 61-67.
• 20 da Costa Martins P. Platelet-Monocyte Complexes Support Monocyte Adhesion to Endothelium by Enhancing Secondary Tethering and Cluster Formation. Ar-terioscl Thromb Vasc Biol 2004; 24: 193-199.
• 21 Sixma J, de Groot P, van Zanten H. et al. A new perfusion chamber to detect platelet adhesion using a small volume of blood. Thromb Res 1998; 92: S43-S46.
• 22 Hoefer I, Sels J, Jukema J. et al. Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study. Clin Res Cardiol 2013; 102: 847-856.
• 23 Hoefer I. Arteriogenesis Proceeds via ICAM-1/Mac-1- Mediated Mechanisms. Circulation Res 2004; 94: 1179-1185.
• 24 Zhang Y, Liu D, Chen X. et al. Secreted Monocytic miR-150 Enhances Targeted Endothelial Cell Migration. Mol Cell 2010; 39: 133-144.
• 25 Heil M, Ziegelhoeffer T, Pipp F. et al. Blood monocyte concentration is critical for enhancement of collateral artery growth. Am J Physiol 2002; 283: H2411-H2419.
• 26 Bernardo A, Bakk C, Nolasco L. et al. Platelets adhered to endothelial cell-bound ultra-large von Willebrand factor strings support leukocyte tethering and rolling under high shear stress. J Thromb Haemost 2005; 03: 562-570.
• 27 De Maeyer B, De Meyer S, Feys H. et al. The distal carboxyterminal domains of murine ADAMTS13 influence proteolysis of platelet-decorated VWF strings in vivo. J Thromb Haemost 2010; 08: 2305-2312.
• 28 Urra X, Villamor N, Amaro S. et al. Monocyte subtypes predict clinical course and prognosis in human stroke. J Cerebral Blood Flow Metabol 2009; 29: 994-1002.
• 29 Wrigley BJ, Shantsila E, Tapp LD. et al. Increased formation of monocyte-pla-telet aggregates in ischaemic heart failure. Circulation Heart Fail 2013; 06: 127-135.
• 30 Passacquale G, Vamadevan P, Pereira L. et al. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PloS one 2011; 06: e25595.