Effect of dexamethasone therapy on factors of adhesiveness and coagulation in acute lower limb ischemia

Leukocyte-platelet adhesion during hypoxia, tissue damage, activation of inflammation and coagulation is associated with the expression of ICAM-1 membrane molecules and integrins by blood and tissue cells. At the same time, platelet adhesion receptors determine their adhesion to the endothelium and recruited lymphocytes. The role of platelets in the pathogenesis of ischemic cardiovascular diseases also consists in their ability to modulate both hemostasis and inflammatory reactions, which is accompanied by the secretion of inflammatory mediators and factors that promote the recruitment of leukocytes to tissue damage sites. Purpose of the study: to study the effect of the synthetic glucocorticoid dexamethasone on the expression of adhesion receptors CD18⁺ and CD54⁺ on leukocytes, the content of platelets and fibrinogen in the blood of patients with ALLI, the relationship of these indicators with the severity and outcome of the disease.

To study the effect of anti-inflammatory therapy, a group of 32 patients treated with dexamethasone was formed; the comparison group was represented by 71 patients with basic therapy, the control group consisted of 15 volunteers. After revascularization, all patients received antiplatelet and anticoagulant therapy. Dexamethasone infusions were carried out in a course of 4 to 6 days after reconstructive surgery. In all patients, the content of C-reactive protein in the blood, the content of platelets and fibrinogen were determined. The number of lymphocytes expressing adhesion molecules ICAM-1 (CD54⁺) and integrins (CD18⁺) was counted using the immunocytochemical method. Studies were performed before surgery and on days 1, 3, 7, and 10 after surgery.

With exacerbation of ischemia and damage to the endothelium, the accumulation of cytolysis products, the expression of adhesion molecules increases both on endotheliocytes and on inflammatory effector cells – leukocytes and platelets. Adhesion molecules conduct an activation signal inside the cell, which promotes adhesion of leukocytes and platelets to the endothelium, lymphocytic-platelet adhesion, the formation of a parietal thrombus, and possible occlusion of damaged vessels. Increased expression of adhesion molecules is associated with the activation of metabolism, inflammation, coagulation and oxidative stress, stimulates all hematopoietic lineages, including platelets. The level of involvement of cellular reactions in the pathogenesis of the disease affects the effectiveness and duration of treatment, the risk of recurrent thrombosis and death. Anti-inflammatory therapy with dexamethasone contributed to earlier remission, a decrease in the proportion of infectious complications, such as wound suppuration from 10% to 6%, the number of necessary amputations from 32% to 16%, the frequency of deaths from 31% to 6%, and a reduction in hospital stay from 13 days to 10.

Inflammation, adhesiveness of effector cells and thrombosis are important factors in the pathogenesis of acute lower limb ischemia. Therapy with dexamethasone helps to reduce the level of systemic inflammatory response, the number of necessary amputations, the number of complications and adverse outcomes in the treatment of ALLI, and reduce the length of stay in the hospital.

1. Baran K.W., Nguyen M., McKendall G.R. Lambrew C.T., Dykstra G., Palmeri S.T., Gibbons R.J., Borzak S., Sobel B.E., Gurlay S.G., Rundle A.C., Gibson K.M., Barron H.V. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation, 2001, Vol. 104, pp. 2778-2783.

2. Carlos T.M., Harlan J.M. Leukocyte-endothelial adhesion molecules. Blood, 1994, Vol. 84, no. 7, pp. 2068-2101.

3. Charlson M.E., Pompei P., Ales K.L., McKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J. Chron. Dis., 1987, Vol. 40, no. 5, pp. 373-383.

4. Faxon D., Gibbons R.J., Chronos N.A.F., Gurbel P.A., Sheehan F. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J. Am. Coll. Cardiol., 2002, Vol. 40, pp. 1199-1204.

5. Gonzalez-Amaro R., Sanchez-Madrid F. Drugs, inflammation and cell adhesion receptors. Expert Opin. Pharmacother., 2001, Vol. 2, pp. 3-17.

6. Harlan J.M, Winn R.K. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit. Care Med., 2002, Vol. 30, no. 5, Suppl., pp. S214-S219.

7. Magamedov I.D., Pivovarova L.P., Nokhrin S.P., Ariskina O.B. Soroka V.V. Markers of inflammation and oxidative stress in the treatment of acute ischemia of the lower extremities. Russian Journal of Immunology, 2019, Vol. 13 (22), no. 2, pp. 1054-1056. (In Russ.)

8. Magamedov I.D., Pivovarova L.P., Ariskina O.B., Nokhrin S.P., Soroka V.V., Ryazanov A.N., Belousov E.Yu., Kurilov A.B., Malinovsky Yu .P., Magomedov S.B., Radjabov I.M., Gaipov M.M., Goncharova O.V. The development of oxidative stress in acute ischemia of the lower extremities in elderly and senile patients. Electronic Journal of Clinical and Experimental Surgery, 2019, no. 4, pp. 23-31. (In Russ.)

9. Moskalets O.V. Cell adhesion molecules ICAM-1 and VCAM-1 in infectious pathology. Pacific Medical Journal, 2018, no. 2, pp. 21-25. (In Russ.)

10. Pitzalis C., Pipitone N., Perretti M., Pitzalis C. Regulation of leukocyte-endothelial interactions by glucocorticoids. Ann. N. Y. Acad. Sci., 2002, Vol. 966, pp. 108-118.

11. Sherman D.G., Bes A., Easton J.D., Hacke W. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology, 2001, Vol. 57, no. 8, pp. 1428-1434.

12. Suchkov I.A., Pshennikov A.S., Gerasimov A.A., Agapov A.B., Kamaev A.A. Prevention of restenosis in reconstructive surgery of the main arteries. Eruditio Juvenium, 2013, Vol. 2, pp. 12-19.

13. Ulbrich H., Eriksson E.E., Lindbom L. Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. Trends Pharmacol. Sci., 2003, Vol. 24, no. 12, pp. 640-647.

14. Ye W., Liu C.W., Ricco J.B., Mani K., Zeng R., Jiang J. Early and late outcomes of percutaneous treatment of TransAtlantic Inter-Society Consensus class C and D aorto-iliac lesions. J. Vasc. Surg., 2011, Vol. 53, no. 6, pp. 1728-1737