Mirjana Kovac

Trauma is defined as an injury caused by external mechanical forces ranging from physical, chemical, biochemical, or physchological. The Injury Severity Score (ISS) is established on the Abbreviated Injury Scale (AIS). Advanced Trauma Life Support (ATLS) contains basic procedures for securing the airway, establishing and maintaining hemodynamic stability, and adequately assessing injuries based on diagnostic tests. The damage control strategy is a multidisciplinary approach to the polytraumatized patient, including Damage control resuscitation and Damage control surgery. In the emergency room management of a polytraumatized patient, several critical steps are taken to guarantee comprehensive care: all clothing and jewelry are removed from the patient, monitoring devices are placed, circulatory status is evaluated, blood typing and cross-matching are done, and possibly, the transfusion of blood and blood products is initiated. The Initial Hemorrhage Management Steps are: controlling the bleed source, maintaining permissive hypotension and adequate fluid resuscitation, providing coagulation support and treating/reversing trauma-induced coagulopathy. Supportive perfusion therapy provides maintenance of adequate pH, which, together with maintaining body temperature above 36℃. The shift to directed therapy based on standard coagulation tests and point-of-care methods (viscoelastic haemostatic assays), should be done as soon as possible. Substitution therapy is selected with the aim to correct the identified hemostasis disorder associated with trauma.

Coumarin derivatives (coumarins) are widely used for the treatment and prevention of thrombotic disorders; however, their clinical use remains challenging due to substantial interindividual variability in therapeutic response. This variability is largely attributable to genetic variation in genes involved in the pharmacodynamics (VKORC1 and CYP4F2) and pharmacokinetics (CYP2C9) of coumarins. The contribution of these factors differs among ethnic groups which justifies conducting population-specific studies. In Serbia, no data are currently available regarding the relevance of the CYP4F2 c.1297G>A variant. However, based on the literature, the c.1297A allele has been associated with increased coumarin dose requirements. The aim of this study was to obtain preliminary data on the frequency of the CYP4F2 c.1297G>A variant in the general Serbian population and to evaluate its potential relevance for pharmacogenetic research. Genomic DNA was isolated from peripheral blood lymphocytes of 50 unrelated individuals (29 females and 21 males; mean age 55 ± 4.5 years). Genotyping was performed using a TaqMan allelic discrimination assay. Twenty carriers of the c.1297A allele were identified (14 heterozygotes and 6 homozygotes), corresponding to a carrier frequency of 40%. The allele frequency was 26%, consistent with the average reported in European populations (27%). This frequency was lower than that observed in North America and Central and South Asia (40%), higher than in East Asia (23%), and markedly higher than in sub-Saharan Africa (9%) and Afro-Caribbean populations (7%). These findings support the inclusion of the c.1297G>A variant in pharmacogenetic studies and suggest its potential value in optimizing personalized coumarin therapy.

Changes in the hemostatic system during COVID infection lead to hypercoagulability. Numerous studies have evaluated hemostatic abnormalities in COVID patients during acute infection, in the period of hospitalization. However, the hemostatic status following hospital discharge has not been sufficiently assessed. Considering the importance of FVIII and D-dimer levels as markers for the assessment of thrombosis, our study aimed to evaluate changes in these markers, as well as the influence of patient's age and clinical presentation of COVID infection on those hemostatic markers in the post-COVID phase. This prospective study (July 2020 to December 2022) included 115 COVID patients, 68 (59%) with asymptomatic/mild and 47 (41%) with moderate/severe clinical presentation. Patient follow-up included laboratory evaluation of FVIII and D-dimer levels at 1, 3, and 6 months following the COVID infection. Three months after the COVID infection, elevated FVIII was recorded in 44% of younger versus 65% of older individuals, p = 0.05, respectively, and 30 versus 57% (p = 0.008) 6 months post–COVID infection. With a focus on clinical presentation, a higher number of patients with moderate/severe COVID had elevated FVIII activity, but a statistically significant difference was observed only for the 6 months (32% mild vs. 53% moderate/severe, p = 0.041) post-infection time point. Following a COVID infection, an increase in FVIII activity suggests a continued hypercoagulable state in the post-COVID period and correlates with elevated D-dimer levels. This increase in FVIII is more pronounced in patients with moderate/severe clinical picture and those patients older than 50 years.

Introduction/research objective: COVID-19 coagulopathy is a disorder of the hemostatic system that occurs in critically ill patients infected with the SARS-CoV 2 virus and it increases the risk of mortality. The goal of the research is to evaluate changes in hemostatic parameters and determine their prognostic significance in patients with a severe form of the COVID-19 disease. Methods: The study was designed as a retrospective cohort study, which included 146 patients treated from June to September 2020 in the Intensive Care Unit (ICU) of the Clinical Hospital Center "Bežanijska Kosa" in Belgrade, diagnosed with COVID-19 pneumonia. Inclusion criteria were as follows: the age over 18 years, proven current SARSCoV2 infection, and admission to ICU. Results: 82 patients (56.2%) died during the treatment, while 64 (43.8%) were discharged. Significantly higher D-dimer values on admission to the ICU were recorded in subjects who died during treatment 888 (1226.5) ng/ml compared to persons who were discharged from treatment 666 (1207.3) ng/ml (p = 0.03). Differences were not demonstrated for INR, aPTT and fibrinogen. D-dimer values on admission to the ICU greater than or equal to 760ng/ml are a statistically significant predictor of death during hospitalization (p = 0.04). Conclusion: COVID coagulopathy is a complication that increases the mortality of people infected with the SARS-CoV2 virus. The main feature is a state of hypercoagulability, which is detected by elevated D-dimer values. D-dimer greater than or equal to 760 ng/ml on admission to the ICU may have prognostic significance for survival during hospitalization.

Introduction/Objective. There is very limited data regarding the need for transfusion and its effect on the overall mortality of patients with coronavirus disease 2019 (COVID-19). The aim of our study is to determine the need for blood component transfusion in patents treated for COVID-19 infection. Methods. This retrospective observational study included 4426 COVID-19-positive patients treated at the Bezanijska Kosa University Hospital Medical Center between June 23, 2020 and May 2, 2021. Of these patients, 826 were treated in the intensive care units of the hospital. Of the total number of patients, 326 (7.4%) received transfusions. The clinical presentation, the structure of the applied transfusion therapy, the laboratory parameters, and the treatment outcome were analyzed in this study. Results. Of the 828 patients treated in the intensive care units, 151 (18.2%) patients required transfusion, while transfusion was necessary in a total of 4.9% of patients treated in the hospital wards. Of the total number of all transfused patients, 86% received erythrocytes, one-third of them received fresh frozen plasma, 10% received cryoprecipitate, while platelets were administered in around 6% of the patients. The mortality rate in the tested group was 46%. Conclusion. The frequency of the application of blood components was significantly higher in patients with a severe form of the disease. The presence of comorbidities did not affect the need for transfusion therapy. In the group of patients treated in the intensive care units, 85% received erythrocytes, 39% received fresh frozen plasma, 19% received cryoprecipitate and 7% received platelets.

Objective: Elevated factor VIII has been shown to be an independent risk factor for deep venous thrombosis and pulmonary embolism. It has been suggested that increased factor VIII levels by itself is insufficient to cause thrombosis; however, increased factor VIII with other risk factors could increase the risk of thrombosis. The aim of the study was to evaluate the factor VIII level with regard to the type of thrombosis and patient’s risk factors such as age or comorbidity. Materials and Methods: In total, 441 patients who were referred for thrombophilia testing from the period of January 2010 to December 2020 were included in the study. The patients who developed the first thrombosis before the age of 50 were eligible for the study. The patients’ data that were used in statistical analyses were collected from our thrombophilia register. Results: The number of the subjects with increased factor VIII over 1.5 IU/mL is equal regardless of the thrombosis type. Factor VIII activity already begins to increase over 40 years old and reaches the mean values of 1.45 IU/mL close to the cut-off (1.5 IU/mL), showing a statistically significant difference compared to those under 40, P = .001. Comorbidities other than thyroid disease or malignancy had no influence on the increase of factor VIII. In the mentioned conditions, the average factor VIII of 1.82 (0.79) and 1.65 (0.43) was obtained, respectively. Conclusion: Factor VIII activity is significantly affected by age. Thrombosis type and comorbid diseases other than thyroid disease and malignancy had no effect on factor VIII. Cite this article as: Basaric D, Saracevic M, Bosnic V, Vlatkovic A, Tomic B, Kovac M. Factor VIII activity in relation to the type of thrombosis and patient’s risk factors for thrombosis, age and comorbidity. Eurasian J Med 2023;55(1):9-13.

Background: Chronic obstructive pulmonary disease (COPD) is a complex disorder with unexplained heritability. Interactions of genetic and environmental factors are thought to be crucial in COPD. So, we aim to examine interactions of the endothelial nitric oxide synthase (eNOS) and angiotensin converting enzyme (ACE) genes and cigarette smoking in COPD. Methods: The eNOS G 894T and ACE ID variants were analyzed in 122 COPD patients and 200 controls from Serbia. The effect of the variants on COPD was assessed by logistic regression. Interactions between eNOS, ACE and cigarette smoking in COPD were evaluated using a case-control model. Interaction between the genes was analyzed in silico. Results: No effect of the eNOS G 894T and ACE ID variants on COPD was found in our study. Gene-gene interaction between the eN OS T T and A CE D was identified (p=0.033) in COPD. The interaction is realized within the complex network of biochemical pathways. Gene-environment interactions between the eNOS T and cigarette smoking (p=0.013), and the ACE II and cigarette smoking (p=0.009) were detected in COPD in our study. Conclusions: This is the first research to reveal interactions of the eNOS and ACE genes and cigarette smoking in COPD progressing our understanding of COPD heritability and contributing to the development of appropriate treatments

Normal pregnancy associated with complex changes of hemostasis, leading to hypercoagulability states. The presence of acquired or genetic prothrombotic risk factors might affect the proper maternal-fetal circulation and result in pregnancy loss. Hence, the screening for the novel prothrombotic variants associated with pregnancy loss would be beneficial. Our aim was to investigate the potential association of recently reported c.*64_*66del variant in prothrombin gene with the etiology of pregnancy loss. Study included 105 women with pregnancy loss and 155 controls. Analyses in patients? plasma samples, as well as in vitro analyses on transfected Cos-7 cell line were performed in order to investigate the mechanism by which this variant could perturb the coagulation and lead to pregnancy loss. Analyses in patients' DNA and plasma samples involved: DNA sequencing and PCR-RFLP assay for detection of FII c.*64_*66del variant, routine thrombophilia screening, thrombin generation assay and Western blot analysis of prothrombin plasma level. In vitro analyses included transient transfections of Cos-7 cell line with wild-type and c.*64_*66del mutated constructs of pCIneo?SV40 expression vector. Real-Time PCR and Western blot analysis were used to determine the effect of FII c.*64_*66del variant on mRNA and protein level in constructs. Three women in patients group (2.9%) were detected as heterozygous carriers of FII c.*64_*66del, while none was found among controls. The carriers routine thrombophilia parameters were in reference range and similar prothrombin plasma level in FII c.*64_*66del carriers and non-carriers were detected. The endogenous thrombin potential was slightly increased in FII c.*64_*66del carriers compared to control plasma, but this difference was not statistically significant. Results of in vitro analyses showed significantly decreased prothrombin mRNA and protein level for c.*64_*66del variant compared to wild-type. Results of our pilot study have shown a trend of higher prevalence of FII c.*64_*66del variant in women with pregnancy loss. However, further studies are needed to completely elucidate whether FII c.*64_*66del variant affects prothrombin expression during pregnancy and to account its potential role in etiology of pregnancy loss.