COVID-19-associated Coagulopathy Characterization using Rotational Thromboelastometry in a Prospective, Observational Cohort Study: The HemoCoV Study.

INTRODUCTION: COVID-19-associated coagulopathy includes systemic and endothelial inflammation with coagulation dysregulation related to immunothrombosis. The aim of this study was to characterize this complication of SARS-CoV-2 infection in patients with moderate to severe COVID-19. METHODS: An open-label, prospective observational study conducted in patients with COVID-19 moderate to severe acute respiratory failure admitted to an intensive care unit (ICU). Coagulation testing, including thromboelastometry, biochemical analysis and clinical variables, were collected at prespecified time points during the 30 days of ICU stay. RESULTS: The study included 145 patients, 73.8% male, with a median age of 68 years (interquartile range - IQR 55 - 74). The most prevalent comorbidities were arterial hypertension (63.4%), obesity (44.1%) and diabetes (22.1%). Simplified acute physiology score II (SAPS II) was on average 43.5 (11 - 105) and sequential organ failure assessment (SOFA) at admission was 7.5 (0 - 14). During ICU stay, 66.9% of patients underwent invasive mechanical ventilation and 18.4% extracorporeal membrane oxygenation support; thrombotic and hemorrhagic events occurred in 22.1% and 15.1% of the patients respectively; anticoagulation with heparin was present in 99.2% of patients since early ICU stay. Death occurred in 35% of patients. Longitudinal studies revealed changes in almost all coagulation tests during the ICU stay. SOFA score, lymphocyte counts, some biochemical, inflammatory and coagulation parameters, including hypercoagulability and hypofibrinolysis seen in thromboelastometry, differed significantly (p < 0.05), between ICU admission and discharge. Hypercoagulability and hypofibrinolysis persisted throughout ICU hospitalization, showing higher incidence and severity in non-survivors. CONCLUSION: COVID-19-associated coagulopathy is characterized by hypercoagulability and hypofibrinolysis from ICU admission, and persisted throughout the clinical course in severe COVID-19. These changes were more pronounced in patients with higher disease burden and in non-survivors.

Pharmacogenetic profile of a South Portuguese population: results from the pilot study of the European Health Examination Survey in Portugal.

BACKGROUND: The genetic inter-individual variability of drug response can lead to therapeutic failure or adverse drug reactions (ADRs). The aims of this study were to assess the pharmacogenetic profile of a South Portuguese population according to established dosing guidelines for commonly prescribed drugs and to compare it with that of previously genotyped populations. METHODS: A cross-sectional study was developed in the context of the Portuguese Component of the European Health Examination Survey (EHES). A total of 47 pharmacogenetically relevant variants in 23 different genes were genotyped in 208 participants. Allelic and genotypic frequencies were calculated, and the pharmacogenetic profile of the participants was defined. A comparative analysis was conducted through electronic database search. Pairwise Fst calculations were performed to assess the genetic distance between populations. RESULTS: We found a significant small differentiation between the Portuguese regional populations regarding CYP2C9 rs1057910, CYP2D6 rs3892097, MTHFR rs1801133 and F5 rs6025. When consid-ering 4 HapMap populations, ADH1B rs2066702, ADH1B rs1229984, NAT2 rs1799931 and VKORC1 rs9923231 displayed a significant population differentiation. We found that 18.9% of the participants are intermediate or poor metabolizers for at least 3 drugs simultaneously and that 84.6% of the participants have at least one therapeutic failure or ADR risk allele for the considered drugs. CONCLUSIONS: There is a high prevalence of risk alleles associated with an altered drug metabolism regarding drugs largely used by the South Portuguese population. This knowledge contributes to the prediction of their clinical efficacy and/or toxicity, optimizing therapeutic response while improving cost-effectiveness.

Genetic variation at the CYP2C19 gene associated with metabolic syndrome susceptibility in a South Portuguese population: results from the pilot study of the European Health Examination Survey in Portugal.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of conditions that occur together, increasing the risk of heart disease, stroke and diabetes. Since pathways implicated in different diseases reveal surprising insights into shared genetic bases underlying apparently unrelated traits, we hypothesize that there are common genetic components involved in the clustering of MetS traits. With the aim of identifying these common genetic components, we have performed a genetic association study by integrating MetS traits in a continuous MetS score. METHODS: A cross-sectional study developed in the context of the Portuguese Component of the European Health Examination Survey (EHES) was used. Data was collected through a detailed questionnaire and physical examination. Blood samples were collected and biochemical analyses were performed. Waist circumference, blood pressure, glucose, triglycerides and high density lipoprotein cholesterol (HDL) levels were used to compute a continuous MetS score, obtained by Principal Component Analysis. A total of 37 single nucleotide polymorphisms (SNPs) were genotyped and individually tested for association with the score, adjusting for confounding variables. RESULTS: A total of 206 individuals were studied. Calculated MetS score increased progressively with increasing number of risk factors (P < 0.001). We found a significant association between CYP2C19 rs4244285 and the MetS score not detected using the MetS dichotomic approach. Individuals with the A allelic variant seem to be protected against MetS, displaying a lower MetS score (Mean difference: 0.847; 95%CI: 0.163-1.531; P = 0.015), after adjustment for age, gender, smoking status, excessive alcohol consumption and physical inactivity. An additive genetic effect of GABRA2 rs279871, NPY rs16147 and TPMT rs1142345 in the MetS score variation was also found. CONCLUSIONS: This is the first report of a genetic association study using a continuous MetS score. The significant association found between the CYP2C19 polymorphism and the MetS score but not with the individual associated traits, emphasizes the importance of lipid metabolism in a MetS common etiological pathway and consequently on the clustering of different cardiovascular risk factors. Despite the sample size limitation of our study, this strategy can be useful to find genetic factors involved in the etiology of other disorders that are defined in a dichotomized way.