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.

INTRODUCTION: Earlier, an ability of exogenous fibrin monomer (FM) introduced at low doses to considerably limit posttraumatic blood loss was established by us on an experimental model of warfarin coagulopathy in vivo. However, the morphologic peculiarities of fibrin formation in the wound area were not considered. AIM: To compare morphologic, hemostasiologic and hemostatic data based on the results of systemic application of exogenous FM to interpret their effects in the model of posttraumatic bleeding with the underlying intake of warfarin. MATERIALS AND METHODS: In the work, Chinchilla male rabbits were used. A comparative analysis of hemostasiologic effects and of morphologic picture of the surface of the liver in the wound area was conducted after a dosed trauma, with a preliminary systemic introduction of FM (0.25 mg/kg intravenously) or a concentrate of prothrombin complex factors (40 IU/kg intravenously) with the underlying intake of warfarin by animals (0.40.5 mg/kg/day per os for 2 weeks). RESULTS: Introduction of FM in warfarinised animals in the conditions of a dosed experimental liver injury promoted a hemostatic effect comparable with that of a concentrate of prothrombin complex factors. Both hemostatic drugs led to intense fibrin formation that reduced posttraumatic blood loss. The use of FM was associated with increase in the thickness of thrombotic deposits and fibrin fibers in the wound surface in comparison with placebo by 4.0 and 1.6 times, respectively (р 0.000001). This process actively involved platelets, which led to 1.7 times reduction of their quantity in the lumen of the blood vessels in the wound vicinity (р 0.0002). No effect of FM on systemic hemostatic reactions in venous blood was found, in contrast to concentrate of prothrombin complex factors. CONCLUSION: Exogenous FM can produce a local hemostatic effect in the conditions of dosed experimental trauma and coagulopathy induced by warfarin intake. The hemostatic effect was mediated by intense thrombosis on the wound surface with the active recruitment of platelets in the process. The peculiarities of the demonstrated effects of FM may be mediated though the mechanisms of its action that have not yet been identified, which necessitates continuation of the research in this direction.

Introduction . Earlier studies of low-dose fibrin monomer (FM) demonstrated that low-dose FM has unique hemostatic properties in vivo. Aim — to compare the morphological consequences of intravenous administration of tranexamic acid (TXA) and FM with the hemostatic and hemostasiological effects in hypofibrinogenemia caused by the use of streptokinase after controlled liver injury. Materials and methods . The morphological pattern of fibrin formation in the liver injury area after spontaneous arrest of bleeding in the animals treated with streptokinase or placebo was studied in 73 male rabbits of the Chinchilla breed, split into four groups. In three groups, the study was performed under the conditions of intravenous administration of placebo, TXA, or FM against the background of fibrinolysis activation by streptokinase. Platelet count in the blood, the concentration of fibrinogen, as well as the results of calibrated thrombography, were taken into account. Results . Sequential administration of streptokinase and TXA was accompanied by decreased fibrinogen concentration (by 29.6 %) and, at the same time, a reduction in blood loss (by 15.4 times) in comparison with animals where placebo was used instead of TXA. A decrease in blood loss was associated with increased thickness of thrombotic deposits at the edge of the wound, mainly consisting of red blood cells. These observations were combined with data on the acceleration of thrombin formation in venous blood plasma in a calibrated thrombography test (Peak thrombin 65.4 nmol/L to 109.6 nmol/L in the placebo group). Compared to the observations where placebo was administered instead of FM, however, the sequential use of streptokinase and FM also led to a decrease in blood loss (by 11.0 times) despite decreased fibrinogen concentration (by 23.3 %). A decrease in blood loss was also associated with platelet consumption in venous blood and with increased thickness of thrombotic deposits on the injury surface, where, in addition to red blood cells, the accumulation of fibrin masses was determined by the morphological pattern. Conclusion . The mechanisms of the systemic hemostatic effect of TXA and FM are different, despite the similarity of the achieved hemostatic effects in the conditions of stimulation of blood fibrinolytic activity. These findings expand the understanding of new therapeutic possibilities for reducing post-traumatic blood loss.

Aim. To identify and compare the morphological, hemostatic and hemostasiological consequences of intravenous administration of tranexamic acid and fibrin monomer in controlled liver injury against drug-induced thrombocytopathy. Methods. The morphological features of fibrin formation in the area of liver injury after spontaneous bleeding arrest combined with the indicators of blood loss in the animals treated with intravenous placebo, tranexamic acid or fibrin monomer was studied in 69 male rabbits. The effects of these drugs were assessed against thrombocytopathy associated with the combined use of acetylsalicylic acid and clopidogrel. Platelet number and function (adnosine diphosphate-induced aggregation), the data of thromboelastometry and calibrated automated thrombogram, fibrinogen concentration and D-dimer level were considered in the blood test. The feature distribution in the samples was assessed using the ShapiroWilk test. Depending on the distribution, Student's t-test, MannWhitney U test or Wilcoxon signed-rank test were used to test for a significant difference between the features. Differences in mortality rate were established by using Fisher's exact test. The differences were considered statistically significant at p 0.05. Results. A model of thrombocytopathy which showed decreased platelet aggregation function (by 4.5 times), increased blood loss (by 40%), and high mortality (53.9%) was reproduced. Only a small accumulation of thrombotic material was noted on the injured surface of such animals. The use of tranexamic acid led to decreased post-traumatic bleeding (2.5 times) and animal mortality (20%). The latter was provided on the wound surface by increasing the thickness of both thrombotic deposits and fibrin strands. When fibrin monomer was used, the phenomenon of an overcompensated decrease in blood loss (by 6.7 times) accompanied by zero mortality was noted despite a pronounced decrease in platelet aggregation. The maximum increase in the thickness of thrombotic material and fibrin strands was morphologically determined in the injury area compared with other animal groups. Conclusion. Morphological features of traumatic hemostatic effect at the injured area when using tranexamic acid and fibrin monomer have a number of differences despite the similarity of the achieved results in minimizing blood loss.

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 contributionsConception and study design: A.P. Momot, V.M. Vdovin, I.I. ShakhmatovData collection: V.M. Vdovin, D.A. Orekhov, V.O. Krasyukova, N.A. Lycheva, D.A. Momot, V.E. Chernus, V.V. TerjaevData analysis: A.P. Momot, V.M. VdovinDrafting the article: V.M. Vdovin, A.P. MomotCritical revision of the article: A.P. Momot, В V.M. VdovinStatistical analysis: V.M. VdovinFinal 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

Background. In previous studies using the heparin model of post-traumatic blood loss, a hemostatic effect of exogenous fibrin monomer (FM) (0.25 mg/kg) was observed, which was comparable in intensity to the effect of protamine sulfate (PS) and remained unexplained due to the lack of morphological study data for the area of liver injury. Aim. To compare hemostatic, hemostasiological, and morphological consequences of intravenous administration of FM 0.25 mg/kg following controlled liver injury in heparinized animals. Methods. Hypocoagulation was simulated by i.v. administration of unfractionated heparin (UFH) 150 U/kg to 77 healthy Chinchilla rabbits. Intraoperative bleeding was prevented by i.v. administration of FM 0.25 mg/kg one hour prior to the injury or PS 1.5 mg/kg 10 minutes prior to the injury. After the controlled liver injury, blood loss was measured and expressed in % of the circulating blood volume. Blood platelet count, activated partial thromboplastin time (APTT), fibrinogen concentration, D-dimer concentration, and data of calibrated thrombography were also studied. Samples of liver tissue from the wound surface area were collected for histology after spontaneous arrest of bleeding. Results. Heparinized animals were characterized by increased blood loss due to pronounced hypocoagulation and decreased thrombin production. The use of the UFH antidote, PS, minimized the blood loss (by 75% compared to placebo) and resulted in restoration of the hemostatic potential. According to results of the morphological study, this effect was due to increased thickness of thrombotic masses (15.1 times compared to placebo). At least equal hemostatic effect was obtained when PS was replaced with FM (80% decrease in blood loss compared to placebo). These effects were not associated with correction of the hypocoagulation shift or recovery of the thrombin generation. In this process, fibrin formation in the injury area was less pronounced (fibrin thickness 55.2 µm vs 201.8 µm with PS; p < 0.001). Another distinctive feature was the absence of the fibrillar structure of fibrin and the presence of numerous platelets in thrombotic masses while the platelet number in the lumen of blood vessels near the wound surface was minimal. Conclusion. The study results allow identifying possible mechanisms and ways to stop post-traumatic bleeding when heparin is used.

Актуальность. В проведенных ранее исследованиях на «гепариновой» модели посттравматической кровопотери был продемонстрирован гемостатический эффект экзогенно вводимого фибрин-мономера (ФМ) (доза 0,25 мг/кг), сопоставимый по выраженности с применением протамина сульфата (ПС), что не получило своего объяснения из-за отсутствия данных морфологического исследования в зоне травмы печени. Цель. Сопоставить гемостатические, гемостазиологические и морфологические последствия использования ФМ, при его внутривенном введении в дозе 0,25 мг/кг, у гепаринизированных животных, после дозированной травмы печени. Материалы и методы. На 77 здоровых кроликах породы «Шиншилла» моделировали гипокоагуляцию нефракционированным гепарином (НГ) в/в в дозе 150 ед/кг. Профилактику интраоперационных кровотечений осуществляли введением ФМ в/в в дозе 0,25 мг/кг, за один час до травмы, и ПС в/в в дозе 1,5 мг/кг за 10 мин до травмы. После нанесения дозированной травмы печени кровопотерю оценивали в % от объема циркулирующей крови. Исследовали также содержание тромбоцитов в крови, активированное парциальное тромбопластиновое время (АПТВ), уровень фибриногена и количество D-димера, параметры калиброванной тромбографии. Ткани печени в области раневой поверхности для гистологических исследований получали после спонтанной остановки кровотечения. Результаты. Гепаринизированным животным была свойственна повышенная кровопотеря на фоне выраженной гипокоагуляции и снижении генерации тромбина. Применение антидота НГ - ПС, минимизировало потерю крови (снижение кровопотери в 4,0 раза по сравнению с плацебо) и приводило к восстановлению гемостатического потенциала. Согласно морфологическим исследованиям, это достигалось увеличением толщины тромботических масс (в 15,1 раза по сравнению с плацебо). В не меньшей степени гемостатический эффект был достигнут при замене ПС на ФМ (уменьшение кровопотери в 5,1 раза по сравнению с плацебо). Данные эффекты не сопровождались коррекцией гипокоагуляционного сдвига и восстановлением генерации тромбина. В последнем случае определено меньшее по выраженности фибринообразование в зоне травмы (толщина фибрина 55,2 мкм против 201,8 мкм при применении ПС; р < 0,001). Еще одной отличительной особенностью явилось отсутствие фибриллярной структуры фибрина и наличие в тромботических массах многочисленных тромбоцитов, тогда как их число в просветах сосудов рядом с раневой поверхностью было минимальным. Заключение. Приведенные данные позволяют обозначить возможные механизмы и пути остановки постравматического кровотечения при использовании гепарина. Background. In previous studies using the heparin model of post-traumatic blood loss, a hemostatic effect of exogenous fibrin monomer (FM) (0.25 mg/kg) was observed, which was comparable in intensity to the effect of protamine sulfate (PS) and remained unexplained due to the lack of morphological study data for the area of liver injury. Aim. To compare hemostatic, hemostasiological, and morphological consequences of intravenous administration of FM 0.25 mg/kg following controlled liver injury in heparinized animals. Methods. Hypocoagulation was simulated by i.v. administration of unfractionated heparin (UFH) 150 U/kg to 77 healthy Chinchilla rabbits. Intraoperative bleeding was prevented by i.v. administration of FM 0.25 mg/kg one hour prior to the injury or PS 1.5 mg/kg 10 minutes prior to the injury. After the controlled liver injury, blood loss was measured and expressed in % of the circulating blood volume. Blood platelet count, activated partial thromboplastin time (APTT), fibrinogen concentration, D-dimer concentration, and data of calibrated thrombography were also studied. Samples of liver tissue from the wound surface area were collected for histology after spontaneous arrest of bleeding. Results. Heparinized animals were characterized by increased blood loss due to pronounced hypocoagulation and decreased thrombin production. The use of the UFH antidote, PS, minimized the blood loss (by 75% compared to placebo) and resulted in restoration of the hemostatic potential. According to results of the morphological study, this effect was due to increased thickness of thrombotic masses (15.1 times compared to placebo). At least equal hemostatic effect was obtained when PS was replaced with FM (80% decrease in blood loss compared to placebo). These effects were not associated with correction of the hypocoagulation shift or recovery of the thrombin generation. In this process, fibrin formation in the injury area was less pronounced (fibrin thickness 55.2 µm vs 201.8 µm with PS; p < 0.001). Another distinctive feature was the absence of the fibrillar structure of fibrin and the presence of numerous platelets in thrombotic masses while the platelet number in the lumen of blood vessels near the wound surface was minimal.

Aim. The study objective was to examine fibrin monomer hemostatic effects in post-traumatic parenchymal hemorrhage in the setting of pharmacologically associated platelet aggregation inhibition.Materials and methods. In the in vivo experimental study on male rabbits, the hemostatic effects of fibrin monomer (FM) (0.25 mg/kg) were evaluated in comparison with tranexamic acid (TA) (15 mg/kg) in post-traumatic parenchymal hemorrhage against the background of preliminary inhibition of platelet aggregation function with acetylsalicylic acid (2.0 mg/kg) and clopidogrel (8.0 mg/kg). Volume and rate of blood loss were estimated, as well as the parameters of the hemostatic system.Results. It has been established that FM versus placebo when administered intravenously 1 hour before the injury can prevent severe bleeding associated with taking antiplatelet agents. The volume of blood loss after FM administration decreased in median by 6.0 times, the rate of blood loss – by 5.9 times, and when using TA – by 2.4 (РFM-TA < 0.02) and 4.8 times respectively. The hemostatic effects of TA were realized when the hemostatic balance was shifted towards the increased fibrin formation (an increase in the level of D-dimer in the blood plasma). The use of FM was not accompanied by any significant changes in the blood coagulation system.Conclusion. The fibrin monomer at a dose of 0.25 mg/kg i.v. is capable of preventing severe posttraumatic parenchymal bleeding caused by the combined use of drugs with different antiplatelet action. The phenomenon is not completely clear and needs to be analyzed in further research. The mechanism of hemostatic effects associated with FM is currently being studied.

Aim. To assess the effect of fibrin monomer on the rate of blood loss after controlled liver injury in hypofibrinogenemia induced by systemic administration of Malayan pit viper venom (Agkistrodon rhodostoma). Methods. A placebo-controlled study of the hemostatic effect of fibrin monomer administered intravenously at 0.25 mg/kg, and coagulation parameters in the controlled liver injury with profound hypofibrinogenemia caused by administration of Malayan pit viper venom was conducted in 34 male Chinchilla rabbits. The distribution of the studied parameters was investigated by the ShapiroWilk test. Statistical differences between groups were tested by Students t-test, MannWhitney U test, or Wilcoxon test, as appropriate. Differences in mortality rate were examined using Fisher's exact test. Results. A model of experimental toxogenic disseminated intravascular coagulation was reproduced, manifested by high mortality of animals (50.0%), severe blood loss (increased blood loss by 1.78 times), hemolysis, a decreased platelet count (by 19.6% of median) and platelet dysfunction, fibrinogen consumption (protein content less than 0.9 g/l), hypocoagulation as well as intensive D-dimer production (increased concentration by 25.0 times of median). A high level of the fibrin derivative demonstrated activation of fibrin formation and fibrinolysis in the bloodstream of the animals. Systemic prophylactic administration of exogenous fibrin monomer after receiving snake venom did not lead to a decrease in post-traumatic bleeding, whereas earlier, during reproduction of disseminated intravascular coagulation caused by streptokinase infusion, such a hemostatic effect of fibrin monomer was shown. Conclusion. The absence of fibrin monomer effect (at a dose of 0.25 mg/kg) on the severity of blood loss in toxogenic disseminated intravascular coagulation may be associated with more profound disseminated intravascular coagulation and a sharp 25-fold increase in D-dimer levels that can act as a fibrin monomer polymerization inhibitor.

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.

Введение. Ранее было показано, что фибринмономер (ФМ) в низких дозировках обладает системным гемостатическим действием в условиях дозированной травмы. Авторами выдвинута гипотеза, согласно которой ФМ способен оказывать регулирующее гемостатическое действие in vivo на фоне сниженного гемостатического потенциала. Цель исследования: изучение системных гемостатических и гемостазиологических эффектов ФМ на фоне дозированной травмы печени при гипокоагуляции, обусловленной приемом варфарина. Материалы и методы. В работе использовали 40 кроликов породы Шиншилла. Для индукции кумаринобусловленной гипокоагуляции животным per os вводили варфарин в дозе 0,4 0,5 мг/кг 14 дней до достижения международного нормализованного отношения (МНО) более 2,0. Далее животным в краевую вену уха вводили концентрат факторов протромбино вого комплекса (КФПК) в дозе 40 ЕД/кг, ФМ в дозе 0,25 мг/кг или плацебо. Через 1 ч после введения препаратов наносили травму печени и оценивали кровопотерю (в процентах от объема циркулирующей крови). Исследовали число тромбоцитов, активированное парциальное тромбопластиновое время, МНО, содержание фибриногена и Ддимера, оценивали результаты тромбоэластографии крови. Результаты. Объем кровопотери в группах животных после внутривенного введения ФМ и КФПК на фоне приема варфарина был в 9,1 раза и 6,7 раза меньше, соответственно, по сравнению с группой плацебо, получавшей тот же антикоагулянт. Вместе с тем ФМ не влиял на параметры коагулограммы (отсутствие видимого гемостазиологического эффекта) и тромбоэластограммы, тогда как применение КФПК в качестве антидота варфарина сопровождалось нормализацией параметров тромбоэластометрии и коррекцией гипокоагуляционного сдвига по МНО. Заключение. Установлено, что ФМ способен проявлять свое системное гемостатическое действие в условиях сниженного тромбинообразования, обусловленного нарушением синтеза витамин Кзависимых факторов свертывания крови. Данное действие реализуется без признаков восстановления гемостатического равновесия. Introduction. It was shown earlier that fibrinmonomer (FM) in low doses had a systemic hemostatic effect in a controlled injury condition. The authors suggest that FM is able to exert a regulating hemostatic effect in vivo under reduced hemostatic potential. Aim: to study the systemic hemostatic and hemostasiological effects of FM under controlled liver injury during hypocoagulation caused by warfarin administration. Materials and methods. In this study 40 Chinchilla rabbits were used. For the induction of coumarinmediated hypocoagulation, animals were administered per os warfarin at a dose of 0.4 0.5 mg/kg for 14 days, until an international normalized ratio (INR) was more than 2.0. Subsequently, a prothrombin complex concentrate (PCC) at a dose of 40 U/kg, FM at a dose of 0.25 mg/kg or placebo were administered into the marginal ear vein of the animals. An hour later, a liver injury was inflicted and blood loss was assessed (in percents of the circulating blood volume). The number of platelets, activated partial thromboplastin time, INR, levels of fibrinogen and Ddimer were studied and the results of blood thromboelastography were evaluated. Results. Blood loss volume in animals groups after intravenous administration of FM and PPC, under warfarin reception, was 9.1 times and 6.7 times less, respectively, compared to the placebo group receiving the same anticoagulant. However, FM did not affect on coagulogram parameters (no visible hemostasiological effect) and thromboelastogram, whereas the use of PPC as warfarin antidote was accompanied by the normalization of thromboelastometry parameters and hypocoagulation shift correction according to INR. Conclusion. It was found that FM able to manifest its systemic hemostatic effect in conditions of reduced thrombin formation caused by impaired synthesis of vitamin Kdependent blood coagulation factors. This effect is implemented without any signs of recovery of hemostatic balance.

The systemic hemostatic and hemostasiological effects of intravenous injection of fibrin monomer (FM; 0.25 mg/kg) together with dabigatran etexilate (15-20 mg/kg) administration were compared to placebo (0.5 ml), prothrombin complex concentrate (d = 40 U/kg) and Eptacog alfa (activated) (d = 270 μg/kg) in a model of a controlled liver injury in 62 rabbits of the Chinchilla breed. It was found that FM, in comparison to placebo, reduced the volume of blood loss by 2.9 times and the rate of blood loss by 1.7 times, despite the dabigatran-induced hypocoagulation. Comparators did not show hemostatic efficacy. FM did not affect the parameters of the coagulogram (no visible hemostasiological effect), while the compared drugs showed some signs of increased hemostatic potential. It is assumed that the hemostatic effects of low, physiological doses of FM can be realized bypassing thrombin (factor IIa), which determines the need for further studies.

Objective of the study is to experimentally evaluate system hemostatic and prothrombotic effects of intravenous fibrin monomer (FM). Materials and methods. Eighty two Chinchilla rabbits weighing 3–4 kg were used in the study. In addition to the placebo, animals were administered an aqueous solution of fibrin monomer (FM) intravenously at doses of 0.1, 0.25, 0.5, 1.0, 2.5 and 5.0 mg/kg. After 1 hour, a standard liver injury was performed and the blood loss (% of the circulating blood volume) resulting from parenchymal hemorrhage was estimated. Hemostatic system examination included platelet number in venous blood and fibrinogen and D-dimer levels in blood plasma. Results and discussion. Blood loss after dosed injury with placebo was 10.0 [4.0; 15.7] % blood volume (median [25th percentile; 75th percentile]). FM preparation doses of 0.25, 2.5 and 5.0 mg/kg resulted in a decrease of blood loss by 6.3 (p < 0.001), 7.8 (p < 0.001) and 2.7 times (p = 0.04) (1.6 [1.0; 3.0], 1.3 [0.6; 1,6] and 3.7 [2.8; 5.3] % blood volume, respectively).High doses of FM preparation (2.5 and 5.0 mg/kg) minimized blood loss due to activation of coagulation and thrombus formation, which was illustrated by a 7.0–8.0-fold increase in D-dimer level (compared to placebo). 0.25 mg/kg of FM preparation did not lead to an increase of D-dimer content, although the blood loss was greatly reduced. Conclusion. The data obtained show the presence of unique hemostatic properties in low-dose FM preparation (0.25 mg/kg), which allows creating system hemostatic agents of a new generation.

Цель исследования - изучение способности фибрин-мономера предупреждать тяжелую интраоперационную кровопотерю, ассоциированную с введением нефракционированного гепарина, при дозированной травме печени. Методика. На кроликах «Шиншилла» индуцировали гипокоагуляцию нефракционированным гепарином (150 ед/кг). Профилактику интраоперационных кровотечений осуществляли внутривенным введением фибрин-мономера (0,25 мг/кг) за 1 ч до травмы или протамина сульфата (1,5 мг/кг) за 10 мин до травмы. После нанесения стандартной травмы печени оценивали объем (в % ОЦК) и темп (мг/с) кровопотери. Анализировали число тромбоцитов, активированное парциальное тромбопластиновое время, протромбиновое и тромбиновое время свертывания, уровень фибриногена и активность антитромбина III, параметры ротационной тромбоэластометрии крови. Результаты. Объем кровопотери в группах животных после в/в введения фибрин-мономера и протамина сульфата на фоне гепаринизации был, соответственно, в 5,1 и 4,0 раза меньше по сравнению с группой плацебо, получавшей тот же антикоагулянт. Вместе с тем, фибрин-мономер не влиял на параметры коагулограммы (отсутствие видимого гемостазиологического эффекта) и тромбоэластограммы, тогда как применение протамина сульфата в качестве антидота гепарина сопровождалось нормализацией данных тромбоэластометрии и коррекцией гипокоагуляционного сдвига по активированному парциальному тромбопластиновому времени, протромбиновому и тромбиновому времени. Заключение. Установлено, что фибрин-мономер (0,25 мг/кг) снижает посттравматическое кровотечение в условиях блокады свертывания крови гепарином без видимых признаков восстановления гемостатического равновесия. The research objective was to study the ability of fibrin monomer to prevent severe intraoperative blood loss associated with administration of unfractionated heparin in controlled liver injury. Methods. Hypocoagulation was induced in chinchilla rabbits with unfractionated heparin (150 U/kg). Intraoperative bleeding was prevented by administration of fibrin monomer (FM, 0.25 mg/kg, i.v.) one hour prior to the injury and of protamine sulfate (PS, 1.5 mg/kg, i.v.) 10 min prior to the injury. Following the liver injury, blood loss was assessed as percentage of circulating blood volume and the blood loss rate (mg/s). Platelet counts, aPTT, PT, TT, fibrinogen level, antithrombin III activity, and parameters of blood rotation thromboelastometry were analyzed. Results. The volume of blood loss was 5.1 times and 4.0 times less, respectively, after the FM and PS administration during heparinization compared to the placebo group treated with the same anticoagulant. However, FM affected neither coagulogram indexes (no visible hemostasiological effect) nor thromboelastogram while the use of PS as an antidote for heparin was associated with normalization of thromboelastometric data and correction of hypercoagulative changes in aPTT, PT, TT. Conclusion. FM at a dose of 0.25 mg/kg reduced severity of posttraumatic bleeding induced by heparin inhibition of coagulation with no visible signs of hemostatic balance recovery.