Posttraumatic bleeding reduction by systemic administration of fibrin monomer in thrombolytic therapy
Published 2020-04-07
Keywords
- fibrin monomer,
- hemostatic effect,
- posttraumatic blood loss,
- streptokinase,
- tranexamic acid
How to Cite
Copyright (c) 2020 Vdovin V.M., Momot A.P., Orekhov D.A., Krasyukova V.O., Shakhmatov I.I., Lycheva N.A., Momot D.A., Chernus V.E., Terjaev V.V.

This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
Background. There is a continued search for effective and safe drugs with systemic hemostatic effects. Experimental data from previous studies show that low-dose fibrin monomer (FM) can reduce posttraumatic bleeding without causing activation of clotting in the circulating blood.
Aim. To study the systemic hemostatic and hemostasiological effects of prophylactic intravenous administration of FM on the background of fibrinolysis activation by streptokinase.
Methods. In a placebo-controlled study using male rabbits, fibrinolysis was activated by intravenous administration of streptokinase at a dose of 150,000 IU/kg. One hour before liver injury, FM was administered intravenously at a dose of 0.25 mg/kg. Tranexamic acid (TXA) was administered intravenously at a dose of 15 mg/kg 30 min before injury as a reference drug. After metered-dose injuring, blood loss was estimated as % of the circulating blood volume and by the rate of blood loss (mg/s). The study of blood platelet count, activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen concentration and the results of rotational blood thromboelastometry were taken into consideration.
Results. Administration of FM and TXA before fibrinolysis activation by streptokinase reduced the blood loss volume by 11.0 and 15.4 times, respectively. FM and TXA both reduced the blood loss rate by 3.8 times compared to the placebo group that received the same fibrinolytic. The administration of streptokinase in all cases was accompanied by 23–30% a decrease in the fibrinogen concentration without affecting APTT and TT. The hemostatic effects of FM and TXA were observed in vivo while preserving the density properties of the blood clot (according to the parameters of α angle, MCF and A10 in thromboelastometry) despite the administration of streptokinase, whereas a significant decrease in these parameters was observed in the placebo group.
Conclusion. The systemic hemostatic effects of FM at a dose of 0.25 mg/kg with fibrinolysis activation by streptokinase were close to the effects of TXA. Thus, FM administration can be considered a promising hemostatic therapy for the reduction of thrombolysis-associated bleeding.
Received 18 December 2019. Accepted 22 January 2020.
Funding: The study was supported by a grant from the Russian Foundation for Basic Research (No. 18-415-220001), Altai State Medical University.
Conflict of interest: Authors declare no conflict of interest.
Author contributions
Conception and study design: A.P. Momot, V.M. Vdovin, I.I. Shakhmatov
Data collection: V.M. Vdovin, D.A. Orekhov, V.O. Krasyukova, N.A. Lycheva, D.A. Momot, V.E. Chernus, V.V. Terjaev
Data analysis: A.P. Momot, V.M. Vdovin
Drafting the article: V.M. Vdovin, A.P. Momot
Critical revision of the article: A.P. Momot, В V.M. Vdovin
Statistical analysis: V.M. Vdovin
Final approval of the version to be published: V.M. Vdovin, A.P. Momot, D.A. Orekhov, V.O. Krasyukova, I.I. Shakhmatov, N.A. Lycheva, D.A. Momot, V.E. Chernus, V.V. Terjaev
References
- Rossaint R., Bouillon B., Cerny V., Coats T.J., Duranteau J., Fernández-Mondéjar E., Filipescu D., Hunt B.J., Komadina R., Nardi G., Neugebauer E.A., Ozier Y., Riddez L., Schultz A., Vincent J.L., Spahn D.R. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100. http://dx.doi.org/10.1186/s13054-016-1265-x
- Damage control resuscitation at level IIb/III treatment facilities. Joint Theater Trauma System Clinical Practice Guideline. 2013. 32 р.
- Hoffman M., Monroe D.M. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21(1):1-11. PMID: 17258114. http://dx.doi.org/10.1016/j.hoc.2006.11.004
- Hoffman M. Remodeling the blood coagulation cascade. J Thromb Thrombolysis. 2003;16(1-2):17-20. PMID: 14760207. http://dx.doi.org/10.1023/B:THRO.0000014588.95061.28
- Кузник Б.И. Клеточные и молекулярные механизмы регуляции системы гемостаза в норме и патологии. Чита: Экспресс-издательство, 2010. 832 с. [Kuznik B.I. Cellular and molecular regulation mechanisms of hemostasis system in health and disease. Chita: Ehkspress-izdatelstvo; 2010. 832 р. (In Russ.)].
- Бутылин А.А., Пантелеев М.А., Атауллаханов Ф.И. Пространственная динамика свертывания крови. Российский химический журнал. 2007;LI(1):45-50. [Butylin A.A., Panteleev M.A., Ataullakhanov F.I. Spatial dynamics of blood clotting. Russian Chemical Journal. 2007;LI(1):45-50. (In Russ.)].
- Зубаиров Д.М. Молекулярные основы свертывания крови и тромбообразования. Казань: Фэн, 2000. 364 с. [Zubairov D.M. Molecular basis of blood clotting and thrombus formation. Kazan: Fen, 2000. 364 р. (In Russ.)].
- Луговской Э.В., Макогоненко Е.М., Комисаренко С.В. Молекулярные механизмы образования и разрушения фибрина: физико-химический и иммунохимический анализ. Киев: Наукова думка, 2013. 230 с. [Lugovskoj EH.V., Makogonenko E.M., Komisarenko S.V. Molecular mechanisms of fibrin formation and degradation: physicochemical and immunochemical analysis. Kiev: Naukova dumka; 2013. 230 р. (In Russ.)].
- Бышевский А.Ш., Галян С.Л., Калинин Е.П., Карпова И.А., Полякова В.А. О регуляции неферментативного этапа свертывания крови (аутополимеризация и агрегация фибрина). Тромбоз, гемостаз и реология. 2012;49(1):27-46. [Byshevskiy A.Sh., Galyan S.L., Kalinin E.P., Karpova I.A., Polyakova V.A. About regulation of non-enzymatic stage of blood coagulation (autopolymerization and aggregation of fibrin). Tromboz, Gemostaz i Reologia. 2012;49(1):27-46. (In Russ.)].
- Момот А.П., Вдовин В.М., Шахматов И.И., Толстокоров И.Г., Орехов Д.А., Шевченко В.О., Лычёва Н.А., Кудинов А.В., Белозерская Г.Г., Киселёв В.И. Системные гемостатические и протромботические эффекты фибрин-мономера в эксперименте при дозированной травме печени. Сибирский научный медицинский журнал. 2019;39(1):6-12. [Momot A.P., Vdovin V.M., Shahmatov I.I., Tolstokorov I.G., Orekhov D.A., Shevchenko V.O., Lycheva N.A., Kudinov A.V., Belozerskaja G.G., Kiseljov V.I. Systemic hemostatic and prothrombotic effects of fibrin monomer in the experiment with dosed injury of the liver. Siberian Scientific Medical Journal. 2019;39(1):6-12. (In Russ.)] http://dx.doi.org/10.15372/SSMJ20190101
- Вдовин В.М., Момот А.П., Красюкова В.О., Толстокоров И.Г., Орехов Д.А., Шевченко В.О., Шахматов И.И., Лычёва Н.А. Системные гемостатические и гемостазиологические эффекты фибрин-мономера при прямом ингибировании тромбина в эксперименте. Российский физиологический журнал. 2019;105(2):207-2015. [Vdovin V.M., Momot A.P., Krasyukova V.O., Tolstokorov I.G., Orekhov D.A., Shevchenko V.O., Shakhmatov I.I., Lycheva N.A. Systemic hemostatic and hemostasiological effects of the fibrin monomer with direct inhibition of thrombin in the experiment. Russian Physiological Journal. 2019;105(2):207-2015. (In Russ.)] http://dx.doi.org/10.1134/S0869813919020109
- Вдовин В.М., Момот А.П., Орехов Д.А., Толстокоров И.Г., Шевченко В.О., Шахматов И.И., Лычёва Н.А., Красюкова В.О. Системные гемостатические и гемостазиологические эффекты низкой дозы фибрин-мономера на фоне действия варфарина в эксперименте. Тромбоз, гемостаз и реология. 2019;79(3):16-23. [Vdovin V.M., Momot A.P., Orekhov D.A., Tolstokorov I.G., Shevchenko V.O., Shakhmatov I.I., Lycheva N.A., Krasyukova V.O. Systemic hemostatic and hemostasiological effects of fibrin monomer in low dose in experiment on the background of warfarin. Tromboz, Gemostaz i Reologia. 2019;79(3):16-23. (In Russ.)] https://doi.org/10.25555/THR.2019.3.0885
- Момот А.П., Вдовин В.М., Орехов Д.А., Лычёва Н.А., Толстокоров И.Г., Шевченко В.О., Красюкова В.О., Шахматов И.И. Профилактика массивных интраоперационных кровотечений, ассоциированных с гепарином, при системном применении фибрин-мономера в эксперименте. Патологическая физиология и экспериментальная терапия. 2019;63(4):48-55. [Momot A.P., Vdovin V.M., Orekhov D.A., Lycheva N.A., Tolstokorov I.G., Shevchenko V.O., Krasyukova V.O., Shakhmatov I.I. Prevention of massive intraoperative bleedings associated with heparin with the systemic use of fibrin monomer in the experiment. Patol. Fiziol. Eksp. Ter. 2019;63(4):48-55. (In Russ.)]. https://doi.org/10.25557/0031-2991.2019.04.48-55
- Dreijer A.R., Kruip M.J., Diepstraten J., Polinder S., Brouwer R., Leebeek F.W., Vulto A.G., Bemt P.M. Antithrombotic stewardship: a multidisciplinary team approach towards improving antithrombotic therapy outcomes during and after hospitalisation: a study protocol. BMJ Open. 2016;6(12):e011537. http://dx.doi.org/10.1136/bmjopen-2016-011537
- Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений (ВТЭО). Флебология. 2015;9(4-2):1-52. [Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications (VTEC). Phlebology. 2015;9(4-2):1-52. (In Russ.)].
- Миронов А.Н. Руководство по проведению доклинических исследований лекарственных средств. Ч. 1. М.: Гриф и К, 2012. 944 р. [Mironov A.N. Guidelines for conducting preclinical studies of drugs. Part 1. Moscow: Grif and K, 2012. 944 р. (In Russ.)].
- Абрашова Т.В., Гущин Я.А., Ковалева М.А., Рыбакова А.В., Селезнева А.И., Соколова А.П., Ходько С.В. Физиологические, биохимические и биометрические показатели нормы экспериментальных животных. СПб: ЛЕМА, 2013. 116 с. [Abrashova T.V., Gushhin Ja.A., Kovaleva M.A., Rybakova A.V., Selezneva A.I., Sokolova A.P., Hod'ko S.V. Physiological, biochemical and biometric parameters of the norm of experimental animals. Saint Petersburg: LEMA, 2013. 116 p. (In Russ.)].
- Хабриев Р.У. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. М.: Медицина, 2005. 828 с. [Khabriev R.U. Guidelines for experimental (preclinical) study of new pharmacological substances. Moscow: Meditsina, 2005. 828 p. (In Russ.)].
- Close B., Banister K., Baumans V., Bernoth Е.М., Bromage N., Bunyan J., Erhardt W., Flecknell P., Gregory N., Hackbarth H., Morton D., Warwick C. Recommendations for euthanasia of experimental animals: Part 1. Laboratory Animals. 1996;30(4):298-316.
- Close B., Banister K., Baumans V., Bernoth Е.М., Bromage N., Bunyan J., Erhardt W., Flecknell P., Gregory N., Hackbarth H., Morton D., Warwick C. Recommendations for euthanasia of experimental animals: Part 2. DGXT of the European Commission. Laboratory Animals. 1997;31(1):1-32.
- Баркаган З.С., Момот А.П. Диагностика и контролируемая терапия системы гемостаза. М.: Ньюдиамед, 2008. 283 с. [Barkagan Z.S., Momot A.P. Diagnostics and controlled therapy of the hemostatic system. Moscow: N`yudiamed, 2008. 283 p. (In Russ.)].
- Айсина Р.Б., Мухаметова Л.И., Гулин Д.А., Гершкович К.Б., Варфоломеев С.Д. Стрептокиназа и стафилокиназа: различия кинетики и механизма взаимодействия с плазминогеном, ингибиторами и фибрином. Биоорганическая химия. 2015;41(5):565-578. [Aisina R.B., Mukhametova L.I., Varfolomeyev S.D., Gulin D.A., Gershkovich K.B. Streptokinase and staphylokinase: Differences in the kinetics and mechanism of their interaction with plasminogen, inhibitors, and fibrin Russian Journal of Bioorganic Chemistry. 2015;41(5):565-578]. http://dx.doi.org/10.7868/S0132342315050036
- Будник И.П., Морозова О.Л., Цымбал А.А., Шенкман Б., Эйнав Ю. Анализ влияния транексамовой кислоты, фактора XIII и концентрата фибриногена на формирование и лизис кровяного сгустка при избыточном фибринолизе, индуцированном тканевым и урокиназным активатором плазминогена. Гематология и трансфузиология. 2018;63(1):55-64. [Budnik I.A., Morozova O.L., Tsymbal A.A., Shenkman B., Einav Yu. Effects of tranexamic acid, factor XIII, and fibrinogen on clot formation and lysis in the model of hyperfibrinolysis induced by tissuevs urokinase-type plasminogen activator. Russian Journal of Hematology and Transfusiology. 2018;63(1):55-64. (In Russ.)] http://dx.doi.org/10.25837/HAT.2018.86..1..005
- Hunt B.J., Allard S., Keeling D., Norfolk D., Stanworth S.J., Pendry K. A practical guideline for the haematological management of major haemorrhage. British Journal of Hematology. 2015;170(6):788-803. PMID: 26147359. https://doi.org/10.1111/bjh.13580
