The endothelium is the main target of coronavirus infection

Background. The world currently has a wealth of clinical experience in the treatment of SARS-Co-2. However, more and more work is emerging that opens up new data on the manifestations of this viral disease and its consequences, which can affect both the change in its clinical picture and the quality of life of patients with COVID-19. Therefore, this work was aimed to summarize the results of literature research and our experience of intensive care of endothelial dysfunction in coronavirus infection. Material and methods. The work is based on the results of a study on the Internet search engines Google and PubMed, with the keywords: intensive care SARS-CoV-2, pathophysiological changes in coronavirus in- fection, endothelial dysfunction. Results. This review presents the pathogenetic links of COVID-19, mechanisms of viral endothelial damage, mechanisms of hypercoagulopathy, the main directions of prevention and treatment of endothelial dysfunction. Conclusions. The examination convincingly showed that SARS-CoV-2 infection promotes the development of endotheliitis in various organs as a result of viral infection. The presence of COVID-19-induced endotheliitis can explain the systemic microcirculation disorders in various vascular channels and their clinical consequences. © 2022. The Authors.

Economic aspects of COVID-19 treatment in a hospital setting

In April 2020 in order to prevent the spread of the new coronavirus infection COVID-19 on the territory of the Russian Federation, strict quarantine measures were introduced. In the shortest possible time, a large number of general hospitals were repurposed into COVID hospitals, recommendations were issued on the management of patients with a new coronavirus infection based on the existing global experience. The limited resources of the healthcare system in a pandemic require research into the pharmacoeconomic aspects of COVID-19. In the course of the study, a continuous retrospective analysis of the case histories of 6255 patients admitted to the Central Clinical Hospital RZD-Medicine was carried out. During the study period, 22% of patients received biological therapy. The average mortality rate of patients on biological therapy is 11.6%. An individual selection of the therapeutic dose of low molecular weight heparins was carried out, which showed high clinical efficacy. The developed methods were assessed from the perspective of pharmacoeconomics. The increase in the degree of damage to the lung tissue in patients with COVID-19, as well as the presence of concomitant diseases, entails an increase in the cost of treatment. Biotherapy can reduce the cost of treating patients with CT-4 by 16% by reducing the length of stay in the intensive care unit, the need for mechanical ventilation and reducing mortality.Copyright © 2021 Infectious Diseases: News, Opinions, Training. All rights reserved.

APTT vs AntiХa: Concept Substitution when Monitoring Low-Molecular-Weight Heparin Therapy

Purpose. To compare diagnostic capabilities of antiXa and activated partial thromboplastin time (APTT) in monitoring low-molecular-weight heparin therapy. Materials and methods. To achieve the purpose of the study, a retrospective analysis of clinical and laboratory data of 20 patients who were hospitalized at the State Institution "Republican Clinical Medical Center" of the Administration of the President of the Republic of Belarus from September to December 2021 was carried out. The collection of laboratory data was carried out at the stage of hospitalization of patients with COVID-19 infection in inpatient departments. A total of 89 coagulograms were evaluated, including the levels of APTT, RAPTT and antiXa. Data are presented as median and interquartile range Me (Q1:Q3), mean and standard deviation (M±SD), and minimum (MIN) and maximum (MAX) values. Statistical analysis was performed using SPSS Statistics (IBM, USA) and Excel 2016 (Microsoft, USA) software packages. The level of statistical significance of the tests was determined by p<0.05. Results. Statistical analysis of coagulograms revealed that the mean and median values of aPTT did not reach the reference values being 32.89±9.65 sec and 30.1 (27.55;34.7), respectively. RAPTT in most samples did not reach the value of 1.5, and in 75% tests its level was less than 1.1. Linear regression analysis revealed that for coagulograms groups with antiXa levels ranging from 0.5 to 1.0 IU/ml and more than 1.0 IU/ml there was no linear relationship between APTT and antiXa values: the coefficients of determination R2 of the obtained prediction models were 0.0036 and 0.0649 respectively. At the same time, a linear regression model was obtained for the group of tests with antiXa levels up to 0.5 IU/ml, successfully predicting the results of coagulogram values in 38% of tests, indicating a closer relationship between aPTT and antiXa at low ranges of the latter, but the relation strength between values was not sufficient to reason about the high identity between the tests. Conclusion. Today we can say that the determination of the level of antiXa is an effective method for monitoring therapy with low molecular weight heparins. Although the APTT is a cheap and readily available test that is commonly used to monitor the use of unfractionated heparin, it cannot adequately control the target dosage of low molecular weight heparins. To date, it is reasonable to assume that the determination of antiXa levels is an effective method for monitoring low-molecular-weight heparin therapy. Although APTT is a low-cost and readily available test commonly used to monitor unfractionated heparin administration, it cannot provide adequate control of the target dosage of low-molecular-weight heparin. © 2022, Professionalnye Izdaniya. All rights reserved.

Intensive-Dose Tinzaparin in Hospitalized COVID-19 Patients: The INTERACT Study.

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). (2) INTERACT is a retrospective, phase IV, observational cohort study aiming to evaluate the overall clinical effectiveness and safety of a higher than conventionally used prophylactic dose of anticoagulation with tinzaparin administered for VTE prevention in non-critically ill COVID-19 patients with moderate disease severity. (3) Results: A total of 705 patients from 13 hospitals in Greece participated in the study (55% men, median age 62 years). Anticoagulation with tinzaparin was initiated immediately after admission. A full therapeutic dose was received by 36.3% of the participants (mean ± SD 166 ± 33 IU/Kgr/day) and the remaining patients (63.9%) received an intermediate dose (mean ± SD 114 ± 22 IU/Kgr/day). The median treatment duration was 13 days (Q1-Q3: 8-20 days). During the study (April 2020 to November 2021), 14 thrombotic events (2.0%) were diagnosed (i.e., three cases of pulmonary embolism (PE) and 11 cases of deep venous thrombosis, DVT). Four bleeding events were recorded (0.6%). In-hospital death occurred in 12 patients (1.7%). Thrombosis was associated with increasing age (median: 74.5 years, Q1-Q3: 62-79, for patients with thrombosis vs. 61.9 years, Q1-Q3: 49-72, p = 0.0149), increased D-dimer levels for all three evaluation time points (at admission: 2490, Q1-Q3: 1580-6480 vs. 700, Q1-Q3: 400-1475, p < 0.0001), one week ± two days after admission (3510, Q1-Q3: 1458-9500 vs. 619, Q1-Q3: 352-1054.5, p < 0.0001), as well as upon discharge (1618.5, Q1-Q3: 1010-2255 vs. 500, Q1-Q3: 294-918, p < 0.0001). Clinical and laboratory improvement was affirmed by decreasing D-dimer and CRP levels, increasing platelet numbers and oxygen saturation measurements, and a drop in the World Health Organization (WHO) progression scale. (4) Conclusions: The findings of our study are in favor of prophylactic anticoagulation with an intermediate to full therapeutic dose of tinzaparin among non-critically ill patients hospitalized with COVID-19.

Spontaneous Hematomas and Deep Vein Thrombosis during the Recovery from a SARS-CoV-2 Infection: Case Report and Literature Review.

Background: The frequent occurrence of thromboembolic events in patients infected with the severe acute respiratory syndrome CoV2 (SARS-CoV-2) virus is a well-recognized fact in the medical literature, but less data is available about possible hemorrhagic incidents. Methods: We report the case of a 76-year-old patient who suffered from a mild COVID-19 infection in September 2021 and after four weeks, experienced a completely spontaneous popliteal hematoma followed by deep vein thrombosis (DVT). Therapy with low molecular weight heparins (LMWH) was started, but subsequently, the patient developed a massive sub-pectoral and calf hematoma leading to moderate post-hemorrhagic anemia and acute kidney injury. This patient was treated completely conservatively. Conclusions: Considering the continuous spread of the infection with various, continuously evolving strains of this virus and the extended use of LWMH in clinical practice, such cases were seldom described in the medical literature, but should be considered as a potential cause for hemorrhagic events.

Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans.

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.

Hypoxia may be a determinative factor in COVID-19 progression.

The disease which develops following SARS-CoV-2 virus infection, known as COVID-19, in most affected countries displays mortality from 1.5% to 9.8%. When leukocytosis due to granulocytosis, thrombocytopenia, and increased level of D-dimers are detected early during the disease course, they are accurate predictors of mortality. Based on the published observations that each of the aforementioned disturbances by itself may appear as a consequence of hypoxia, a hypothesis is presented that early hypoxia consequential to sleep apnea and/or blunted respiratory response to chemical stimuli is an early determinant of COVID-19 progression to the severe and critical stage. Further, it is noted that host-directed therapies which may counteract hypoxia and its early downstream effects are initiated only upon hospitalization of COVID-19 patients, which is too late to be fully effective. An example is anticoagulation treatment with low molecular weight heparin. Repurposing drugs which could counteract some early posthypoxic events, such as fluvoxamine, amantadine and N-acetylcysteine, for post-exposure prophylaxis of SARS-CoV-2 infection and early prehospital treatment of COVID-19, is indicated.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Treatment for COVID-19: An overview.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by coronavirus-2 (SARS-CoV-2) that causes a severe acute respiratory syndrome, a characteristic hyperinflammatory response, vascular damage, microangiopathy, angiogenesis and widespread thrombosis. Four stages of COVID-19 have been identified: the first stage is characterised by upper respiratory tract infection; the second by the onset of dyspnoea and pneumonia; the third by a worsening clinical scenario dominated by a cytokine storm and the consequent hyperinflammatory state; and the fourth by death or recovery. Currently, no treatment can act specifically against the SARS-CoV-2 infection. Based on the pathological features and different clinical phases of COVID-19, particularly in patients with moderate to severe COVID-19, the classes of drugs used are antiviral agents, inflammation inhibitors/antirheumatic drugs, low molecular weight heparins, plasma, and hyperimmune immunoglobulins. During this emergency period of the COVID-19 outbreak, clinical researchers are using and testing a variety of possible treatments. Based on these premises, this review aims to discuss the most updated pharmacological treatments to effectively act against the SARS-CoV-2 infection and support researchers and clinicians in relation to any current and future developments in curing COVID-19 patients.