Morphological determinants for the local hemostatic effect of exogenous fibrin monomer in its systemic administration after injury with inhibition of platelet aggregation in the experiment

Background. In our previously published studies, we demonstrated a high hemostatic activity of a low dose of exogenous fibrin monomer during its systemic administration in a model of dosed liver injury with preliminary inhibition of platelet aggregation. However, the analysis of platelet involvement in the mechanisms of local fibrin formation has not been analyzed.

The aim of the study. To conduct a comparative analysis of the cellular composition of venous and wound blood, as well as blood in the wound vessels to assess the contribution of platelets to the hemostatic effect of exogenously administered fibrin monomers in dosed liver injury under conditions of pharmacologically determined thrombocytopathy.

Methods. In a model of dosed liver injury in rabbits after inhibition of platelet aggregation by  acetylsalicylic acid in combination with clopidogrel, the effect of the administration of fibrin monomer was evaluated in comparison with the use of tranexamic acid. We studied the number of platelets in venous and wound blood smears, as well as in the contents of wound vessels.

Results. It has been established that with the systemic administration of exogenous fibrin monomer, the number of platelets in wound blood smears decreases by 17.2 % in comparison with free circulating venous blood. Platelets in wound blood form aggregates and are in an activated state. In the wound vessels, the number of these cells was maximum (150 per lower field) compared with the number of platelets in the placebo and tranexamic acid groups (55 and 84 per lower field, respectively). Also in the wound blood, erythrocytes with altered forms (echinocytes, schistocytes, stomatocytes and ovalocytes) were found.

Conclusion. Systemic administration of exogenous fibrin monomer affects the redistribution of platelets between the systemic circulation, wound vessels and wound blood, determining its hemostatic effect and local wound fibrin formation in dosed liver injury. The presence of receptor-mediated platelets recruitment due to fibrin monomer in the wound vessels with the  participation of damaged erythrocytes is assumed.

1. Panteleev MA, Dashkevich NM, Ataullakhanov FI. Hemostasis and thrombosis beyond biochemistry: Roles of geometry, flow and diffusion. Thromb Res. 2015; 136(4): 699-711. doi: 10.1016/j.thromres.2015.07.025

2. Hoffman M, Monroe DM. Coagulation 2006: A modern view of hemostasis. Hematol Oncol Clin North Am. 2007; 21(1): 1-11. doi: 10.1016/j.hoc.2006.11.004

3. Ho KM, Pavey W. Applying the cell-based coagulation model in the management of critical bleeding. Anaesth Intensive Care. 2017; 45(2): 166-176. doi: 10.1177/0310057X1704500206

4. Wang J, Changxin Yu, Zhuang J, Wenxin Qi, Jiawen J, Xuanting L, et al. The role of phosphatidylserine on the membrane in immunity and blood coagulation. Biomark Res. 2022; 10(1): 4. doi: 10.1186/s40364-021-00346-0

5. Momot AP, Vdovin VM, Shakhmatov II, Tolstokorov IG, Orekhov DA, Shevchenko VO, et al. Systemic hemostatic and prothrombotic effects of fibrin-monomer in experiment with dosed liver therapy. Siberian Scientific Medical Journal. 2019; 39(1): 6-12. (In Russ.). doi: 10.15372/SSMJ20190101

6. Vdovin VM, Momot AP, Orekhov DA, Tolstokorov IG, Shevchenko VO, Krasyukova VO, et al. Time-dependent systemic hemostatic effects of fibrin monomer in controlled liver injury in the experiment. Kazan Medical Journal. 2019; 100(2): 257-263. (In Russ.). doi: 10.17816/KMJ2019-257

7. Momot AP, Vdovin VM, Orekhov DA, Lycheva NA, Tolstokorov IG, Shevchenko VO, et al. Prevention of heparin-associated massive intraoperative bleedings by systemic administration of fibrin monomer in experiment. Pathological Physiology and Experimental Therapy. 2019; 63(4): 48-55. (In Russ.). doi: 10.25557/0031-2991.2019.04.48-55

8. Vdovin VM, Bobrov IP, Shakhmatov II, Momot AP. Morphological consequences of systemic application of fibrin monomer in conditions of hemostatic potential suppression and fibrinolytic potential amplification in dosed liver injury in experiment. Bulletin of Medical Science. 2021; 21(1): 74-87. (In Russ.).

9. Vdovin VM, Momot AP, Krasyukova VO, Tolstokorov IG, Orekhov DA, Shevchenko VO, et al. Systemic hemostatic and hemostasiological effects of fibrin monomer in direct thrombin inhibition in experiment. Russian Journal of Physiology. 2019; 105(2): 207-215. (In Russ.). doi: 10.1134/S0869813919020109

10. Vdovin VM, Momot AP, Orekhov DA, Tolstokorov IG, Lycheva NA, Shevchenko VO, et al. Experimental study of systemic hemostatic effects of fibrin monomer in inhibition of platelet aggregation function. Bulletin of Siberian Medicine. 2020; 19(1): 36-42. (In Russ.). doi: 10.20538/1682-0363-2020-1-36-42

11. Vdovin VM, Momot AP, Shakhmatov II, Bobrov IP, Orekhov DA, Terjaev VV, et al. Effects of tranexamic acid and exogenous fibrin monomer on the liver injury area and systemic circulation in pharmacological suppression of platelet function in an experiment. Kazan Medical Journal. 2021; 102(5): 642-653. (In Russ.). doi: 10.17816/KMJ2021-642

12. Ziganshin AU. New antiaggregants – blockers of platelet P2 receptors. Kazan Medical Journal. 2010; 91(1): 73-79. (In Russ.)

13. Mironov AN (ed.). Guidelines for conducting preclinical studies of drugs. Part 1. Moscow: Grif I K; 2012. (In Russ.).

14. Ostroumova OD, Kravchenko EV, Kochetkov AI. Drug-induced thrombocytopenia. Clinical Pharmacology and Therapy. 2019; 28(4): 56-64. (In Russ.). doi: 10.32756/0869-5490-2019-4-56-64

15. Holinstat M. Normal platelet function. Cancer Metastasis Rev. 2017; 36(2): 195-198. doi: 10.1007/s10555-017-9677-x

16. Chuchalin AG, Khokhlov AL (eds). Federal guidelines for the use of medicines (formulary system). Issue XVIII. Moscow: Vidoks; 2017. (In Russ.).

17. Jia S, Hongwen J, Facheng R, Gang W, Meiying X, Yuliang X, et al. Protective effects of tranexamic acid on clopidogrel before coronary artery bypass grafting: A multicenter randomized trial. JAMA Surg. 2013; 148(6): 538-547. doi: 10.1001/jamasurg.2013.1560

18. Tengborn L, Blombäck M, Berntorp E. Tranexamic acid – an old drug still going strong and making a revival. Thromb. Res. 2015; 135(2): 231-242. doi: 10.1016/j.thromres.2014.11.012

19. Larrieu MJ. Action of fibrinogen degradation products and fibrin monomer soluble complexes on platelet aggregation. Scand J Haematol Suppl. 1971; 13: 273-279.

20. Pastorova VE, Lyapina LA, Kudryashov BA, Lugovskoy EV. Platelet aggregation caused by fibrin monomer and the effect of complex compounds of heparin with adrenaline or plasmin on this process. Russian Journal of Hematology and Transfusiology. 1990; 7: 5-7. (In Russ.).

21. Momot AP, Sukhanova GA. Platelet aggregation induced by fibrin monomer and its disturbances during intravascular coagulation. Russian Journal of Hematology and Transfusiology. 1991; 11: 25-26. (In Russ.).

22. Vasilyeva TM, Petrukhina GN, Makarov VA, Momot AP, Barkagan ZS. In vitro aggregation of human platelets with simultaneous exposure to fibrin monomer and some proaggregants. Russian Journal of Hematology and Transfusiology. 2002; 2: 23-26. (In Russ.).

23. Levin GYa, Egorikhina MN, Taranenko IA, Momot AP. Effect of fibrin monomer on spontaneous platelet aggregation. Russian Clinical Laboratory Diagnostics. 2011; 3: 39-42. (In Russ.).

24. Levin GY, Egorihina MN. Aggregation of erythrocytes in burn disease. Int J Burns Trauma. 2011; 1(1): 34-41.

25. Zubairov DM. Molecular basis of blood coagulation and thrombosis. Kazan: Fen; 2000. (In Russ.).

26. Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature. 1984; 309(5963): 30-33. doi: 10.1038/309030a0

27. Farrell DH, Thiagarajan P, Chung DW, Davie EW. Role of fibrinogen alpha and gamma chain sites in platelet aggregation. Proc Natl Acad Sci USA. 1992; 89(22): 10729-10732. doi: 10.1073/pnas.89.22.10729

28. Weisel JW, Nagaswami C, Vilaire G, Bennett JS. Examination of the platelet membrane glycoprotein IIb–IIIa complex and its interaction with fibrinogen and other ligands by electron microscopy. J Biol Chem. 1992; 267(23): 16637-16643.

29. Zubairov DM, Zubairova LD. Microvesicles in the blood. Functions and their role in thrombosis. Moscow: GEOTAR-Media; 2009. (In Russ.).

30. Zubairov DM, ShcherbatenkoLushnikova LA, Andrushko IA, Gabitov SZ, Litvinov RI, Kalbina AV, et al. Diagnostics of thromboplastinemia in myocardial infarction. Terapevticheskii arhiv. 1981; 53(8): 29-30. (In Russ.).

31. Kolesnik EA, Derkho MA. Artifacts of formed elements and plasma of bird blood, their genesis and diagnostic significance. Scientific Notes Kazan Bauman State Academy of Veterinary Medicine. 2021; 248(4): 129-135. (In Russ.). doi: 10.31588/2413-4201-1883-248-4-129-135