THE SIZE OF PLATELET-LEUKOCYTE AGGREGATES IN PATIENTS WITH VARIOUS DEGREE OF CORONARY ATHEROSCLEROSIS

An increased content of platelet-leukocyte aggregates indicates an elevated thrombogenic and inflammatory activity of periphery blood cells. The aim of this study was to investigate the percentage and properties of platelet-monocyte and platelet-lymphocyte aggregates in patients with coronary atherosclerosis. The study included 19 patients with coronary artery disease and coronary atherosclerosis (15 men; 4 women; 59.0 (55.0; 69.0) y.o.). A comparison group consisted of 8 high cardiovascular risk patients without coronary atherosclerosis. The severity of atherosclerosis was assessed by coronary angiography and Gensini Score. Platelet-leukocyte aggregates were analyzed by imaging flow cytometry. We assessed the percentage of platelet-monocyte and platelet-lymphocyte aggregates; the percentage of P-selectin (CD62P)+ aggregates; the number of platelets aggregated with each individual leukocyte (either monocyte or lymphocyte). A significantly lower number of monocytes formed small aggregates, consisting of 1 monocyte and 1 platelet, in patients with coronary atherosclerosis compared to patients without atherosclerosis (Gensini Score>0) (78.8 (68.1; 86.2) versus 84.7 (83.8; 87.1)% (p=0.039)). At the same time, in patients with more sever atherosclerosis (Gensini Score³42.5), the percentage of lymphocyte aggregates with more than 3 platelets tended to increase (0.6 (0.3; 1.6)%) compared to patients with Gensini Score<42.5 (0.1 (0; 0.8)%, p=0.075). The proportion of large platelet-lymphocyte aggregates (with 3 or more platelets) directly correlated with Gensini Score, IL-1b concentration, systemic inflammatory indices, the ratio of triglycerides to glucose and triglycerides to high-density lipoprotein cholesterol (insulin resistance indices), and inversely correlated with high-density lipoprotein cholesterol concentration. The percentage of small aggregates (1 lymphocyte with 1 platelet) inversely correlated with the severity of coronary atherosclerosis, IL-1b concentration, and insulin resistance index. Thus, the distinguishing feature of patients with coronary atherosclerosis appears to be not the increased number of platelet-leukocyte aggregates, but the increased size of heterotypic aggregates. An unfavorable sign is the formation of large aggregates (with 3 or more platelets), which is also associated with the intensity of systemic inflammation and metabolic imbalance.

1. Павлов О.В., Чепанов С.В., Селютин А.В., Сельков С.А. Тромбоцитарно-лейкоцитарные взаимодействия: иммунорегуляторная роль и патофизиологическое значение // Медицинская иммунология. – 2022. – Т. 24, № 5. – С. 871-888.

2. Pavlov O.V., Chepanov S.V., Selutin A.V., Selkov S.A. Platelet-leukocyte interactions: immunoregulatory role and pathophysiological relevance. Medical Immunology (Russia)/Meditsinskaya Immunologiya, 2022, Vol. 24, no. 5, pp. 871-888. https://www.mimmun.ru/mimmun/article/view/2511 [doi: 10.15789/1563-0625-PLI-2511]

3. Åberg M., Björklund E., Wikström G., Christersson C. Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH. Platelets, 2022, Vol. 33, no. 8, pp. 1199-1207. https://www.tandfonline.com/doi/full/10.1080/09537104.2022.2087867 [doi: 10.1080/09537104.2022.2087867]

4. Chacko B.K., Smith M.R., Johnson M.S., Benavides G., Culp M.L., Pilli J., Shiva S., Uppal K., Go Y.M., Jones D.P., Darley-Usmar V.M. Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets. Redox. Biol., 2019, Vol. 22, 101165. https://www.sciencedirect.com/science/article/pii/S2213231719302034?via%3Dihub [doi: 10.1016/j.redox.2019.101165]

5. Cunha J., Chan M.V., Nkambule B.B., Thibord F., Lachapelle A., Pashek R.E., Vasan R.S., Rong J., Benjamin E.J., Hamburg N.M., Chen M.H., Mitchell G.F., Johnson A.D. Trends among platelet function, arterial calcium, and vascular function measures. Platelets, 2023, Vol. 34, no. 1, 2238835. https://www.tandfonline.com/doi/full/10.1080/09537104.2023.2238835 [doi: 10.1080/09537104.2023.2238835]

6. Feng R., Dai Y., Du S., Liang W., Chen H., Chen C., He T., Tao T., Hu Z., Guo P., Ye W. Leukocyte and platelet related inflammatory indicators and risk of carotid and femoral plaques: a population-based cross-sectional study in Southeast China. Angiology, 2024, Vol. 75, no. 1, pp. 79-89. https://journals.sagepub.com/doi/10.1177/00033197221129723?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed [doi: 10.1177/00033197221129723]

7. Finsterbusch M., Schrottmaier W.C., Kral-Pointner J.B., Salzmann M., Assinger A. Measuring and interpreting platelet-leukocyte aggregates. Platelets, 2018, Vol. 29, no. 7, pp. 677-685. https://www.tandfonline.com/doi/full/10.1080/09537104.2018.1430358 [doi:10.1080/09537104.2018.1430358]

8. Gensini G.G. A more meaningful scoring system for determining the severity of coronary heart disease. Am. J. Cardiol., 1983, Vol. 51, no. 3, P. 606. https://www.sciencedirect.com/science/article/abs/pii/S0002914983801052?via%3Dihub [doi: 10.1016/s0002-9149(83)80105-2]

9. Hui H., Fuller K.A., Erber W.N., Linden M.D. Imaging flow cytometry in the assessment of leukocyte-platelet aggregates. Methods, 2017, Vol. 112, pp. 46-54. https://www.sciencedirect.com/science/article/pii/S1046202316303395?via%3Dihub [doi: 10.1016/j.ymeth.2016.10.002]

10. Jin J.L., Cao Y.X., Wu L.G., You X.D., Guo Y.L., Wu N.Q., Zhu C.G., Gao Y., Dong Q.T., Zhang H.W., Sun D., Liu G., Dong Q., Li J.J. Triglyceride glucose index for predicting cardiovascular outcomes in patients with coronary artery disease. J. Thorac. Dis., 2018, Vol. 10, no. 11, pp. 6137-6146. https://jtd.amegroups.org/article/view/25083/19092 [doi: 10.21037/jtd.2018.10.79]

11. Kologrivova I.V., Suslova T.E., Koshelskaya O.A., Kravchenko E.S., Kharitonova O.A., Romanova E.A., Vyrostkova A.I., Boshchenko A.A. Intermediate monocytes and circulating endothelial cells: interplay with severity of atherosclerosis in patients with coronary artery disease and type 2 diabetes mellitus. Biomedicines, 2023, Vol. 11, no. 11, 2911. https://www.mdpi.com/2227-9059/11/11/2911 [doi: 10.3390/biomedicines11112911]

12. Li N., Ji Q., Hjemdahl P. Platelet-lymphocyte conjugation differs between lymphocyte subpopulations. J. Thromb. Haemost., 2006, Vol. 4, no. 4, pp. 874-881. https://www.sciencedirect.com/science/article/pii/S1538783622130886?via%3Dihub [doi: 10.1111/j.1538-7836.2006.01817.x]

13. Libby P. The changing landscape of atherosclerosis. Nature., 2021, Vol. 592, no. 7855, pp. 524-533. https://www.nature.com/articles/s41586-021-03392-8 [doi: 10.1038/s41586-021-03392-8]

14. Ludwig N., Hilger A., Zarbock A., Rossaint J. Platelets at the crossroads of pro-inflammatory and resolution pathways during inflammation. Cells, 2022, Vol. 11, no. 12, 1957. https://www.mdpi.com/2073-4409/11/12/1957 [doi: 10.3390/cells11121957]

15. Manke M.C., Ahrends R., Borst O. Platelet lipid metabolism in vascular thrombo-inflammation. Pharmacol. Ther., 2022, Vol. 237, 108258 https://www.sciencedirect.com/science/article/pii/S0163725822001528?via%3Dihub [doi: 10.1016/j.pharmthera.2022.108258]

16. Nagasawa A., Matsuno K., Tamura S., Hayasaka K., Shimizu C., Moriyama T. The basis examination of leukocyte-platelet aggregates with CD45 gating as a novel platelet activation marker. Int. J. Lab. Hematol., 2013, Vol. 35, no. 5, pp. 534-541. https://onlinelibrary.wiley.com/doi/10.1111/ijlh.12051 [doi: 10.1111/ijlh.12051]

17. Pluta K., Porębska K., Urbanowicz T., Gąsecka A., Olasińska-Wiśniewska A., Targoński R., Krasińska A., Filipiak K.J., Jemielity M., Krasiński Z. Platelet-leucocyte aggregates as novel biomarkers in cardiovascular diseases. Biology (Basel), 2022, Vol. 11, no. 2, 224. https://www.mdpi.com/2079-7737/11/2/224 [doi: 10.3390/biology11020224]

18. Ponomarev E.D. Fresh evidence for platelets as neuronal and innate immune cells: their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation. Front. Immunol., 2018, Vol. 9, 406. https://www.frontiersin.org/articles/10.3389/fimmu.2018.00406/full [doi: 10.3389/fimmu.2018.00406]

19. Rolling C.C., Barrett T.J., Berger J.S. Platelet-monocyte aggregates: molecular mediators of thromboinflammation. Front. Cardiovasc. Med., 2023, Vol. 10, 960398. https://www.frontiersin.org/articles/10.3389/fcvm.2023.960398/full [doi: 10.3389/fcvm.2023.960398]

20. Sagar R.C., Ajjan R.A., Naseem K.M. Non-traditional pathways for platelet pathophysiology in diabetes: implications for future therapeutic targets. Int. J. Mol. Sci., 2022, Vol. 23, no. 9, 4973. https://www.mdpi.com/1422-0067/23/9/4973 [doi: 10.3390/ijms23094973]