Corona Virus Disease 2019 (COVID-19) as a System-Level Infectious Disease With Distinct Sex Disparities

The current global pandemic of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) causing COVID-19, has infected millions of people and continues to pose a threat to many more. Angiotensin-Converting Enzyme 2 (ACE2) is an important player of the Renin-Angiotensin System (RAS) expressed on the surface of the lung, heart, kidney, neurons, and endothelial cells, which mediates SARS-CoV-2 entry into the host cells. The cytokine storms of COVID-19 arise from the large recruitment of immune cells because of the dis-synchronized hyperactive immune system, lead to many abnormalities including hyper-inflammation, endotheliopathy, and hypercoagulability that produce multi-organ dysfunction and increased the risk of arterial and venous thrombosis resulting in more severe illness and mortality. We discuss the aberrated interconnectedness and forthcoming crosstalks between immunity, the endothelium, and coagulation, as well as how sex disparities affect the severity and outcome of COVID-19 and harm men especially. Further, our conceptual framework may help to explain why persistent symptoms, such as reduced physical fitness and fatigue during long COVID, may be rooted in the clotting system.

Thrombosis in pre- and post-vaccination phase of COVID-19

Acute infections may be complicated by thrombosis occurring in the venous and arterial circulation. This may be observed in patients with community-acquired pneumonia (CAP) and also in patients with coronavirus 2019 (COVID-19), that is a pandemic characterized by severe acute respiratory syndrome (SARS-CoV-2) needing mechanical ventilation and intensive care unit treatment. However, the type and rate of thrombosis can vary according to the cause of pneumonia as is more frequently complicated by arterial thrombosis in CAP, while an equal incidence of venous and arterial thrombosis occurs in SARS-CoV-2. The mechanisms of disease are overall platelet-related in CAP while activation of both platelets and clotting system is implicated in the pathogenesis of thrombosis in SARS-CoV-2; this finding could imply a different therapeutic approach of the two settings. Thrombosis may also occur in subjects vaccinated against SARS-CoV-2 even if its incidence is not so high (1/100 000); this rare effect occurs more prevalently in young women, is independent from known risk factors of thrombosis, is caused by antibodies against platelet PF4 and is counteracted by treatment with immunoglobulin and glucocorticoids.

Blood clotting parameters in revision knee replacement patients with aseptic instability and periprosthetic infection

Введение. Представляет интерес оценка адаптационных возможностей системы гемостаза у пациентов, поступающих для ревизионного эндопротезирования коленного сустава, с использованием теста генерации тромбина (ТГТ). Цель исследования: оценить на основании ТГТ дооперационное состояние системы гемокоагуляции у больных, поступивших для ревизионного эндопротезирования коленного сустава по поводу асептической нестабильности протеза или перипротезной инфекции. Материалы и методы. Пациенты с воспалительными осложнениями, поступившие для ревизионного эндопротезирования коленного сустава, были разделены на 2 группы: 28 человек с асептическим воспалением и 24 с инфекционным. По результатам ТГТ в каждой группе были выделены подгруппы: пациенты с адекватной реакцией и пациенты с напряжённой реакцией системы гемостаза (всего 4 подгруппы). О состоянии плазменного гемостаза судили по тестам скрининговой коагулограммы. Активность воспаления оценивали по уровням С-реактивного белка (СРБ) и фибриногена. Результаты. Показано, что в каждой из 4 подгрупп больных адаптационные возможности системы гемокоагуляции различны. Выявлены наиболее угрожаемые по развитию тромбогеморрагических осложнений пациенты — это больные (подгруппы 3 и 4) с парадоксальной реакцией процесса тромбинообразования. Влияние воспалительного процесса на развитие гиперкоагуляционного синдрома у пациентов подгруппы 4 подтверждает наличие корреляционных связей между параметрами ТГТ и СРБ. Заключение. Анализ полученных данных показал различные адаптационные возможности системы гемостаза у пациентов с воспалительными осложнениями, развившимися после эндопротезирования коленного сустава. Background. The assessment of adaptive abilities of blood clotting system using thrombin generation assay (TGA) in revision knee replacement patients is a promising issue for researching. Objectives: to assess pre-surgical condition of blood clotting system using TGA in patients admitted for revision knee replacement due to prosthesis aseptic instability or periprosthetic infection. Patients/Methods. Patients with progressing inflammatory complications admitted for revision knee replacement were divided into two groups: 28 patients with aseptic inflammation and 24 patients with infectious inflammation. Based on TGA findings these groups were divided into subgroups: patients with adequate reaction and those with expressed hemostasis reactions (total of four groups). Plasma hemostasis was assessed by screening coagulogram tests. Inflammation severity was assessed by C-reactive protein (CRP) and fibrinogen levels. Results. It has been demonstrated that patients of these four groups had different adaptive abilities of their blood clotting systems. The most threatened patents for thrombohemorrhagic complications were found in groups 3 and 4 with their responses of thrombin generation process being paradoxical. The impact of inflammation on hypercoagulable syndrome in patients of group 4 proved correlations between TGA and CRP. Conclusions. Analysis of the data obtained revealed the diversity of adaptive abilities of hemostasis in patients with inflammation complications after total knee replacement.

The main pathogenetic mechanisms of hypercoagulation in diabetes and the possibility of its drug correction

Disorders in the blood coagulation system play an important role in the development of cardiovascular pathology in diabetes. Factors that cause them are hyperglycemia, insulin deficiency, insulin resistance, dyslipidemia, oxidative stress. The most significant changes are observed in the vascular-platelet link of hemostasis. Diabetes is characterized by morphological and functional changes in the endothelium of blood vessels. The activity of platelets increases, which is manifested by their high level of spontaneous aggregation and increased sensitivity to the action of activating factors. The role in the disturbance of hemostasis is played by increasing the activity of the von Willebrand factor, reflecting damage to endothelial cells. Diabetes is characterized by an increase in the activity of plasma clotting factors (I, II, III, VII, VIII, IX, XI, XII and XIII), activation of the callicrein-kinin system. In some cases, this correlates with the development of complications of diabetes. Characteristic disorders in the coagulation inhibition system are a decrease in the activity of antithrombin III, reduced formation of thrombin-antithrombin complexes, reduction of thrombomodulin and protein C. In diabetes, there is a decrease in fibrinolysis, due to a decrease in the expression of tissue activator plasminogen and an increase in the level of the inhibitor of the activator plasminogen. The possibilities of drug correction of hypercoagulation factors in diabetes are to achieve glycemic control with sugar-reducing drugs and elimination of dyslipidemia through hypolipidemic therapy. The most well-studied sugar-lowering drug that improves the state of the blood clotting system is metformin. The system of hemostasis in diabetic patients is positively affected by statins both due to the direct hypolipidemic effect, and by improving endothelial function and increasing fibrinolysis.

Innocent blood

Haemorrhages occurring in the newborn without trauma have been observed by obstetricians since the 17th century, but were considered different diseases depending on their location. Umbilical haemorrhage associated with obstructed bile canals was described by Cheyne in 1802. Grandidier in 1871 and Townsend in 1894 grouped together various forms of neonatal bleeds and associated them with disturbed coagulation. When the clotting system became better understood in the last decade of the 19th century, effective symptomatic treatment was developed: gelatine, serum injection, and the transfusion of fresh blood. In 1935, Dam detected the function of vitamin K in the coagulation system and 4 years later, Waddell introduced vitamin K administration into therapy and prevention of neonatal haemorrhagic disease. When high doses of synthetic water-soluble vitamin K analogues were given to preterm infants, kernicterus occurred, reminding physicians that progress in neonatal therapy rests on the cornerstones of controlled trials and follow-up.

The influences of selected clotting and fibrinolysis factors on survival of patients with kidney tumors – a prospective study

IntroductionMultiple studies suggest cancer leads to activation of clotting and fibrinolysis pathways, elevating the risk of thromboembolic events. Kidney cancer is often complicated by clotting disorders. In this study, hypothesize preoperative clotting and fibrinolysis parameters are altered in healthy volunteers and kidney tumor patients. We also hypothesize these differences may be associated with survival in patients who have undergone operations due to kidney tumors.Material and methodsIn this study, 96 patients with kidney tumors and 30 healthy volunteers were recruited at single university center. All patients were assessed for pre-operative serum concentrations of tissue factor (TF), tissue factor pathway inhibitor (TFPI, total TFPI, full-length TFPI, truncated TFPI), plasmin-antiplasmin complex (PAP), thrombin-antithrombin complex (TAT), von Willebrand factor (vWF), clotting factor XIII A1 (FXIIIA1), D-dimers, and fibrinogen. Additionally, standard peripheral blood morphology was evaluated.ResultsMalignant kidney tumors were diagnosed in 85 of 96 tumor patients. In patients with kidney tumors, there were statistically higher concentration of fibrinogen, D-dimers, TAT, PAF, TF, TFPI, vWF, FXIIIA1, and leukocyte counts compared to control group. There were statistically significant correlations visible between multiple parameters. This points to significant clotting system alterations. Cox stepwise hazard analysis showed that pre-operative fibrinogen and D-Dimer concentrations were significantly associated with survival.ConclusionsIn patients with kidney tumors, multiple clotting and fibrinolysis parameters are significantly altered. Routine pre-operative measures should include determination of fibrinogen and D-dimers concentrations as these markers aid in prediction of survival probability.

Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.

Prospects for the use of prolonged concentrates of blood clotting factor IX in the treatment of hemophilia B

Hemophilia B is a hereditary disease of the blood clotting system caused by a deficiency or molecular abnormalities of blood clotting factor IX. The main method of treatment is intravenous administration of coagulation factor IX concentrates. To optimize treatment and increase patient adherence to therapy, concentrates with a prolonged half-life have been developed.

Microparticles of blood cells in patients with COVID-19 as a marker of hemostasis activation

Введение. Наблюдения за больными COVID-19 показали развитие коагулопатии на фоне тяжелой инфекции, вызванной SARC–CoV-2. Патогенетические механизмы влияния SARC–CoV-2 на систему гемостаза в настоящее время активно исследуются, однако для практического здравоохранения крайне актуальным является поиск маркеров активации системы свертывания крови с целью ранней профилактики тромбоэмболических осложнений у пациентов с COVID-19. Цель исследования: определить количество микрочастиц, отделяющихся от клеток крови, у больных COVID-19 и здоровых индивидуумов и проанализировать корреляцию числа микрочастиц с лабораторными и клиническими характеристиками пациентов. Материалы и методы. Обследованы 10 пациентов с COVID-19, госпитализированных в ФГБОУ ВО СЗГМУ им. И. И. Мечникова Минздрава России в период июнь-июль 2020 г., контрольную группу составили 12 сотрудников ФГБОУ ВО СЗГМУ им. И.И. Мечникова Минздрава России без признаков острого респираторного заболевания, без сердечно-сосудистых и тромбоэмболических эпизодов в анамнезе. У всех обследованных выполнен клинический анализ крови, исследованы маркеры активации и воспаления, а также измерено количество внеклеточных микровезикул — экзосом на проточном цитометре. Результаты. У пациентов с COVID-19 по сравнению с контрольной группой наблюдалось увеличение относительного количества нейтрофилов и снижение тромбоцитов. Такие маркеры как фибриноген, С-реактивный белок, ферритин, интерлейкин-6 и лактатдегидрогеназа значительно превышали верхнюю границу референтных значений. При этом количество экзосом оказалось значимо выше у пациентов с COVID-19 по сравнению со здоровыми лицами (% позитивных событий) — 93,2 [88,7–96,5] против 56,2 [50,5–73,5] соответственно (p = 0,00001) и коррелировало с относительным уровнем нейтрофилов. Среди проанализированных экзосом преобладали микрочастицы тромбоцитарного и лейкоцитарного происхождения. Заключение. Увеличение количества внеклеточных микрочастиц у больных COVID-19 может быть использовано как маркер активации гемостаза и повышенного риска тромботических осложнений на фоне инфекционного заболевания. Background. The monitoring of COVID-19 patients showed the development of coagulopathy in the context of severe infection caused by SARC–CoV-2. The pathogenetic mechanisms of SARC–CoV-2 influence on hemostasis are currently being actively examined, but the search for markers of the blood-clotting system activation for early prevention of thromboembolic complications in patients with COVID-19 is highly relevant for the practical health care. Objectives: to analyze the number of microparticles that separate from blood cells due to the hemostasis activation in COVID-19 patients and in healthy donors and to analyze the correlation between microparticles number and laboratory and clinical characteristics of patients. Patients /Methods. The study included 10 patients with COVID-19 who were hospitalized in Mechnikov North- Western State Medical University in June- July 2020; the control group consisted of 12 employees of Mechnikov North- Western State Medical University without signs of acute respiratory disease, without cardiovascular and thromboembolic episodes in the history. All patients and individuals in the control group had their blood clinically tested on a 5-Diff hematological analyzer, markers for activation and inflammation were examined, and the number of extracellular microvesicles (exosomes) was measured on the flow cytometer. Results. Patients with COVID-19 had an increase in the relative amount of neutrophiles and a decrease in platelets compared to controls. Markers such as fibrinogen, C-reactive protein, ferritin, interleukine-6 and lactate dehydrogenase significantly exceeded the upper reference limit. The number of exosomes was significantly higher in patients with COVID-19 compared to healthy controls (% of positive events) — 93.2 [88.7–96.5] vs. 56.2 [50.5–73.5] respectively (p = 0.00001), and correlated with the relative level of neutrophiles. Among the exosomes analyzed, platelet and leukocyte microparticles prevailed. Conclusions. The increase of extracellular microparticles in COVID-19 patients can be used as a marker of hemostasis activation and increased risk of thrombotic complications in the context of severe infectious disease.