[Peculiarities of hemostasis in patients with COVID-19].

AIM: Analysis of the dynamics of different stages of clot formation and its lysis in patients with different COVID-19 severity. MATERIALS AND METHODS: We prospectively included 58 patients with COVID-19 (39 patients with moderate disease severity and 18 patients with severe disease) and 47 healthy volunteers as a control group. All participants underwent the assessment of flow-mediated dilation (FMD) of brachial artery, impedance aggregometry, rotational thromboelastometry and thrombodynamics. Von Willebrand factor antigen (vWF:Ag) quantification was also performed in patients with COVID-19. Measurements were repeated on the 3rd and 9th day of hospitalization. RESULTS: Compared to the control group, patients with COVID-19 showed reduced values of platelet aggregation and greater values of the clot growth rate, as well as its size and density. On the first day of hospitalization, we found no differences in the activity of plasma hemostasis and endogenous fibrinolysis between subgroups of patients. With the progression of the disease, the growth rate and size of the clot were higher in the severe subgroup, even despite higher doses of anticoagulants in this subgroup. An increase in platelet aggregation was noted during the progression of the disease, especially in the severe subgroup. There were no differences in the results of the FMD test by subgroups of patients. The vWF:Ag level was significantly higher in the severe subgroup. CONCLUSION: Thus, plasma hemostasis followed by secondary platelet activation correlates with the severity of COVID-19. Patients with moderate to severe coronavirus infection have predominantly local rather than generalized endothelial dysfunction.

Is endothelial dysfunction a driving force of COVID-19 induced coagulopathy?

Background/Introduction: There are numerous reports regarding the direct endothelial damage by the SARS-CoV-2 that can lead to activation of both plasma hemostasis and platelet aggregation. However, the mechanism of interaction between endothelium and haemostasis in COVID-19 remains unclear. Purpose: The aim of our study was to assess the relationship between each link of clot formation process (endothelial function, plasma coagulation, platelet aggregation) with the severity of the disease. Methods: 58 COVID-19 patients were included in our study. Patients were divided into moderate (n=39) and severe (n=18) subgroups. All patients underwent a flow-mediated dilation (FMD) test, impedance aggregation, rotational thromboelastometry, thrombodynamics and von Willebrand factor antigen (vWF: Ag) quantification. All measurements were repeated on days 3 (point 2) and 9 (point 3) of hospitalization. Results: COVID-19 patients demonstrated the enhanced plasma coagulation (clotting time, s 613,0 [480;820], clot growth rate, μm/min 32,75 [29,3;38,7]). At point 1 no significant difference in parameters of plasma coagulation between patients' subgroups was noted. At point 2 a significant decrease in the size (CS, μm 1278.0 [1216.5;1356.5] vs 965.0 [659.8;1098.0], p<0,01) and clot growth rate (μm/min 32,4 [29,2;35,0] vs 17,7 [10,3;24,4], p<0,01) under the influence of anticoagulants in the moderate subgroup compared with point 1 was observed. We didn't observe such phenomenon in severe subgroup. There was no significant difference in platelet aggregation between subgroups at point 1. During the course of the disease the patients in the moderate and severe subgroups demonstrated a significant increase in platelet aggregation induced by arachidonic acid and ADP (severe: AUC ARA 48,0 [25,0;59,0] vs 77,5 [55,8;92,7], p=0,04;AUC ADP 44,0 [41,0;56,0] vs 58,0 [45,5;69,0], p=0,04;moderate: AUC ARA 31,5 [19,8;50,7] vs 56,0 [39,0;76,0], p=0,01;AUC ADP 43,0 [20,0;59,0] vs 56,6 [50,3;70,5], p=0,04;), in moderate subgroup the significant increase in TRAP-induced aggregation was also noted (AUC TRAP 58,0 [41,0;69,5] vs 76,0 [58,3;81,5], p=0,048). There were no significant differences in the FMD-test results between the patient subgroups. FMD-test results were predominantly within the reference ranges (7,1 [4,0;8,8]). Patients in the severe subgroup had significantly higher levels of vWF: Ag (228,0 [205,3;240,7] vs 232,0 [226,0;423,0], p=0,03). Conclusion: SARS-CoV-2 infection was characterized by increased levels of vWF:Ag, that could represent the local endothelial damage, meanwhile there was no generalized endothelial dysfunction assessed via FMD-test in moderate to severe patients. At the same time the enhanced plasma coagulation in COVID-19 patients was observed.

Dynamic monitoring of hemostasis and correction of heparin therapy can halve the number of thromboticcomplications in patients with severe COVID-19

Background : Anticoagulant thromboprophylaxis is recommended for all hospitalized COVID-19 patients. However, the dosage regimen is debated, as thrombogenicity may vary in different patients and during the course of infection. Aims : 1. Conduct observational study of various hemostatic tests to achieve accurate dynamic monitoring in COVID-19 patients. 2. Evaluate effectiveness of heparin therapy correction in response to the ongoing changes in hemostasis system. Methods : 1. Hemostasis was monitored in 1,859 patients with severe COVID-19 in seven hospitals in Moscow. Blood was taken at hospital admission before the start of thromboprophylaxis and every 1-3 days throughout the treatment. To minimize the presence of heparin in blood sample, blood was collected 12 h after heparin injection. Hemostasis was investigated using APTT, INR, D-dimer test, Thromboelastography and Thrombodynamics. 2. Correction of heparin therapy was carried out in 218 COVID-19 patients monitored using Thrombodynamics in three hospitals. Results : 1. APTT and INR parameters did not change after the start of heparin therapy and indicated hypocoagulation during entire thromboprophylaxis. D-dimer was strongly elevated in most patients but was also unchanged during the therapy. Thromboelastography and Thrombodynamics showed hypercoagulability in 60-70% of patients prior to therapy. Subsequently, these tests revealed normal coagulation in 70% of the patients. From all examined hemostatic tests, the most sensitive indicator of the state of hemostasis was the rate of clot growth determined with Thrombodynamics. 2. Based on the results of the observational study, heparin therapy was corrected in ICU patients to maintain the rate of clot growth at 12-20 μm/min, as determined with Thrombodynamics. Thrombotic complications were observed in 19% of patients, compared with 32% in the control group with 151 patients, who received standard heparin therapy with no correction. Conclusions : Dynamic monitoring of hemostasis via Thrombodynamics in patients with severe COVID-19 enables effective correction of heparin therapy, significantly reducing thrombotic complications.

Results of multicenter monitoring of hemostasis parameters in patients with COVID-19

Materials and methods: a prospective non-randomized pilot multicenter study of the informativeness and clinical significance of hemostasis laboratory tests in 1210 patients with COVID-19 in disease course, including favorable and unfavorable outcomes, was performed. Hemostasis was assessed using clotting tests and D-dimer concentration, thromboelastography (TEG) and thrombodynamics (TD). Results: comparison of COVID-19 laboratory parameters and clinical picture showed that 75% of patients have pronounced activation of the plasma coagulation system upon admission to the hospital. Hypercoagulation is recorded in all tests, reaching a maximum in patients with subtotal (CT-3) and total (CT-4) lung lesion and/or resuscitation patients with a clinical picture of pulmonary embolism and unfavorable outcome. Low molecular weight heparins (LMWH) in a standard dosage leads to suppression of the initial hypercoagulable syndrome in more than half of the patients (from 75 to 31%). All patients without LMWH laboratory effect developed thrombotic complications. For clotting tests, insufficient sensitivity to changes in hemostasis against the background of LMWH was revealed. The D-dimer test effectively correlates with the severity and outcomes of COVID-19, but is not suitable for the control of heparin therapy, which is associated with the effect of lysis of existing blood clots and the lack of response to a decrease in the coagulation activity of patients. Methods of thromboelastography and thrombodynamics effectively record a decrease in the activity of the coagulation system and can be used to control heparin therapy. The correlation coefficient between the methods was 0,77. The dynamic indices of D-dimers, TEG and TD in severe patients and, especially, in patients with fatal outcomes revealed the greatest sensitivity to the control of heparin therapy in the Thrombodynamics test, which allows, along with thrombosis, to record hypercoagulable states and the risk of bleeding, which are the outcome of thrombohemorrhagic syndrome in patients with COVID-19. Материалы и методы исследования: проведено проспективное открытое нерандомизированное пилотное многоцентровое исследование информативности и клинической значимости лабораторных тестов гемостаза у 1210 пациентов с COVID-19 в динамике заболевания, включая благоприятные и неблагоприятные исходы. Оценку гемостаза проводили с использованием клоттинговых тестов и концентрации D-димера, тромбоэластографии (ТЭГ) и тромбодинамики (ТД). Результаты: при сопоставлении лабораторных показателей и клинической картины COVID-19 показано, что у 75% больных при поступлении в стационар наблюдается выраженная активация плазменной системы свертывания. Гиперкоагуляция фиксируется по всем тестам, достигая максимума у больных с субтотальным (КТ-3) и тотальным (КТ-4) поражением легких и/или реанимационных больных с клинической картиной тромбоэмболии легочной артерии и неблагоприятным исходом. Назначение низкомолекулярных гепаринов (НМГ) в стандартной дозировке приводит к подавлению исходного гиперкоагуляционного синдрома более чем у половины больных (с 75 до 31%). Все пациенты без лабораторного эффекта НМГ развили тромботические осложнения. Для клоттинговых тестов выявлена недостаточная чувствительность к изменениям гемостаза на фоне НМГ. Тест на D-димер эффективно коррелирует с тяжестью и исходами COVID-19, но непригоден для контроля гепаринотерапии, что связано с эффектом лизиса существующих тромбов и отсутствием ответа на снижение коагуляционной активности больных. Методы ТЭГ и ТД эффективно регистрируют снижение активности свертывающей системы и могут использоваться для контроля гепаринотерапии. Коэффициент корреляции между методами составил 0,77. Заключение: динамические индексы D-димеров, ТЭГ и ТД у тяжелых больных и особенно у пациентов с летальными исходами выявили наибольшую чувствительность к контролю гепаринотерапии у теста ТД, что позволяет наряду с тромбозами фиксировать гиперкоагуляционные состояния и риск кровотечений - исходы тромбогеморрагического синдрома у больных с COVID-19.