[Morphological compound and indicators of the blood clotting system in severe COVID-19 patients of middle aged and elderly during treatment of Tocilizumab and Thymalin.]

The aim of the work was a comparative study of Tocilizumab and Thymalin effects on the morphological composition and indicators of the blood clotting system in COVID-19 of middle aged and elderly patients. Severe COVID-19 patients were divided into 3 groups: 1st - control (basic therapy), 2nd - basic therapy +Tocilizumab, 3rd - basic therapy +Thymalin. Hospital mortality in COVID-19 patients after standard therapy, Tocilizumab and Thymalin application was 40,9;28,4 and 20,6% accordingly. The number of platelets increased by 1,5 times, the concentration of fibrinogen in blood decreased by 78% and activated partial thromboplastin time decreased by 9,3% in patients taking Tocilizumab. Under the influence of Tocilizumab, the platelet/white blood cell and platelet/lymphocyte ratios increased by 1,6 and 1,4 times, which may be a predictor of an unfavorable outcome of COVID-19. Thymalin increased the number of lymphocytes and monocytes by 2 times, the number of leukocytes - by 1,3 times, the number of platelets in the blood - by 1,5 times. Thymain decreased the platelet/lymphocyte and neutrophil/lymphocyte ratios by 1,4 times and 2 times. The use of Thymalin decreased the level of fibrinogen, lactate dehydrogenase and D-dimer in the blood by 1,2;1,8 and 1,7 times, respectively. Thymalin, compared with Tocilizumab, meets the principles of pathogenic therapy for severe COVID-19 of middle aged and elderly patients to a greater extent, having a normalizing effect on the morphological composition and indicators of the blood clotting system.

The Use of Thymalin for Immunocorrection and Molecular Aspects of Biological Activity

The polypeptide drug thymalin is used for various diseases associated with immune dysfunction, viral and bacterial infections, regeneration normalization, immunodepression, and the depression of hematogenesis after chemical and radiotherapy. The molecular mechanism of the action of thymalin and its components, EW dipeptide (the drug thymogen), the dipeptide KE, and the tripeptide EDP, are analyzed. These short peptides regulate gene expression and the synthesis of heat-shock protein, cytokines, fibrinolysis, gerontogenes, and the differentiation, proliferation, apoptosis of cells. Thymalin and thymogen have practically no side effects and are used for various viral infections. These peptide drugs can likely be effective in the complex therapy for the coronavirus infection COVID-19.

Thymalin: Activation of Differentiation of Human Hematopoietic Stem Cells.

Thymalin is a polypeptide complex isolated from the thymus and regulating the functions of the immune system. Thymalin is effective in therapy of acute respiratory syndrome, chronic obstructive bronchitis, and other immunopathology. Thymalin increases functional activity of T lymphocytes, but the targeted molecular mechanism of its biological activity requires further study. We studied the influence of thymalin on differentiation of human hematopoietic stem cells (HSC) and expression of CD28 molecule involved in the implementation of antiviral immunity in COVID-19 infection. It was found that thymalin reduced the expression of CD44 (stem cell marker) and CD117 (molecule of the intermediate stage of HSC differentiation) by 2-3 times and increased the expression of CD28 (marker of mature T lymphocytes) by 6.8 times. This indirectly indicates that thymalin stimulated differentiation of CD117+ cells into mature CD28+T lymphocytes. It is known that in patients with severe COVID-19, the number of CD28+, CD4+, CD8+T lymphocytes in the blood decreased, which attested to a pronounced suppression of immunity. It is possible that the antiviral effect of thymalin consists in compensatory stimulation of HSC differentiation into CD28+T lymphocytes at the stage of immunity suppression in unfavorable course of viral infection. Thymalin can be considered as an immunoprotective peptide drug for the prevention of COVID-19.

COVID-19: Impact on Immunity, Hemostasis and Possible Methods of Correction

Summary. This review summarizes molecular aspects of pathogenesis and perspectives of coronavirus infection COVID-19 therapy. Severe forms of COVID-19 lead to immune system hyperactivation, “cytokine storm” and hemostatic system dysfunction. With COVID-19, activation of the complement cascade by its classical and lectin pathways occurs along with leukopenia, lymphocytopenia, neutrocytosis, violation of the T-lymphocytes subpopulations ratio. The patients manifest hypercoagulation, accompanied with overexpression of Tissue and von Willebrand factors on the blood vessel endothelium, enhanced platelet aggregation, increased D-dimer, and fibrinogen/fibrin degradation products. At the same time, microangiopathy, immunothrombosis and disseminated intravascular coagulation takes place. This leads to a pronounced inflammatory reaction and the development of thrombosis, accompanied by the lung tissue destruction and multiple organ failure, often fatal. Around 40% of patients with severe COVID-19 forms revealed dysfunctions of the central nervous system. Immunomodulating peptides (Thymopentin, Thymalin, Thymogen), anticoagulants and antiplatelet agents appear to be a promising solution for the correction of the immune and hemostasis systems’ dysfunction. A complex peptide drug with neuroprotective properties - Cortexin, isolated from the brain of calves, can be recommended to normalize the nervous system functions in case of COVID-19. В обзоре представлены молекулярные аспекты патогенеза и перспективы терапии коронавирусной инфекции COVID-19. При тяжелой форме COVID-19 возникает гиперактивация иммунной системы, “цитокиновый шторм”, нарушение функций системы гемостаза. При COVID-19 наблюдается активация системы комплемента по классическому и лектиновому путям, лейкопения, лимфоцитопения, нейтрофилез, нарушение соотношения субпопуляций Т-лимфоцитов. У пациентов возникает гиперкоагуляция, сопровождаемая повышением экспрессии тканевого фактора и фактора фон Виллебранда на эндотелии кровеносных сосудов, усиленной агрегацией тромбоцитов, увеличением D-димера и продуктов деградации фибриногена/фибрина. При этом развивается микроангиопатия, иммунотромбоз, диссеминированное внутрисосудистое свертывание крови. Это приводит к выраженной воспалительной реакции и развитию тромбоза, что сопровождается деструкцией ткани легких и полиорганной недостаточностью, часто приводящей к летальному исходу. У 40% пациентов с тяжелой формой COVID-19 наблюдаются нарушения функций центральной нервной системы. Перспективными препаратами для коррекции дисфункции иммунной системы и системы гемостаза являются иммуномодулирующие пептиды (тимопентин, тималин, тимоген), антикоагулянты и антиагреганты. Для нормализации функций нервной системы при COVID-19 может быть рекомендован лекарственный комплексный пептидный нейропротекторный препарат кортексин, выделенный из мозга телят.