Molecular Pathogenesis of COVID-19: The Role of Genetic, Hemostatic, and Immunological Factors in the Progression of Severe Cases, Development of Coagulopathies, and Long COVID.
Name: DANIELLE RIBEIRO CAMPOS DA SILVA
Publication date: 21/03/2025
Examining board:
Name |
Role |
|---|---|
| ALESSANDRA NUNES LOUREIRO PREZOTTI | Examinador Externo |
| DEBORA DUMMER MEIRA | Coorientador |
| FAUSTO EDMUNDO LIMA PEREIRA | Examinador Externo |
| FLAVIA DE PAULA | Examinador Interno |
| IURI DRUMOND LOURO | Presidente |
Pages
Summary: Introduction: The inflammatory process triggered by SARS-CoV-2 infection leads to abnormal activation of the coagulation system, pathologically manifesting as generalized small-vessel vasculitis and microthrombosis in the alveolar region. Following the pandemic, persistent symptoms and sequelae, collectively referred to as "Long COVID," have frequently been associated with this infection, often negatively impacting individuals' daily activities. Investigating hemostatic, inflammatory, immunological, and genetic or acquired factors influencing hyperinflammation, endothelial dysfunction, and hypoxia is crucial for predicting outcomes in COVID-19 survivors. This study aimed to correlate potential biomarker and gene alterations with the progression of severe COVID-19 and the development of sequelae characteristic of Long COVID. Objective: To investigate molecular and genetic alterations in the hemostatic and inflammatory systems, ABO blood type, and the presence of acquired antibodies in patients testing positive for COVID-19, as well as their association with disease severity, potential thrombotic complications, and the development of Long COVID. Methods: A total of 226 unvaccinated volunteers (considering two doses) with RT-PCR-confirmed COVID-19 were recruited between November 2020 and December 2021. The cohort was divided into three groups: Mild (60), Moderate (65), and Severe (101), following WHO classification. Participants signed informed consent forms, completed a questionnaire, and provided blood samples for analysis. The questionnaire assessed significant pre-existing clinical conditions, medical record data, symptoms, and the occurrence of sequelae. Assays were conducted to evaluate thrombosis, blood typing, hemostatic/inflammatory biomarkers, and genotyping. Participants with results outside reference ranges were re-evaluated after six months. After two years, participants completed a follow-up questionnaire focusing on Long COVID and quality of life. Statistical tests were applied to analyze the data. Results: The severity of COVID-19 was significantly associated with sociodemographic and biomarker data. Key findings include: age (P<0.0001), lower educational level (P<0.0001), ethnicity (P=0.003), overweight (P<0.0001), MTHFR rs1801133 polymorphism (P=0.035), pre-existing cardiovascular diseases (P=0.002), Diabetes Mellitus (DM) (P=0.006), Factor VIII (FVIII) (P=0.046), von Willebrand Factor (vWF) (P=0.0020), and D-dimer (DD) (P<0.0001). After six months, FVIII (P=0.0005), vWF (P=0.0022), and DD (P<0.0001) significantly decreased, with only DD returning to normal levels. Sequelae affecting the musculoskeletal, cardiorespiratory, and vascular systems were investigated. Chronic pulmonary diseases (CPD) and DM increased the likelihood of joint pain and myalgia, while CPD was linked to dyspnea and palpitations. Elevated DD levels were associated with palpitations, and prolonged dry cough was related to lower educational attainment and non-white ethnicity. Women had higher odds of developing phlebitis. FVIII was linked to a higher risk of cramps, while regular physical activity was protective against swelling. The EQ-5D-5L questionnaire evaluated participants' current quality of life, revealing greater impairments in all domains among those with severe COVID-19. The findings suggest that endothelial dysfunction, as indicated by altered biochemical data, may contribute to Long COVID.
