Predictors of Thrombogenicity and Development of Endotheliitis in Patients With Сovid-19 — Associated Cardiac and Vascular Surgical Pathology in the Acute and Post-Covid Periods

Abstract

Summary. Purpose: to identify early immunoinflammatory predictors of the development of disorders of the hemostasis system (coagulation, anticoagulation, and fibrinolysis) in patients with urgent cardiac and vascular surgical pathology in the conditions of joining the SARS-Cov-2 viral infection and in the long term after infection.
 The results. For patients with COVID-19, a characteristic excessive long-term activation of the complement system was revealed, which is manifested by an increase in the level of C3 and C4 components (in the acute period of Covid-19, the level of the C3 component of complement was increased by 83 % and 157 %, respectively, for patients with vascular and cardiac pathology, and the level of the C4 component in these groups exceeded the reference level by 96 % and 124 %, respectively). It was shown that the content of C-reactive protein significantly exceeded the reference level in the acute period of Covid-19 in vascular pathology by 22.7 times, in cardiac pathology by 10.6 times, in the post-covid period this ratio was maintained, namely, in vascular pathology in 26.6 times, with cardiac pathology 15.5 times, that is, in vascular pathology, C-reactive protein was always increased significantly more than in cardiac. Thrombocytopenia, detected in all groups, especially in the acute period of SARS-Cov-2 infection, (vascular pathology — a decrease in the number of platelets by 2 times or by 50 %, cardiac pathology — by 15 %), (vascular pathology in the post-covid period — a decrease by 38 %, cardiac pathology — a decrease of 22.7 %), due to the activation of platelets due to increased thrombin formation and subsequent clearance by the reticulo-endothelial system, activation of thrombus formation and consumption coagulopathy, direct viral-platelet interaction, interaction with immune complexes (antigen + antibody + complement), clearance of platelets due to pronounced endotheliitis in main and capillary vessels. Excessive activation of the complement system along with a significant increase in the content of CRP has a prognostic value for the duration and severity of immunoinflammatory reactions and clinically expressed complications in the distant post-covid period against the background of surgical pathology. A significantly increased concentration of IL-6 in vascular pathology was revealed in the acute period of viral infection by 27.7 times, in the post-viral period by 24.4 times. In cardiac pathology, the concentration of IL-6 was significantly increased in the acute period by 2.5 times, and in the post-epidemic period by 3.2 times due to pro-compensatory and adaptive reactions against the background of suppression of the adhesive and absorbing properties of phagocytic neutrophils. A significant increase in the concentration of IL-18 in the blood serum of all examined patients in the acute period was found: in vascular pathology by 24.6 %, in heart pathology by 70 %, indicating long-term activation of macrophages. Different degrees of increase in complement components and cytokines in the acute period of Covid-19 infection and in the post-covid period may indicate the predominance of one or another inflammatory mechanism in vascular and cardiac pathology. In 100 % of patients with vascular pathology in the acute period, a 79-fold increase in procalcitonin was observed, in the post-covid period — in 50 %, a significant increase of 42 times, with cardiac pathology in the acute period — in 50 % - 43 times, in the post-covid period — in 58 % by 46 times, which indicated the formation of a spectrum of cytotoxic molecules when a bacterial infection occurred and required antibiotic therapy. A significant increase in the concentration of fibrinogen, fibrin, and soluble fibrin-monomeric complexes (FSMC) was observed in all examined groups of patients in all periods. It was proved that the activity of thrombus formation was 4.6 times more pronounced in vascular pathology in the acute period, while in cardiac pathology it was 2 times more pronounced, and in the postoperative period in vascular pathology it was 2.3 times, in cardiac pathology it was 1,8 times. For the first time, it was found that in all examined groups of patients, the concentration of the native physiological anticoagulant antithrombin III was reduced, and this was most pronounced in the group of cardiac pathology in the post-covid period than in vascular, therefore, in cardiac pathology, the anticoagulant properties were the most lost, perhaps even due to not only dependent on viral infection, but also genomic predictors. The change in another link of the hemostasis system indicated the activation of fibrinolysis at the first stage, namely, a significant increase in the concentration of D-dimers in all types of pathology as in acute (vascular pathology — 4.2-fold increase, cardiac pathology — 2.7-fold), and in the post-epidemic periods (vascular pathology — 7.7 times, cardiac pathology — 2.4 times), while it is most pronounced in the group of cardiac pathology in the acute viral period.
 Against the background of a significant increase in the content of IL-6 both in the acute and in the remote period after infection with SARS-Cov-2, in 100 % of patients with cardiac pathology, fibrinolytic activity was significantly reduced in connection with the inhibited activity of plasminogen due to the inhibition of the activity of this pro-inflammatory interleukin activator plasminogen. A decrease in the concentration of plasminogen in all examined groups of patients by 18-29.5 % indicated the phenomenon of consumption of plasminogen for the formation of plasmin during the preliminary activation of fibrinolysis against the background of an actual increase in the concentration of fibrin. Possible clinical consequences of a decrease in the concentration of the native physiological anticoagulant antithrombin III and plasminogen in the acute period of SARS-Cov-2 infection and the post-covid period are a decrease in anticoagulant activity, a threat of thrombus formation, a decrease in fibrinolytic activity, and in combination with an increase in the concentration of fibrin, fibrinogen, soluble fibrin monomers complexes and D-dimers — the threat of DIC-syndrome formation. Hemostasiological markers of DIC in the hypercoagulable phase were detected in 6 patients, namely, in the acute period of SARS-Cov-2 infection in 2 patients with cardiac pathology and 1 patient with vascular pathology, in the post-COVID period in 2 patients with cardiac pathology and in 1 patient with abdominal pathology. DIC in the hypocoagulation phase was not detected in any patient. Therefore, the immune-inflammatory reaction to the SARS-CoV-2 viral infection leads to a noticeable activation of coagulation — the process of thrombosis — with signs of systemic endothelial inflammatory damage, namely — endotheliitis, and the subsequent loss of the physiological properties of the endothelium. The general thing, as a rule, is the presence of common patterns, which are manifested in the fact that the SARS-Cov-2 virus interacts with complement proteins and endothelial cells and platelets, which causes an inflammatory reaction in all organs and systems.
 Conclusions.
 1. Immunopathological mechanisms formed against the background of the interaction of SARS-Cov-2 proteins with endothelial cells and proteins of the complement system, which form membrane-attacking complexes, lead to violations of the structural and functional organization of endothelial cells in both main and capillary vessels, which leads to pathologies of various organs and pathologies of the hemostasis system.
 2. Thus, the processes occurring in the endothelium are characterized by inflammatory changes that cause activation of the plasma link of hemostasis, which includes coagulation, anticoagulation, and fibrinolysis factors, activation of the complement protein system, changes in the function of platelets and their interaction with endothelial cells, which in various combinations indicate risk of thrombogenicity or DIC.
 3. The revealed regularities of the interaction of factors of innate immunity and the SARS-Cov-2 virus, which contribute to the development of a long-term immunoinflammatory reaction in the form of endotheliitis, require personalized treatment for comorbid conditions, taking into account changes in indicators of immunoresistance and the hemostasis system.