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During the pandemic of the new coronavirus infection, there is increasing evidence of neurological complications associated with COVID-19. There is no doubt that stroke can be a major complication in patients with severe disease course.Objective: to determine the safest and most effective anticoagulant for stroke prevention in patients with severe COVID-19.Patients and methods. A prospective study enrolled 520 patients with severe COVID-19. We used the following criteria for severe COVID-19: SpO2 2 /FiO2 30 breaths/min, lung infiltrates >50% on computed tomography. The study included 509 patients, divided into three groups depending on the type of anticoagulant therapy: patients of the 1st group received 24–36 thousand IU of heparin, patients of the 2nd group – enoxaparin at a dose of 1 mg/kg per day, patients of the 3rd group – rivaroxaban at a dose of 20 mg/day. The duration of anticoagulant administration depended on the severity of the patient's condition, dynamics of laboratory parameters (D-dimer, fibrinogen, international normalized ratio, activated partial thromboplastin time, platelet count), and varied from 2 to 6 weeks. In addition, we studied the incidence of ischemic and hemorrhagic strokes and transient ischemic attacks during a 6-week follow-up period. The article also presents a clinical case of large artery thrombosis in a young patient with severe COVID-19 without stroke risk factors.Results and discussion. Even against the background of active primary prevention, stroke incidence was 2.6% (0.6% for ischemic stroke, 1.4% for venous stroke, and 0.6% for hemorrhagic stroke). The highest stroke incidence was observed in the group of patients receiving heparin. In contrast, the prevention of thrombotic complications in patients receiving low-molecular-weight anticoagulants or rivaroxaban showed the best results with minimal morbidity and mortality in severe COVID-19.Conclusion. Stroke can be a complication of COVID-19, and preventive anticoagulant therapy using low-molecular-weight heparin or a factor X inhibitor effectively prevents this complication.

The OBJECTIVE was to study the features of changes in the blood coagulation system that contribute to the development of postoperative complications in patients depending on the stage of non-tumor mechanical jaundice at admission.METHODS AND MATERIALS. A total of 537 patients with mechanical jaundice were examined and changes in the blood coagulation system were analyzed. Vascular-platelet hemostasis was characterized by the following tests: capillary resistance, the number of desquamated endothelial cells, the number of blood platelets. Plasma hemostasis was analyzed using activated partial thromboplastin time, plasma soluble fibrin level, thrombin time, prothrombin ratio, prothrombin index, and fibrinogen blood level. Then, XIIa-dependent fibrinolysis in the blood and the level of the fibrin D-dimer in the blood plasma were determined.RESULTS. It was found that in the first stage of mechanical jaundice, with cholestasis, there were no changes in blood coagulation system that go beyond the normal limits. In the second stage, during cytolysis of hepatocytes, hyperbilirubinemia and hypertransaminasemia contribute to the activation of platelet first, and then plasma hemostasis. In the third stage (cholangitis), the death of endotheliocytes increases and there is a deficiency of blood coagulation factors due to their consumption and increased fibrinolysis.CONCLUSION. In the stage of cholestasis in patients with non-tumors mechanical jaundice, the parameters of the coagulation system remain within the reference values. In the stage of cytolysis, as endotheliotoxicosis increases, platelet and plasma hemostasis begins to activate, which can lead to thrombosis and thromboembolism in vital organs. In the stage of cholangitis, further activation of plasma hemostasis causes hemorrhagic syndrome. The occurrence of the described disorders in blood coagulation system with the progression of MJ dictates the need to monitor the changes in the blood coagulation system and their correction for the prevention of intra-and postoperative complications.

Introduction.Preeclampsia (PE) is a specific complication of pregnancy holding a lead place in maternal and perinatal morbidity and mortality worldwide. The development of PE in the maternal body is accompanied by severe hypercoagulation, disturbed anticoagulation and fibrinolytic systems. As a result, vascular microthrombosis in diverse organs with developing endothelial dysfunction, impaired utero-placental blood circulation emerge that leads to adverse perinatal outcomes.Aim:to study status of coagulation arm in pregnant women with moderate and severe PE, after delivery by cesarean section, to optimize management of the postoperative period.Materials and Methods.There were enrolled 50 pregnant women with PE: 16 with moderate and 34 with severe PE after surgical delivery. A status of coagulation arm was examined by evaluating major parameters in coagulogram (fibrinogen, activated partial thromboplastin time, prothrombin, international normalized ratio) as well as assay for early diagnostics of blood clotting disorders to reveal bleeding and thrombosis risks.Results.It was found that prior to surgery patients with severe PE had significantly increased clot growth rate (V) by 1.09-fold (p = 0.001), relative clot density (D) by 1.15-fold (p = 0.001), and time of spontaneous clot appearance (Tsp) was accelerated by 2-fold (p = 0.001) compared to moderate PE. After surgical delivery, patients from both groups had changes evidencing about activated coagulation system: increased V, D, as well as the Tsp. Upon that, all such parameters in patients with severe PE were significantly elevated: the V – by 1.25-fold (p = 0.005); the D – by 1.1-fold (p = 0.02); the Tsp was accelerated by 2-fold (p = 0.03) compared to patients with moderate PE. All parameters in both groups tended to normalize on day 5 after surgical delivery, but patients with severe PE were shown to have significantly increased the V – by 1.5-fold (p = 0.001); the D – by 1.14-fold (p = 0.001); the clot size – by 1.14-fold (p = 0.001); the Tsp – accelerated by 41 % (p = 0.001) compared to patients with moderate PE.Conclusion.Thus, patients with moderate and severe PE after surgical delivery by cesarean section were featured with markedly activated coagulation hemostasis, which may justify a prolonged use of low-molecular-weight heparins in the postoperative period, especially in patients with PE.

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

Aim . To present a clinical case describing the management of a patient with Crohn’s disease complicated by recurrent intestinal bleeding and autoimmune hemophilia A. General provisions: A 21-year-old patient was admitted to St. Petersburg City Hospital No. 26 and diagnosed with Crohn’s disease with the lesions of the ileum, sigmoid and rectum in inflammatory form and continuously recurrent course. Upon admission, the patient demonstrated an elongated activated partial thromboplastin time (aPTT). In this connection, the levels of VIII (FVIII) and IX (FIX) coagulation factors and the content of von Willebrand factor antigen were determined. A study was conducted to the antibodies to these factors connecting von Willebrand factor capabilities with type I and III collagen. A 7 % decrease in the FVIII level and the presence of FVIII antibodies were detected. The patient was diagnosed with autoimmune hemophilia A. On August 14 in 2019, pulse therapy with methylprednisolone of 1000 mg per day by intravenous drip was started. After the first infusion, the aPTT index returned to normal and comprised 30 seconds, while the FVIII activity increased to 255 %. Conclusion. The presented clinical case demonstrates the importance of timely diagnosis and treatment of acquired coagulopathy. Acquired hemophilia A can be a life-threatening condition. When acquired coagulopathy develops in a patient with bleeding against the background of an inflammatory bowel disease, it aggravates the course of the disease and worsens the prognosis.

Previously it was shown that the use of regulatory peptides of the glyprolin family helps to normalize the hemostasis system and blood glucose levels in experimental resistant hyperglycemia in rats, similar to type 2 diabetes mellitus in humans. It is also known that the anticoagulant heparin inhibits blood coagulation and exhibits a hypoglycemic effect in the body. The aim of the study is to obtain a complex of the Pro-Gly-Pro-Leu (PGPL) peptide and the unfractionated heparin, to study its effect on glucose and anticoagulant fibrinolytic properties and show its ability to restore the impaired functions of the insular and coagulating blood systems in experimental hyperglycemia in rats. Materials and Methods . Laboratory Wistar male rats, intact and with experimentally induced hyperglycemia, were used in the experiment. A complex compound of PGPL and heparin was created with a component ratio of 1:1 (mol/mol), which was administered intranasally to hyperglycemic rats once a day for 5 days at the dose of 1 mg/kg. Similarly, the constituent parts of the complex were administrated in equivalent amounts. The anticoagulant activity was determined by the test of activated partial thromboplastin time, fibrinolysis parameters - by tests of total, enzymatic and non-enzymatic fibrinolytic activities, as well as the activity of a tissue plasminogen activator. In addition, blood glucose was measured using special test strips. Results. The use of the PGPL-heparin complex in the animals with hyperglycemia led to normalization of blood glucose levels, an increase in the anticoagulant and fibrinolytic background of blood plasma. These effects persisted for 6 days after the cancellation of the peptide-heparin complex administration to rat. Conclusion . In the development of experimental hyperglycemia, the PGPL complex with heparin exhibits a combined hypo-glycemic, anticoagulant and fibrinolytic enzymatic and non-enzymatic nature of the effect. In the future, the studied peptide-heparin complex can be used for the prevention and treatment of type 2 diabetes mellitus, complicated by increased blood coagulation.

The paper presents a clinical case of treatment of staghorn nephrolithiasis complicated in the postoperative period by bleeding caused by a latent deficiency of factor VII of the blood coagulation system. Often the disease is latent and is detected in serious injuries or during the surgeries. Sometimes the diagnosis is made in profuse bleeding. Under endotracheal anesthesia, the left-sided nephrolithotomy and intrarenal stenting with clamping of the renal artery was performed. The time of clamping of the renal artery was 12 minutes. Before clamping the renal artery, 3 mg of furosemide 0.2 mg of verapamil and 1 mg of methylethylpiridinol were introduced intravenously per kilogram of patient' weight. A stone sized 3.02.5 cm was removed from the kidney, and a number of small stones were washed out from the lower group of calyces. At the time of diagnosis, prothrombin time and prothrombin index were checked. The patient's hemostasis system, including clotting factors, were examined. The results showed that the patient's blood clotting time by LeeWhite method increased to 15 minutes (reference, 713 minutes), and the time of activated partial thromboplastin time (aPTT) to 41.6 seconds (reference, 2838 seconds), while the activity of factor VII decreased to 40% (reference, 70120%). After that, the patient was diagnosed with factor VII deficiency or hypoproconvertinemia. During treatment, the patient was transfused twice a day with fresh frozen plasma and only once during the entire period, 1000 IU of antiinhibitoty coagulant complex (FEIBA) was administered intravenously. From the first day of treatment hematuria decreased, there was a reverse development of hemorrhagic syndrome. Obvious and latent comorbidities before and after the surgery should not be left out without attention. Only in this case it is possible to successfully complete the treatment and achieve the correct results.

New oral anticoagulants are effective for the prevention of thromboembolic complications in patients with atrial fibrillation, or after orthopedic surgery. The use of these drugs may be associated with the risk of bleeding from the gastrointestinal tract — a dangerous complication, which can potentially lead to death. The aim of this research was systematization and analysis of information on the interactions of new oral anticoagulants with other drugs and food products, and the identification of potentially dangerous combinations that increase the risk of gastrointestinal bleeding. To assess the risk of a heavy bleeding in patients with atrial fibrillation taking oral anticoagulants to prevent thromboembolic complications, HAS-BLED scale is used. In some cases activated partial thromboplastin time, ecarin clotting time, anti-FXa, etc. can be used to assess the effectiveness of the oral anticoagulants. Potential combinations that increase the risk of bleeding include the simultaneous administration of new oral anticoagulants with antiplatelet agents, anticoagulants, including vitamin K antagonists, unfractionated heparin, low molecular weight heparins, nonsteroidal anti-inflammatory drugs, antidepressants along with other drugs and foods (curcumin, grapefruit juice, peppermint, eucalyptus, etc.). The administration of proton pump inhibitors, as well as the elimination of potentially dangerous combinations of drugs and food with new oral anticoagulants, can help prevent gastrointestinal bleeding.

Objective. Identification of laboratory parameters that are used in routine practice and can serve as diagnostic and prognostic criteria for the development of sepsis and its outcomes in patients with purulent-inflammatory diseases of soft tissues.Materials and methods. The study included 48 patients with purulent-inflammatory diseases of soft tissues. Recorded the occurrence of such clinical events as the development of sepsis or septic shock, intensive therapy, death or recovery and discharge from the hospital. For the diagnosis of sepsis, a SOFA (Sepsis-related organ failure assessment score) ³ 2 points was used. Patients were divided into subgroups according to the number of points according to the SOFA scale, intensive care and depending on the outcome of the disease: Subgroup 1 – 26 patients with sepsis (SOFA ³ 2 points) and 22 patients with systemic inflammatory response syndrome (SIRS) and SOFA Results. In patients with sepsis, albumin concentration was 24,07 g / l in median versus 34,65 g / l in the control group of patients with SOFA Conclusion. Routine laboratory indicators as the level of total protein, albumin, glucose, sodium and urea, as well as indicators of the blood coagulation system (INR and APTT), can serve as diagnostic and prognostic criteria for the development of sepsis and its outcomes in patients with purulentinflammatory diseases. soft tissue.

Background: Sepsis is a severe life-threatening condition characterized by combined dysfunction of the inner organs and systems and by dysregulation of the platelet and coagulation compartments of hemostasis, in particular. Aim: To assess the character of abnormalities in morphofunctional state of platelets in the pathophysiology of sepsis and the multiple organ failure syndrome by means of coherent interference microscopy. Materials and methods: This single center, prospective, observational study included 78 hospitalized patients with abdominal sepsis; in 40 of them, the syndrome of multiple organ failure was diagnosed. The causes of sepsis were peritonitis of various etiologies in 55 patients, acute necrotic pancreatitis with suppurative and septic complications in 23. The control group included 25 physically healthy subjects. Coherent interference microscopy was used for vital assessment of the platelet morphofunctional state, with simultaneous analysis of routine coagulogram and platelet aggregation parameters. Results: The group of patients with sepsis (n = 38) had higher fbrinogen levels, compared to that in the control (4.5 ± 1 g/L, p = 0.0001), with mild thrombocytopenia (238 ± 12 × 109/L, p = 0.0001). Platelet aggregation was also increased (48 ± 3%, p = 0.0001). Assessment of circulating platelets by coherent interference microscopy showed a progressive increase of the mean populational morphodensitometrical parameters, such as the diameter (p = 0.0002), perimeter (p < 0.0001), and area (p = 0.0002), as well as a decrease in mean values of the phase height (p = 0.0002) and volume (p = 0.0002). There was an increase in the proportion of activated cells to 41% (vs. 33% in healthy control) and the proportion of degenerative cells up to 8%. The patients with severe sepsis complicated by multiple organ failure (n = 40), compared to the control ones, demonstrated exhausted of compensatory mechanisms with the development of consumption coagulopathy: prolonged activated partial thromboplastin time (57 ± 2 s, p = 0.0001), increased prothrombin index (117 ± 4, p = 0.0025), decreased fbrinogen level (1.6 ± 2 g/L, p = 0.0001) and platelet counts (110 ± 9 × 109/L, p = 0.0001), and their lower aggregation (24 ± 3%, p = 0.0001). According to the results of the coherent phase microscopy, the types of the morphodensitometrical abnormalities were similar to that in the main group, albeit they were more signifcant. The proportion of the activated cells was 43%, while that of the degenerated and functionally incompetent platelets, 15%. There were signifcant correlations between the morphodensitometrical parameters of the platelets and basic parameters of their aggregation induced by adenosine diphosphate and collagen. Conclusion: Sepsis is associated with advanced abnormalities in the morphofunctional state of peripheral blood platelets progressing concomitantly to the deterioration of the patient's state. Coherent interference microscopy allows for a real-time assessment of the morphological particulars and functioning of circulating thrombocytes. Further studies are required to validate the results of this method.

Низкомолекулярные гепарины (НМГ) рекомендованы всем госпитализированным пациентам с COVID-19. Однако эффективная доза НМГ неизвестна, и эскалация дозы НМГ представляется уместной для лечения COVID-19-ассоциированной коагулопатии. Цель исследования: анализ дозирования НМГ для лечения COVID-19-ассоциированной коагулопатии, а также индикаторов, указывающих на необходимость коррекции доз этих препаратов. Материалы и методы. В период апрель-июнь 2020 г. обследовано 49 человек с диагнозом COVID-19. НМГ получили 43 пациента: 25 человек — эноксапарин натрия, 18 — далтепарин натрия. При лабораторном обследовании определяли С-реактивный белок, количество тромбоцитов, активированное частичное тромбопластиновое время, тромбиновое время, концентрацию фибриногена, активность антитромбина III, протромбиновое время, концентрацию Д-димера и анти-фактор Ха активность (анти- Ха активность). Данные были представлены как медиана (Me), нижний (LQ) и верхний (UQ) квартили. Статистический анализ включал в себя проверку на нормальность распределения по критерию Шапиро–Уилка, сравнение независимых групп по критерию Манна–Уитни при уровне значимости < 0,05, корреляционный анализ с применением критерия Спирмена, регрессионный анализ с использованием F-критерия. Многомерный поэтапный анализ результатов исследования проводили методами кластерного, дискриминантного и ROC-анализа. Результаты. Установлено, что воспалительный ответ у мужчин и у женщин протекает с различающимися акцентами в рамках системы гемостаза. Если анти- Ха активность была ниже 0,4 МЕ / мл, то выбранная доза НМГ никак не влияла ни на процессы тромбообразования и воспаления, ни на течение заболевания в целом. При анти- Ха активности в диапазоне 0,4–0,6 МЕ / мл воспалительный ответ также преодолевал эффект НМГ. Только при анти- Ха активности > 0,6 МЕ / мл была выявлена достоверная корреляция между анти- Ха активностью и суточной дозой НМГ (r = 0,493; p = 0,031). Выявление в этой группе такой связи означает, что часть поступившего в организм НМГ уже была «потрачена» на противовоспалительные цели, а оставшаяся проявила эффект, направленный на другую цель назначения НМГ, т. е. собственно антитромботический. При этом ROC-анализ не подтвердил значимость концентрации фибриногена в прогнозе достижения антитромботической эффективности НМГ. Кластерный анализ достоверно разделил исходную выборку в точке анти- Ха активность = 0,6 ЕД / мл. Из 43 пациентов, получивших НМГ, только у 15 (34,9%) выбранная доза НМГ анти- Ха активность > 0,6 ЕД / мл, тогда как у оставшихся анти- Ха активность оказалась ниже данного значения, несмотря на большую вариацию полученного НМГ: AUC = 0,482 (95% ДИ = 0,298–0,665) со статистической значимостью p = 0,848. Дискриминантный анализ показал, а ROC-анализ подтвердил, что для до- стижения антитромботического эффекта требуется коррекция дозы с учетом веса тела пациента, а целевым значением анти- Ха активности является 0,65 ME / мл. Заключение. Антитромботический эффект как искомый результат применения НМГ достижим только при дозировании с учетом массы тела пациента, независимо от того, снижена она, нормальная или повышена. Развитие антитромботического эффекта должно выявляться, а его стабильность подтверждаться на основе определения анти- Ха активности, которая должна быть не менее 0,65 МЕ/мл. Анти- Ха активность ниже данного значения может служить указанием на необходимость коррекции дозы НМГ у пациентов с COVID-19-ассоциированной коагулопатией., Background. Low molecular weight heparins (LMWH) are guided for all in-hospital patients with COVID-19. However LMWH effective dose is still unknown. Escalating the LMWH dose seems appropriate for the treatment of COVID-19-associated coagulopathy. Objectives: to explore the LMWHs doses effects in the treatment of COVID-19-associated coagulopathy, and to fi nd indicators signaling the need to adjust the LMWH dose. Patients / Methods. From April to June 2020, 49 patients with COVID-19 were examined. LMWH were given to 43 patients: 25 of them received enoxaparin sodium, 18 — dalteparin sodium. Lab testing included C-reactive protein, platelet count, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin III, prothrombin time, D-dimer, and anti-factor Xa activity (anti- Xa activity). The data were presented as median (Me), lower (LQ) and upper (UQ) quartiles. Statistical analysis included the check of the distribution normality by Shapiro–Wilk test, comparing independent groups with Mann- Whitney test for p < 0.05, correlation analysis with Spearman test, and regression analysis with the F-test. Multivariate step-by-step analysis of data was performed using cluster analysis, discriminant analysis and ROC-analysis. Results. It was found that the inflammatory response reflects differently for hemostatic system in men and women. When anti-Xa activity was < 0.4 IU / ml, the LMWH selected dose did not affect either the processes of thrombosis and inflammation, or the course of the disease as a whole. When anti- Xa activity was within 0.4–0.6 IU / ml, the inflammation overcame the LMWH effect as well. A significant correlation between anti- Xa activity and the LMWH daily dose (r = 0.493; p = 0.031) was found only for anti-Xa activity > 0.6 IU / ml. That does mean that part of the administered LMWH was already “spent” for anti-inflammatory purposes, and the remaining part was enough to develop an antithrombotic effect. Other result was that ROC-analysis did not confirm the fibrinogen value for the forecast of LMWH antithrombotic effectiveness. Cluster analysis divided significantly the initial sample at the point with anti- Xa activity = 0.6 IU / ml. Of the 43 patients received LMWH, the selected LMWH dose provided anti- Xa activity > 0.6 IU / ml in 15 (34.9%) only, while in other patients the anti- Xa activity was lower despite a wide variation in the LMWH doses: AUC = 0.482 (95% CI = 0.298–0.665; p = 0.848). Discriminant analysis showed, and then ROC-analysis confirmed, that to an antithrombotic effect, LMWH dose adjustment is required taking into account the patient’s body weight, and the target value of anti- Xa activity is 0.65 IU / ml. Conclusions. The antithrombotic effect as the desired result of the LMWH use is achievable only under dosing with the patient’s body weight regardless of whether it is reduced, normal or increased. The LMWH antithrombotic effect should be detected and then its stability confirmed by testing the anti- Xa activity which should be at least 0.65 IU / ml. Lower anti- Xa activity may indicate the need for LMWH dose adjustment in patients with COVID-19-associated coagulopathy., Тромбоз, гемостаз и реология, Выпуск 4 2020

Введение: Приобретенная гипопротромбинемия, обусловленная циркуляцией волчаночного антикоагулянта (ВА), ассоциируется с высоким риском развития тяжелого кровотечения. Клинический случай: Описан случай приобретенного дефицита протромбина и фактора IX в сочетании с положительным ВА: у пациентки Н. была диагностирована лимфома из клеток маргинальной зоны, выявлен дефицит фактора II (21%) и фактора IX (27,1%), увеличение активированного частичного тромбопластинового времени, протромбинового времени и международного нормализованного отношения, обнаружены положительные маркеры антифосфолипидного синдрома, по данным тромбоэластографии — выраженная гипокоагуляция. Выполнена абдоминальная спленэктомия. Перед операцией пациентке был введен концентрат протромбинового комплекса (КПК) Уман Комплекс Д. И. в дозе 1500 МЕ. После введения КПК мы не достигли целевого значения активности факторов свертывания: фактор II увеличился до 49%, фактор IX — до 47%. Клинически оперативное вмешательство не сопровождалось геморрагическим синдромом. Заключение: Сочетанный приобретенный дефицит протромбина и фактора IX у пациентки Н. с лимфомой при наличии ВА существенно увеличивал риск развития тяжелого интраоперационного кровотечения. Введение КПК с адекватным мониторингом гемостаза позволило избежать развития осложнений в периоперационном периоде., Background: Acquired hypoprothrombinemia due to lupus anticoagulant presence is associated with a high risk of severe bleeding. Clinical case: The article describes the case of acquired prothrombin and factor IX defi ciency combined with a positive lupus anticoagulant (LA). The patient N. was diagnosed lymphoma from marginal zone cells. She had factor II (21%) and factor IX (27.1%) deficit, increased activated partial thromboplastin time, prothrombin time and international normalized ratio, positive markers of antiphospholipid syndrome, severe hypocoagulation according to thromboelastography. An abdominal splenectomy was performed. Before surgery, prothrombin complex concentrate (PCC) Complex DI Uman in a dose of 1500 IU was administrated. After PCC administration, we did not reach the target value of coagulation factors activity: factor II increased to 49%, factor IX — to 47%. Surgery was not associated with hemorrhagic syndrome. Conclusions: The combined acquired defi ciency of prothrombin and factor IX in patient N. with lymphoma and LA significantly increased the risk of severe intraoperative bleeding. PCC administration with adequate monitoring of hemostasis allowed to avoid the development of complications in perioperative period., Тромбоз, гемостаз и реология, Выпуск 3 2020

Введение. Пандемия COVID-19 стала глобальной проблемой мирового сообщества. Основным патогенетическим механизмом заболевания представляется развитие иммунного тромбоза, результатом которого являются нарушение микроциркуляции, артериальные и венозные тромбозы, респираторный дистресс-синдром, полиорганная недостаточность. Изучение механизмов развития гиперкоагуляционных изменений у пациентов с COVID-19 вызывает огромный интерес и позволит улучшить исходы заболевания. Цель исследования: оценка состояния плазменного звена гемостаза у пациентов с коронавирусной инфекцией в остром периоде заболевания. Материалы и методы. Обследованы 59 пациентов с тяжелым и среднетяжелым течением коронавирусной инфекции, получавшие антикоагулянтную профилактику. Определяли следующие параметры системы гемостаза: активированное парциальное тромбопластиновое время, протромбиновый тест, концентрацию фибриногена, активность фактора VIII, антитромбина, протеинов C и S, содержание D-димера, фактора Виллебранда и гомоцистеина, а также генерацию тромбина методом калиброванной автоматизированной тромбинографии. Результаты. У пациентов с COVID-19 по сравнению со здоровыми лицами было выявлено увеличение концентрации фибриногена, уровня фактора Виллебранда, гомоцистеина и D-димера, значительное снижение уровня свободного протеина S, усиление генерации тромбина, снижение чувствительности к тромбомодулину. Была выявлена прямая корреляция между тяжестью состояния пациентов и уровнями фактора Виллебранда и гомоцистеина. Заключение. Несмотря на проводимую антикоагулянтную терапию, у пациентов с коронавирусной инфекцией отмечены выраженные признаки активации системы гемостаза, которые характеризуются как повышением отдельных маркеров гиперкоагуляции, так и значимым усилением генерации тромбина на фоне угнетения работы системы протеина С. Повышенный уровень гомоцистеина плазмы крови является дополнительным фактором риска, ухудшающим течение заболевания. Значительное повышение уровня фактора Виллебранда может быть неблагоприятным прогностическим признаком течения заболевания., Background. The COVID-19 pandemic is a global health care challenge. The concept of immunothrombosis has established as a central pathogenic factor leading to thrombosis complications, respiratory insufficiency and multiple organ failure. The study of hypercoagulability mechanisms in patients with COVID-19 may be useful for improving disease’s outcomes. Objectives: to evaluate plasma hemostasis in patients with coronavirus infection at the acute period of the disease. Patients / Methods. We examined 59 patients with severe and moderate coronavirus infection who received anticoagulant treatment. The following hemostasis parameters were determined: activated partial thromboplastin time, prothrombin test, fibrinogen, factor VIII, von Willebrand factor, D-dimer, protein C and S, homocysteine, and thrombin generation. Results. Fibrinogen, von Willebrand factor, D-dimer, homocysteine, and thrombin generation were higher in patients with COVID-19 than in healthy people, protein S was reduced. The direct correlation between the severity of the patient’s condition and the levels of von Willebrand factor and homocysteine was found. Conclusions. Patients with COVID-19 had significant hypercoagulability despite of the anticoagulant treatment. Signs of hemostasis activation are characterized by both increasing of hypercoagulation individual markers and thrombin generation with inhibition of protein C system. High level of plasma homocysteine is an additional risk factor that worsens the disease course. High level of von Willebrand factor may be an unfavorable prognostic sign of the disease course., Тромбоз, гемостаз и реология, Выпуск 4 2020

Введение. Известно о коагулопатиях при инфекциях коронавирусами SARS и MERS. Цель исследования: изучить накопленную информацию о коагулопатии при инфекции COVID-19. Материалы и методы. В библиотеке PubMed провели поиск по ключевым словам «COVID-19», «coagulopathy». Обнаружили 15 публикаций, содержащих результаты оригинальных исследований. Результаты. При тяжелом течении заболевания наблюдают цитокиновый шторм, более высокие уровни Д-димера и продуктов деградации фибрина (ПДФ), более длительное протромбиновое время и активированное частичное тромбопластиновое время. Данные о частоте развития синдрома диссеминированного внутрисосудистого свертывания противоречивы. Заключение. У пациентов с COVID-19 с острой дыхательной недостаточностью наблюдается выраженная гиперкоагуляция. Всем госпитализированным пациентам с COVID-19 рекомендована фармакологическая тромбопрофилактика низкомолекулярными гепаринами или фондапаринуксом. Донорскую плазму для пассивной иммунотерапии нужно переливать только в рамках клинических исследований., Background. Coagulopathies are known for infections with SARS and MERS coronaviruses. Objectives: the reviewing the early accumulated information on coagulopathy in COVID-19. Patients / Methods. In PubMed Library with the keywords «COVID-19», «coagulopathy» we selected 15 publications containing the results of original studies. Results. In severe cases of the disease, a cytokine storm is observed, higher levels of D-dimer and fibrin degradation products (FDP), longer prothrombin time and activated partial thromboplastin time. Data about incidence of disseminated intravascular coagulation are contradictory. Conclusions. Patients with COVID-19 with acute respiratory failure exhibit severe hypercoagulation. Pharmacological thromboprophylaxis with low molecular weight heparins or fondaparinux is recommended for all hospitalized patients with COVID-19. Donor plasma for passive immunotherapy should be transfused only as part of clinical trials., Тромбоз, гемостаз и реология, Выпуск 4 2020

Aim. To investigate the impact of double filtration plasmapheresis (DFPP) and therapeutic plasma exchange (TPE) on hemostasis in renal transplant recipients. Materials and methods. 54 renal transplant patients with an acute humoral rejection were treated with therapeutic apheresis methods: 24 patients with DFPP and 30 patients with TPE. In all patients was performed 3-4 session. We analyzed international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen concentration and platelet count just before and after each session, and after the course of all procedures. After TPE plasma replacement was performed with an equivalent volume of a fresh frozen plasma. After DFPP was performed 10-20% albumin solution. Results and discussion. After each DFPP session was occurred an increased INR and aPTT. After course of all DFPP procedures fibrinogen level decreased by 46%. It was associated with increase of APTT and INR by 35% and 32% respectively. Mainly it was associated with dose of the procedures (volume of plasma perfusion), but not with the plasma separator type. One patient noted hemorrhagic complication. After each TPE session level of fibrinogen concentration, INR and aPPT remained in the normal range, but there was a moderate reduction in platelet count, more pronounced than during DFPP. Hemorrhagic complications were not. Conclusion. Double cascade plasmapheresis and therapeutic plasma exchange generate preconditions for hemorrhagic complications such as increased aPTT and INR, reduce fibrinogen concentration. However, bleeding complications are rare. At the same time, during high volume DFPP should be careful when initially level of fibrinogen is low. In this case fibrinogen concentration should be controlled after the procedure for timely replenishment of its deficit.

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., №3(79) (2019)

Введение. Метод Борна стал золотым стандартом тромбоцитарной агрегометрии вполне заслуженно: он исторически был разработан первым, первым же вошел в клиническую практику и за счет этого приобрел самую обширную доказательную базу. Имеющиеся сведения наглядно демонстрируют его достоинства и недостатки. Метод Platelet Function Analysis (PFA) был разработан значительно позднее, но во многом в ответ на ограничения метода Борна и в соответствии с клиническим требованием иметь в практике pointofcare метод оценки агрегационной активности тромбоцитов. Особенностью PFA является оценка агрегационного ответа тромбоцитов текущей (это важно) цельной крови в условиях имитации повреждения сосудистой стенки мелких сосудов. Цель исследования: изучить соответствие результатов теста PFA данным, получаемым с помощью золотого стандарта агрегатометрии по Борну, а также определить причины и диагностическое значение расхождений. Материалы и методы. Обследован 51 пациент (28 мужчин и 23 женщины) с хронической цереброваскулярной патологией. Из них 35 человек получали per os препараты ацетилсалициловой кислоты (АСК) в дозе 100 150 мг/сут (группа 1), а 16 пациентов клопидогрел в дозе 75 мг/сут (группа 2). Кроме того, 20 человек, получавших АСК, были обследованы дважды: до начала приема и через 14 дней. Все пациенты были обследованы по следующим показателям: концентрация гемоглобина, количество тромбоцитов, скорость оседания эритроцитов (СОЭ), содержание общего белка, глюкозы, триглицеридов и общего холестерина. Также определяли коагулологические показатели: активированное частичное тромбопластиновое время, протромбиновое время с расчетом международного нормализованного отношения, уровень фибриногена и концентрацию Ддимера методом латексных частиц с высоко специфичными моноклональными антителами к Ддимеру на автоматическом коагулометре ACL ElitePro (США) с использованием наборов реагентов фирмы Instrumentation Laboratory (США). Результаты. Группы оказались практически одинаковыми по возрасту, наличию и выраженности фонового воспалительного процесса и состоянию системы гемостаза. Оценка агрегации тромбоцитов в ответ на АДФ и адреналин у пациентов до начала приема АСК в дозе 150 мг/сут и через 2 нед не выявила противоречивых данных и показала, что оба метода отчетливо регистрируют ее угнетение. На фоне приема АСК результаты агрегометрии тромбоцитов обоими методами с индуктором АДФ совпали с коэффициентом корреляции r 0,74 (p 0,05), с индуктором адреналин с коэффициентом r 0,63 (p 0,05). На фоне приема клопидогрела результаты АДФиндуцированной агрегометрии, полученные обоими метода ми, совпадали с большим коэффициентом корреляции: r 0,82 (p 0,05), адреналининдуцированной агрегации r 0,88 (p 0,05). Корреляционный анализ выявил зависимость результатов, получаемых каждым методом на фоне приема АСК или клопидогрела, от следующих параметров: возраст, концентрация фибриногена, количество тромбоцитов и СОЭ, что в большей степени проявилось для PFA. Заключение. Очевидно, что метод Борна показывает лишь то, насколько тромбоциты в целом чувствительны к действию ингибитора агрегации, тогда как метод PFA демонстрирует реальную картину образования сгустка на фоне всех имеющихся условий, т.е. как результат всего многообразия взаимодействий тромбоцитов per se в цельной крови. Другими словами, метод PFA отражает общий уровень тромбогенности, которая, в свою очередь, очевидно является причиной так называемой резистентности к антиагрегантам, нередко наблюдаемой у данной категории больных., Introduction. Borns method became the gold standard of platelet aggregometry because it has been developed historically the first. On today it has the most extensive evidence base showing clearly its advantages and disadvantages. The Platelet Function Analysis (PFA) is a method developed much later as a response to the limitations of the Borns method in order to have a pointofcare platelet aggregometry in practice. The main feature of PFA is the evaluation of platelet aggregation occurring in flowing whole blood under conditions simulating vascular wall damage. Aim: to study the compliance between PFA test results and the data obtained by Borns aggregatometry as well as to determine the causes and diagnostic value of their discrepancies. Materials and methods. The study included 51 patients (28 men and 23 women) with chronic cerebrovascular pathology, from them 35 were intaking acetylsalicylic acid, ASA (100 150 mg/day per os, group 1), and clopidogrel in 16 patients (75 mg/day per os, group 2). In addition, 20 patients with ASA were examined twice as before as well as in 14 days. Lab testing included hemoglobin, platelet count, erythrocyte sedimentation rate, total protein, glucose, triglyceride, total cholesterol, activated partial thromboplastin time, prothrombin time as international normalized ratio, fibrinogen and Ddimer with using of ACL ElitePro coagulometer and reagents kits by Instrumentation Laboratory (USA). Results. The groups were appeared almost identical in age, the severity of the background inflammatory and the clotting conditions. Both methods have registered clearly platelet aggregation inhibition in 2 weeks of ASA administration both in response to ADP and to epinephrine, and no any disagreements was found between the methods. By ASA administration the ADPinduced aggregations from Borns method and PFA showed the correlation r 0.74 (p 0.05), the epinephrininduced aggregations have coincided with r 0.63 (p 0.05). In cases with clopidogrel we found large correlation coefficients as r 0.82 (p 0.05) and r 0.88 (p 0.05) between ADPinduced aggregations and between epinephrininduced aggregations, respectively. The correlation analysis revealed that the results obtained by each method were closely related to parameters such as age, fibrinogen, platelet count and erythrocyte sedimentation rate, and that was more evident for PFA. Conclusion. Obviously, the Borns method shows only how platelets are sensitive generally to the antiaggregation agents, whereas the PFA method plots a real picture of clot formation against all available conditions, i.e. as a result of the whole variety of platelet interactions per se in whole flowing blood. It does mean the PFA method reflects the overall level of thrombogenicity. In turn that is obviously the cause of the socalled resistance to antiplatelets observed often in such category of patients., №3(79) (2019)

Цель исследования изучить состояние системы гемостаза при хронической интоксикации хлоридом никеля, исследовать взаимосвязь показателей гемокоагуляции с процессами липопероксидации у крыс в эксперименте. Методика. Опыты проводили на крысахсамцах Вистар (n50, 230250 г). Раствор NiCl2 (5 мг/кг) вводили внутрижелудочно ежедневно в течение 2 нед, 1 и 2 мес. По завершении эксперимента исследовали состояние тромбоцитарного и коагуляционного звеньев гемостаза, антикоагулянтную и фибринолитическую активность крови, а также определяли активность процессов перекисного окисления липидов и антиоксидантных ферментов. Результаты. Установлено, что через 2 нед и 1 мес интоксикации у крыс отмечались гиперкоагуляционные изменения показателей свертывающей системы крови: повышение агрегационной активности тромбоцитов, увеличение концентрации фибриногена, снижение активированного частичного тромбопластинового времени (АЧТВ) и протромбинового времени. В этот период регистрировалось увеличение антитромбиновой и фибринолитической активности крови. Через 2 мес наблюдалось подавление активности клеточного звена гемостаза тромбоцитопения, ослабление степени АДФиндуцируемой агрегации тромбоцитов. Выявлялась тенденция к уменьшению концентрации фибриногена. На фоне снижения АЧТВ и тромбинового времени отмечалось увеличение протромбинового времени. В то же время регистрировалось угнетение противосвертывающего звена системы гемостаза (снижалась активность антитромбина III), наблюдалось истощение резервных возможностей фибринолитического звена (замедление фXIIазависимого эуглобулинового лизиса) и увеличение содержания растворимых фибрин мономерных комплексов, что свидетельствует о наличии тромбинемии. Через 2 нед, один и два месяца интоксикации у животных выявлялись корреляционные связи между основными показателями системы гемостаза и активностью процессов перекисного окисления липидов и антиоксидантных ферментов. Заключение. Полученные данные подтверждают наличие взаимосвязи активности процессов липопероксидации и системы гемостаза, в том числе при хронической никелевой интоксикации. Результаты исследования позволяют рекомендовать применение антиоксидантов для разработки способов коррекции гемостатических сдвигов при воздействии на организм тяжелых металлов., The aim. To study the state of the hemostasis system in chronic nickel intoxication and to investigate the relationship between hemocoagulation indices and lipoperoxidation processes in rats. Methods. Experiments were carried out on male Wistar rats (n50, 230250 g). A solution of nickel chloride (5 mg/kg) was administered daily intragastrically for two weeks, one and two months. At the end of the experiments, indices of platelet and coagulation hemostasis systems, anticoagulant and fibrinolytic activity of blood plasma, and activities of lipid peroxidation and antioxidant enzymes were studied. Results. Hypercoagulative changes in indices of the coagulation system were observed in rats after two weeks and one month of intoxication, including increased platelet aggregation and fibrinogen concentration and shortened activated partial thromboplastin time and prothrombin time. During the same period, increased antithrombin and fibrinolytic activities were observed. The depressed activity of the cellular component of hemostasis evident as thrombocytopenia and impaired ADPinduced platelet aggregation was detected after two months of intoxication. A tendency to decrease in fibrinogen concentration was observed. The shortened activated partial thromboplastin time and thrombin time were associated with prolonged prothrombin time. At the same time, inhibition of the anticoagulant component of hemostasis (decreased antithrombin III activity), exhaustion of the fibrinolysis system reserve (delayed fXIIadependent euglobulin lysis), and a significant increase in soluble fibrin monomeric complexes indicative of thrombinemia were observed. After two weeks, one and two months of nickel intoxication, a correlation was found between the major indices of the hemostasis system and the activities of lipid peroxidation and antioxidant enzymes. Conclusion. The study confirmed a relationship between the lipid peroxidation activity and the hemostasis system, specifically in chronic nickel intoxication. This result allows to recommend the use of antioxidants in developing methods for correction of hemostatic induced affected by heavy metals., №1 (2019)

Цель исследования: изучение параметров гемостаза у доноров для оптимизации использования компонентов крови у пациентов с нарушениями свертывания крови. Материалы и методы. Проанализированы результаты коагулологического исследования крови у 200 доноров. Контрольную группу составили 50 человек — здоровые люди (добровольцы), не доноры в возрасте от 20 до 60 лет. Измеряли: время свертывание крови по Ли-Уайту, активированное частичное тромбопластиновое время, международное нормализованное отношение, агрегацию тромбоцитов, антитромбин III (АТ-III), содержание фибриногена по Клаусу, фактор фон Виллебранда (ФВ), активность фактора VIII. Рассчитывали среднюю арифметическую и среднюю ошибку средней арифметической (М ± m), для оценки значимости различий средних величин использовали t-критерий Стьюдента, различия считали статистически значимыми при р < 0,05. Результаты. Оценка показателей гемостаза показала как развитие у доноров склонности к гиперкоагуляции, так и компенсаторную активацию антикоагулянтной системы. В зависимости от возраста и количества кровосдач агрегация тромбоцитов, АТ-III, содержание фибриногена, активность ФВ и фактора VIII в заготовленных компонентах крови получаются различными. Заключение. Трансфузионная терапия коагулопатий может быть оптимизирована за счет применения компонентов крови, целенаправленно заготовленных с учетом характера нарушений свертывания крови у реципиента., Aim: to optimize the usage of blood components in patients with coagulopathy we analyze some hemostasis parameters in donors. Materials and methods. In 200 donors and 50 healthy volunteers (aged from 20 to 60 years old) we analyzed hemostatic parameters: whole blood clotting time, activated partial thromboplastin time, international normalized ratio, platelet aggregation, antithrombin III (AT-III), Claus fibrinogen content, activity of von Willebrand factor (VWF) and factor VIII. The results obtained presented as M ± m. Statistical diff erences by Student test were considered as signifi cant for p < 0,05. Results. All donors had the tendency to hypercoagulation with compensatory activation of anticoagulant system. Depending on the age and number of blood donations, obtained blood components were diff erent in platelet aggregation, AT-III level, fibrinogen content, activity of VWF and factor VIII. Conclusion. Transfusion therapy of coagulopathies can be optimized through the use of blood components purposefully prepared taking into account the nature of blood clotting disorders in the recipient., №3(2018) (2018)