Comparative analysis of the hemostatic effect of systemic recombinant Factor VIIa and exogenous fibrin monomer in an experimental model of heparinization and posttraumatic blood loss

Abstract

This article presents the results of a study of the systemic hemostatic action of recombinant Factor VIIa in a rabbit model of heparin-induced coagulopathy and posttraumatic bleeding, compared to the administration of exogenous fibrin monomer. The coagulopathy was induced by a single intravenous injection of unfractionated heparin at a dose of 150 IU/kg 15 minutes before injury. Recombinant Factor VIIa (270 μg/kg) or fibrin monomer (0.25 mg/kg) was used as systemic hemostatic agents. One hour after administrating the agents, a standardized liver injury was inflicted, followed by an assessment of blood loss characteristics. Using rotational thromboelastometry and coagulation tests, animal venous blood was analyzed for coagulation time, alpha angle, clot formation time, maximum clot firmness, clot density at 10 minutes, activated partial thromboplastin time, prothrombin time, thrombin time, and fibrinogen concentration. Pharmacologically induced coagulopathy resulted in shifts to a hypocoagulable profile, associated with severe blood loss (1.9 times, p = 0.028) and high animal mortality (26.1%, p = 0.022) compared to the control group. Preventive administration of fibrin monomer or recombinant Factor VIIa reduced posttraumatic blood loss (by 5.4 times, p < 0.001, and by 2.1 times, p = 0.009, respectively), resulting in a decrease in mortality rates. However, the administration of these agents did not correct the hypocoagulable profile as observed in thromboelastometry and coagulation tests. These data demonstrate the hemostatic effect of both agents, with a more pronounced effect after fibrin monomer administration, and suggest potential use of low doses of fibrin monomer in trauma-related hemorrhage. The mechanism of action of fibrin monomer requires further investigation. Therefore, fibrin monomer, a fibrinogen derivative obtained from blood plasma, could be a valuable candidate for managing wound bleeding in addition to recommended systemic hemostatics.

Keywords

posttraumatic blood loss / heparin / recombinant Factor VIIa / fibrin monomer / hemostasis system / traumatic coagulopathy / systemic hemostatics / thromboelastometry / wound blood loss management

References

[1] Cap A, Hunt BJ. The pathogenesis of traumatic coagulopathy. Anaesthesia. 2015;70(Suppl. 1):96–101. doi: 10.1111/anae.12914

[2] Cap A., Hunt B.J. The pathogenesis of traumatic coagulopathy // Anaesthesia. 2015. Vol. 70, Suppl. 1. Р. 96–101. doi: 10.1111/anae.12914

[3] Cap A, Hunt BJ. The pathogenesis of traumatic coagulopathy. Anaesthesia. 2015;70(Suppl. 1):96–101. doi: 10.1111/anae.12914

[4] Heckbert SR, Vedder NB, Hoffman W, et al. Outcome after hemorrhagic shock in trauma patients. J Trauma. 1998;45(3): 545–549. doi: 10.1097/00005373-199809000-00022

[5] Heckbert S.R., Vedder N.B., Hoffman W., et al. Outcome after hemorrhagic shock in trauma patients // J Trauma. 1998. Vol. 45, N 3. P. 545–549. doi: 10.1097/00005373-199809000-00022

[6] Heckbert SR, Vedder NB, Hoffman W, et al. Outcome after hemorrhagic shock in trauma patients. J Trauma. 1998;45(3): 545–549. doi: 10.1097/00005373-199809000-00022

[7] Karkouki K, Wijeysundera DN, Yau TM, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004;44(10):1453–1462. doi: 10.1111/j.1537-2995.2004.04144.x

[8] Karkouki K., Wijeysundera D.N., Yau T.M., et al. The independent association of massive blood loss with mortality in cardiac surgery // Transfusion. 2004. Vol. 44, N 10. P. 1453–1462. doi: 10.1111/j.1537-2995.2004.04144.x

[9] Karkouki K, Wijeysundera DN, Yau TM, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004;44(10):1453–1462. doi: 10.1111/j.1537-2995.2004.04144.x

[10] Lloyd L, Jenkins PV, Bell SF, et al. Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study. J Thromb Haemost. 2023;21(4):862–879. doi: 10.1016/j.jtha.2022.11.036

[11] Lloyd L., Jenkins P.V., Bell S.F., et al. Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study // J Thromb Haemost. 2023. Vol. 21, N 4. P. 862–879. doi: 10.1016/j.jtha.2022.11.036

[12] Lloyd L, Jenkins PV, Bell SF, et al. Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study. J Thromb Haemost. 2023;21(4):862–879. doi: 10.1016/j.jtha.2022.11.036

[13] Ageno W, Donadini M. Breadth of complications of long-term oral anticoagulant care. Hematology Am Soc Hematol Educ Program. 2018;30(1):432–438. doi: 10.1182/asheducation-2018.1.432

[14] Ageno W., Donadini M. Breadth of complications of long-term oral anticoagulant care // Hematology Am Soc Hematol Educ Program. 2018. Vol. 30, N 1. P. 432–438. doi: 10.1182/asheducation-2018.1.432

[15] Ageno W, Donadini M. Breadth of complications of long-term oral anticoagulant care. Hematology Am Soc Hematol Educ Program. 2018;30(1):432–438. doi: 10.1182/asheducation-2018.1.432

[16] Pohlman TH, Fecher AM, Arreola-Garcia C. Optimizing transfusion strategies in damage control resuscitation: current insights. J Blood Med. 2018;9:117–133. doi: 10.2147/JBM.S165394

[17] Pohlman T.H., Fecher A.M., Arreola-Garcia C. Optimizing transfusion strategies in damage control resuscitation: current insights // J Blood Med. 2018. Vol. 9. P. 117–133. doi: 10.2147/JBM.S165394

[18] Pohlman TH, Fecher AM, Arreola-Garcia C. Optimizing transfusion strategies in damage control resuscitation: current insights. J Blood Med. 2018;9:117–133. doi: 10.2147/JBM.S165394

[19] Melnik AA. Mechanism of action of haemostatic drugs. Medical and Pharmacy News. 2017;622(10):1–17. (In Russ.)

[20] Мельник А.А. Механизм действия гемостатических лекарственных препаратов // Новости медицины и фармации. 2017. Т. 622, № 10. С. 1–17

[21] Melnik AA. Mechanism of action of haemostatic drugs. Medical and Pharmacy News. 2017;622(10):1–17. (In Russ.)

[22] Rossaint R, Afshari A, Bouillon B, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023;27(1):80. doi: 10.1186/s13054-023-04327-7

[23] Rossaint R., Afshari A., Bouillon B., et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition // Crit Care. 2023 Vol. 27, N 1. Р. 80. doi: 10.1186/s13054-023-04327-7

[24] Rossaint R, Afshari A, Bouillon B, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023;27(1):80. doi: 10.1186/s13054-023-04327-7

[25] Köhler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95(4 Suppl 1):S13–S17. doi: 10.1016/s0049-3848(99)00079-1

[26] Köhler M. Thrombogenicity of prothrombin complex concentrates // Thromb Res. 1999. Vol. 95, (4 Suppl. 1). P. S13–S17. doi: 10.1016/s0049-3848(99)00079-1

[27] Köhler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95(4 Suppl 1):S13–S17. doi: 10.1016/s0049-3848(99)00079-1

[28] 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

[29] Hoffman M., Monroe D.M. Coagulation 2006: a modern view of hemostasis // Hematol Oncol Clin North Am. 2007. Vol. 21, N 1. P. 1–11. doi: 10.1016/j.hoc.2006.11.004

[30] 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

[31] Butylin AA, Panteleev MA, Ataullahanov FI. Spatial dynamics of blood coagulation. Rossijskij Himicheskij Zhurnal. 2007;51(1):45–50. (In Russ.) EDN: HZYZAN

[32] Бутылин А.А., Пантелеев М.А., Атауллаханов Ф.И. Пространственная динамика свертывания крови // Российский химический журнал. 2007. Т. 51, № 1. С. 45–50. EDN: HZYZAN

[33] Butylin AA, Panteleev MA, Ataullahanov FI. Spatial dynamics of blood coagulation. Rossijskij Himicheskij Zhurnal. 2007;51(1):45–50. (In Russ.) EDN: HZYZAN

[34] Momot AP, Vdovin VM, Momot DA, et al. New opportunities to reduce blood loss with systemic administration of low-dose fibrin monomer. Clinical Physiology of Circulation. 2019;16(4):267–73. (In Russ.) EDN: JFCAAS doi: 10.24022/1814-6910-2019-16-4-267-273

[35] Момот А.П., Вдовин В.М., Момот Д.А., и др. Новые возможности снижения кровопотери при системном введении низкой дозы фибрин-мономера // Клиническая физиология кровообращения. 2019. Т. 16, № 4. С. 267–273. EDN: JFCAAS doi: 10.24022/1814-6910-2019-16-4-267-273

[36] Momot AP, Vdovin VM, Momot DA, et al. New opportunities to reduce blood loss with systemic administration of low-dose fibrin monomer. Clinical Physiology of Circulation. 2019;16(4):267–73. (In Russ.) EDN: JFCAAS doi: 10.24022/1814-6910-2019-16-4-267-273

[37] Zhiburt EB, Madzaev SR, Klyueva EA. Recombinant activated factor VII in stopping bleeding on the background of antithrombotic therapy. Effective pharmacotherapy. Anaesthesiology and reanimatology. 2014;(1):12–18. (In Russ.)

[38] Жибурт Е.Б., Мадзаев С.Р., Клюева Е.А. Рекомбинантный активированный фактор VII в остановке кровотечения на фоне антитромботической терапии // Эффективная фармакотерапия. Анестезиология и реаниматология. 2014. № 1. С. 12–18.

[39] Zhiburt EB, Madzaev SR, Klyueva EA. Recombinant activated factor VII in stopping bleeding on the background of antithrombotic therapy. Effective pharmacotherapy. Anaesthesiology and reanimatology. 2014;(1):12–18. (In Russ.)

[40] Nekhaev IV, Prikhodchenko AO, Zhuzhginova OV, et al. Recombinant factor VIIA in intensive care. Russian Journal of Hematology and Transfusiology. 2015;60(2):32–39. (In Russ.) EDN: TXKIRH

[41] Нехаев И.В., Приходченко А.О., Жужгинова О.В., и др. Рекомбинантый VIIa фактор в интенсивной терапии // Гематология и трансфузиология. 2015. Т. 60, № 2. С. 32–39. EDN: TXKIRH

[42] Nekhaev IV, Prikhodchenko AO, Zhuzhginova OV, et al. Recombinant factor VIIA in intensive care. Russian Journal of Hematology and Transfusiology. 2015;60(2):32–39. (In Russ.) EDN: TXKIRH

[43] Khabriev RU. Guidelines for experimental (preclinical) study of new pharmacological substances. 2-nd ed. Moscow. Meditsina; 2005. 826 р. (In Russ.) EDN: QCIIOB

[44] Хабриев Р.У. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. Изд. 2-е, перераб. и доп. Москва: Медицина, 2005. 826 с. EDN: QCIIOB

[45] Khabriev RU. Guidelines for experimental (preclinical) study of new pharmacological substances. 2-nd ed. Moscow. Meditsina; 2005. 826 р. (In Russ.) EDN: QCIIOB

[46] Lisman T, Groot PhGD Mechanism of action of recombinant factor VIIa. J Thromb Haemost. 2003;1(6):1138–1139. doi: 10.1046/j.1538-7836.2003.00225.x

[47] Lisman T., Groot Ph.G.D. Mechanism of action of recombinant factor VIIa // J Thromb Haemost. 2003. Vol. 1, N 6. Р. 1138–1139. doi: 10.1046/j.1538-7836.2003.00225.x

[48] Lisman T, Groot PhGD Mechanism of action of recombinant factor VIIa. J Thromb Haemost. 2003;1(6):1138–1139. doi: 10.1046/j.1538-7836.2003.00225.x

[49] Das K, Keshava S, Ansari SA, et al. Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect. Blood. 2021;137(24):3428–3442. doi: 10.1182/blood.2020008417

[50] Das K., Keshava S., Ansari S.A., et al. Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect // Blood. 2021. Vol. 137, N 24. P. 3428–3442. doi: 10.1182/blood.2020008417

[51] Das K, Keshava S, Ansari SA, et al. Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect. Blood. 2021;137(24):3428–3442. doi: 10.1182/blood.2020008417

[52] Momot AP, Vdovin VM, Orekhov DA, et al. Prevention of massive intraoperative bleedings associated with heparin with the systemic use of fibrin monomer in the experiment. Patological Physiology and Experimental Therapy. 2019;63(4):48–55. EDN: NXWNDC doi: 10.25557/0031-2991.2019.04.48-55

[53] Момот А.П., Вдовин В.М., Орехов Д.А., и др. Профилактика массивных интраоперационных кровотечений, ассоциированных с гепарином, при системном применении фибрин-мономера в эксперименте // Патологическая физиология и экспериментальная терапия. 2019. Т. 63, № 4. С. 48–55. EDN: NXWNDC doi: 10.25557/0031-2991.2019.04.48-55

[54] Momot AP, Vdovin VM, Orekhov DA, et al. Prevention of massive intraoperative bleedings associated with heparin with the systemic use of fibrin monomer in the experiment. Patological Physiology and Experimental Therapy. 2019;63(4):48–55. EDN: NXWNDC doi: 10.25557/0031-2991.2019.04.48-55

[55] Lempert АR, Belozerskaya GG, Makarov VА, et. al. Hemostatic activity of new fibrin-monomer based compound upon intravenous injection in experiment. Experimental and Clinical Pharmacology. 2018;81(11):14–17. EDN: VNUIMU doi: 10.30906/0869-2092-2018-81-11-14-17

[56] Лемперт А.Р., Белозерская Г.Г., Макаров В.А., и др. Гемостатическая активность нового соединения на основе фибрин-мономера при внутривенном введении в эксперименте // Экспериментальная и клиническая фармакология. 2018. Т. 81, № 11. С. 14–17. EDN: VNUIMU doi: 10.30906/0869-2092-2018-81-11-14-17

[57] Lempert АR, Belozerskaya GG, Makarov VА, et. al. Hemostatic activity of new fibrin-monomer based compound upon intravenous injection in experiment. Experimental and Clinical Pharmacology. 2018;81(11):14–17. EDN: VNUIMU doi: 10.30906/0869-2092-2018-81-11-14-17

[58] Vdovin VM, Momot AP, Orehov DA, et al. Influence of exogenous fibrin monomer on hemostatic potential and formation of fibrin in the area of dosed liver injury in experiment. Russian Journal of Physiology. 2020;106(9):1132–1143. EDN: BYAZIN doi: 10.31857/S0869813920070092

[59] Вдовин В.М., Момот А.П., Орехов Д.А., и др. Влияние экзогенного фибрин-мономера на гемостатический потенциал и образование фибрина в области дозированной травмы печени в эксперименте // Российский физиологический журнал им. И.М. Сеченова. 2020. Т. 106, № 9. С. 1132–1143. EDN: BYAZIN doi: 10.31857/S0869813920070092

[60] Vdovin VM, Momot AP, Orehov DA, et al. Influence of exogenous fibrin monomer on hemostatic potential and formation of fibrin in the area of dosed liver injury in experiment. Russian Journal of Physiology. 2020;106(9):1132–1143. EDN: BYAZIN doi: 10.31857/S0869813920070092

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