Time-dependent systemic hemostatic effects of fibrin monomer in controlled liver injury in the experiment

Abstract

Aim. To evaluate the hemostatic effect of fibrin monomer after its intravenous administration at different time periods in experimental trauma.

Methods. In the experiments, in a placebo-controlled study, hemostatic and hemostasiological effects of systemic use of fibrin monomer were studied at different time periods after its administration (in 5 min, 1 h and 3 h) in 97 male rabbits of the Chinchilla breed in the controlled liver injury model.

Results. A pronounced hemostatic effect was demonstrated for fibrin monomer used at a dose of 0.25 mg/kg demonstrated by a 6.3-fold decrease of blood loss volume (% of circulating blood volume) compared to placebo on the background of the intravenous preventive fibrin monomer administration 1 hour prior to controlled liver injury. Fibrin monomer administration at a stated dose was not accompanied by significant changes in haemocoagulative parameters including measurement of platelet count, activated partial thromboplastin time, prothrombin time, thrombin time, echitox time, fibrinogen concentration, level of soluble fibrin monomer complexes, D-dimer content, and antithrombin III activity. The effect of fibrin monomer is probably realized through some effectors, the nature of which has not yet been studied. The obtained results allow choosing the optimal interval between intravenous administrations of fibrin monomer and controlled liver injury for further study of the mechanisms of its hemostatic action.

Conclusion. Fibrin monomer in small doses (0.25 mg/kg) is able to exert a pronounced hemostatic effect with its systemic administration 1 hour prior to the injury without significant changes in haemocoagulative parameters.

Keywords

hemostatic system / fibrin monomer / liver injury / blood loss model / systemic hemostatic effect / rabbits

References

[1] Rossaint R., Bouillon B., Cerny V. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit. Care. 2016; 12 (20): 100. DOI: 10.1186/s13054-016-1265-x.

[2] Cap A., Hunt B.J. The pathogenesis of trauma­tic coagulopathy. Anaesthesia. 2015; 70 (1): 96–101. DOI: 10.1111/anae.12914.

[3] Cap A., Hunt B.J. The pathogenesis of traumatic coagulopathy. Anaesthesia. 2015; 70 (1): 96-101. DOI: 10.1111/anae.12914.

[4] Levi M. Management of bleeding in patients treated with direct oral anticoagulants. Crit. Care. 2016; 20: 249. DOI: 10.1186/s13054-016-1413-3.

[5] Damage Control Resuscitation at Level IIb/III Treatment Facilities. Joint theater trauma system clinical practice guideline. Feb. 2013. http://9thcall.ru/wp-content/uploads/2019/02/Management-of-crush-syndrome-under-prolonged-field-care.pdf (access date: 05.12.2018).

[6] Hayes B.D., Winters M.E., Rosenbaum S.B. et al. What is the role of reversal agents in the management of emergency department patients with dabigatran-associa­ted hemorrhage? J. Emerg. Med. 2018; 54 (4): 571–575. DOI: 10.1016/j.jemermed.2017.12.061.

[7] Hayes B.D., Winters M.E., Rosenbaum S.B. et al. What is the role of reversal agents in the management of emergency department patients with dabigatran-associated hemorrhage? J. Emerg. Med. 2018; 54 (4): 571-575. DOI: 10.1016/j.jemermed.2017.12.061.

[8] Lambourne M.D., Eltringham-Smith L.J., Gataiance S. et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J. Thromb. Haemost. 2012; 10 (9): 1830–1840. DOI: 10.1111/j.1538-7836.2012.04863.x.

[9] Lambourne M.D., Eltringham-Smith L.J., Gataiance S. et al. Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate. J. Thromb. Haemost. 2012; 10 (9): 1830-1840. DOI: 10.1111/j.1538-7836.2012.04863.x.

[10] Kudryashov B.A., Molchanova L.V., Kalishevskaya T.M. et al. About the functional state of the anticoagulation system during intravenous administration of fibrin monomer. Voprosy meditsinskoy khimii. 1969; 15 (5): 483–486. (In Russ.)

[11] Кудряшов Б.А., Молчанова Л.В., Калишевская Т.М. и др. О функциональном состоянии противосвёртывающей системы при внутривенном введении фибрин-мономера. Вопр. мед. хим. 1969; 15 (5): 483-486.

[12] Zubairov D.M. Molekulyarnye osnovy svertyvaniya krovi i tromboobrazovaniya. (Molecular basis of blood clotting and thrombus formation.) Kazan: Fen. 2000; 368 р. (In Russ.)

[13] Зубаиров Д.М. Молекулярные основы свёртывания крови и тромбообразования. Казань: ФЭН. 2000; 368 с.

[14] Weisel J.W., Litvinov R.I. Fibrin formation, structure, and properties. In: Fibrous proteins: structures and mechanisms. D.A.D. Parry, J.M. Squire eds. Subcellular Biochemistry. 2017; 82: 405–456. DOI: 10.1007/978-3-319-

[15] Weisel J.W., Litvinov R.I. Fibrin formation, structure, and properties. In: Fibrous proteins: structures and mechanisms. D.A.D. Parry, J.M. Squire eds. Subcellular Biochemistry. 2017; 82: 405-456. DOI: 10.1007/978-3-319- 49674-0_13.

[16] 49674-0_13.

[17] Момот А.П., Вдовин В.М., Толстокоров И.Г. и др. Способ профилактики интраоперационных кровотечений, вызванных введением гепарина до операции. Патент на изобретение РФ №2544805. Бюлл. от 20.03.2015.

[18] Momot A.P., Vdovin V.M., Tolstokorov I.G. et al. ­Me­thod for preventing intraoperative bleeding caused by pre­operative introduction of heparin. Patent for invention RF №2544805. Bulletin issued on 20.03.2015. (In Russ.)

[19] Момот А.П., Шахматов И.И., Ломаев И.С., Терехов С.С. Способ промышленного получения фибрин-мономера из плазмы крови. Патент на изобретение РФ №2522237. Бюлл. от 15.05.2014.

[20] Momot A.P., Shakhmatov I.I., Lomaev I.S., Terekhov S.S. A method for commercial production of fibrin monomer from blood plasma. Patent for invention RF №2522237. Bulletin issued on 15.05.2014. (In Russ.)

[21] Хабриев Р.Ю. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. Изд. 2-е, перераб. и доп. М.: Медицина. 2005; 828 с.

[22] Khabriev R.Yu. Rukovodstvo po ehksperimentalnomu (doklinicheskomu) izucheniyu novykh farmakologicheskikh veshchestv. (Guidelines for experimental (preclinical) study of new pharmacological substances.) 2-nd ed., Moscow: Meditsina. 2005; 828 p. (In Russ.)

[23] Баркаган З.С., Момот А.П. Диагностика и контролируемая терапия системы гемостаза. М.: Ньюдиамед. 2008; 283 с.

[24] Barkagan Z.S., Momot A.P. Diagnostika i kontroliruemaya terapiya narushenij gemostaza. (Diagnostics and controlled therapy of the hemostatic system.) Moscow: N`yudiamed. 2008; 283 p. (In Russ.)

[25] Соболева И.В., Субханукулова Ф.Б., Миннебаев М.М., Зубаиров Д.М. Циркуляция растворимого фибрин-мономера в организме. Вопр. мед. хим. 1978; 24 (3): 358-361.

[26] Soboleva I.V., Subkhanukulova F.B., Minnebaev M.M., Zubairov D.M. Circulation of soluble fibrin monomer in the body. Voprosy meditsinskoy khimii. 1978; 24 (3): 358–361. (In Russ.)

[27] Бышевский А.Ш., Галян С.Л., Калинин Е.П. и др. О регуляции неферментативного этапа свёртывания крови (аутополимеризация и агрегация фибрина). Тромбоз, гемостаз и реология. 2012; (1): 27-46.

[28] Byshevskiy A.Sh., Galyan S.L., Kalinin E.P. et al. About regulation of non-enzymatic stage of blood coagulation (autopolymerization and aggregation of fibrin). Tromboz, gemostaz i reologiya. 2012; (1): 27–46. (In Russ.)

RIGHTS & PERMISSIONS

Vdovin V.M., Momot A.P., Orekhov D.A., Tolstokorov I.G., Shevchenko V.O., Krasyukova V.O., Shakhmatov I.I., Lycheva N.A., Belozerskaya G.G.