Assessment of Factor VIII Activity and D-Dimer Levels in the Post-COVID Period.

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.

Factor VIII Activity in Relation to the Type of Thrombosis and Patient's Risk Factors for Thrombosis, Age, and Comorbidity.

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.

Interactions of the eNOS and ACE genes and cigarette smoking in chronic obstructive pulmonary disease.

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.

Thrombosis risk assessment in patients with congenital thrombophilia during COVID - 19 infection.

BACKGROUND: Coagulation dysfunction represents a serious complication in patients during the COVID-19 infection, while fulminant thrombotic complications emerge as critical issues in individuals with severe COVID-19. In addition to a severe clinical presentation, comorbidities and age significantly contribute to the development of thrombotic complications in this disease. However, there is very little data on association of congenital thrombophilia and thrombotic events in the setting of COVID-19. Our study aimed to evaluate the risk of COVID-19 associated thrombosis in patients with congenital thrombophilia. METHODS: This prospective, case-control study included patients with confirmed COVID-19 infection, followed 6 months post-confirmation. The final outcome was a symptomatic thrombotic event. In total, 90 COVID-19 patients, 30 with known congenital thrombophilia and 60 patients without thrombophilia within the period July 2020-November 2021, were included in the study. Evaluation of hemostatic parameters including FVIII activity and D-dimer was performed for all patients at 1 month, 3 months and 6 months post-COVID-19 diagnosis. RESULTS: Symptomatic thrombotic events were observed in 7 out of 30 (23 %) COVID-19 patients with thrombophilia, and 12 out of 60 (20 %) without thrombophilia, P = 0.715. In addition, the two patient groups had comparable localization of thrombotic events, time to thrombotic event, effect of antithrombotic treatment and changes in FVIII activity, while D-dimer level were significantly increased in patients without thrombophilia. CONCLUSION: Our findings suggest that patients with congenital thrombophilia, irrespective of their age, a mild clinical picture and absence of comorbidities, should receive anticoagulant prophylaxis, adjusted based on the specific genetic defect.

D-dimer, CRP, PCT, and IL-6 Levels at Admission to ICU Can Predict In-Hospital Mortality in Patients with COVID-19 Pneumonia.

INTRODUCTION: Health care workers have had a challenging task since the COVID-19 outbreak. Prompt and effective predictors of clinical outcomes are crucial to recognize potentially critically ill patients and improve the management of COVID-19 patients. The aim of this study was to identify potential predictors of clinical outcomes in critically ill COVID-19 patients. METHODS: The study was designed as a retrospective cohort study, which included 318 patients treated from June 2020 to January 2021 in the Intensive Care Unit (ICU) of the Clinical Hospital Center "Bezanijska Kosa" in Belgrade, Serbia. The verified diagnosis of COVID-19 disease, patients over 18 years of age, and the hospitalization in ICU were the criteria for inclusion in the study. The optimal cutoff value of D-dimer, CRP, IL-6, and PCT for predicting hospital mortality was determined using the ROC curve, while the Kaplan-Meier method and log-rank test were used to assess survival. RESULTS: The study included 318 patients: 219 (68.9%) were male and 99 (31.1%) female. The median age of patients was 69 (60-77) years. During the treatment, 195 (61.3%) patients died, thereof 130 male (66.7%) and 65 female (33.3%). 123 (38.7%) patients were discharged from hospital treatment. The cutoff value of IL-6 for in-hospital death prediction was 74.98 pg/mL (Sn 69.7%, Sp 62.7%); cutoff value of CRP was 81 mg/L (Sn 60.7%, Sp 60%); cutoff value of procalcitonin was 0.56 ng/mL (Sn 81.1%, Sp 76%); and cutoff value of D-dimer was 760 ng/mL FEU (Sn 63.4%, Sp 57.1%). IL-6 ≥ 74.98 pg/mL, CRP ≥ 81 mg/L, PCT ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL were statistically significant predictors of in-hospital mortality. CONCLUSION: IL-6 ≥ 74.98 pg/mL, CRP values ≥ 81 mg/L, procalcitonin ≥ 0.56 ng/mL, and D-dimer ≥ 760 ng/mL could effectively predict in-hospital mortality in COVID-19 patients.

Phosphatidylserine Exposing Extracellular Vesicles in Pre-eclamptic Patients.

Background: Pre-eclampsia (P-EC) is associated with systemic inflammation, endothelial dysfunction and hypercoagulability. The role of extracellular vesicles (EVs) in coagulation disturbances affecting the development and severity of P-EC remains elusive. We aimed to evaluate the concentration of EVs expressing phosphatidylserine (PS) and specific markers in relation to the thrombin and fibrin formation as well as fibrin clot properties, in pregnant women with P-EC in comparison to healthy pregnant women of similar gestational age. Methods: Blood samples of 30 pregnant women diagnosed with P-EC were collected on the morning following admission to hospital and after delivery (mean duration 5 days). The concentration of the PS-exposing EVs (PS+ EVs) from platelets (CD42a+, endothelial cells (CD62E+), and PS+ EVs expressing tissue factor (TF) and vascular cell adhesion molecule 1 (VCAM-1) were measured by flow cytometry. Further phenotyping of EVs also included expression of PlGF. Markers of maternal haemostasis were correlated with EVs concentration in plasma. Results: Preeclamptic pregnancy was associated with significantly higher plasma levels of PS+ CD42a+ EVs and PS+ VCAM-1+ EVs in comparison with normotensive pregnancy. P-EC patients after delivery had markedly elevated concentration of PS+ CD42a+ EVs, CD62E+ EVs, TF+ EVs, and VCAM-1+ EVs compared to those before delivery. Inverse correlation was observed between EVs concentrations (PS+, PS+ TF+, and PlGF+) and parameters of overall haemostatic potential (OHP) and fibrin formation, while PS+ VCAM-1+ EVs directly correlated with FVIII activity in plasma. Conclusion: Increased levels of PS+ EVs subpopulations in P-EC and their association with global haemostatic parameters, as well as with fibrin clot properties may suggest EVs involvement in intravascular fibrin deposition leading to subsequent microcirculation disorders.

Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry.

STUDY QUESTION: What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes? SUMMARY ANSWER: Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA). WHAT IS KNOWN ALREADY: Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity. STUDY DESIGN, SIZE, DURATION: Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider's current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4-6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0-22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7-7.9). LIMITATIONS, REASONS FOR CAUTION: While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding. WIDER IMPLICATIONS OF THE FINDINGS: Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: NCT02385461.

Evaluation of global haemostatic assays and fibrin structure in patients with pre-eclampsia.

INTRODUCTION: Haemostatic balance shifted towards hypercoagulability in normal pregnancy is even more pronounced in pre-eclampsia (P-EC). The aim of this study was to analyse haemostatic disturbances and fibrin clot properties in women with pre-eclampsia and to investigate their association with maternal and foetal outcomes. METHODS: Forty-six pregnant women diagnosed with pre-eclampsia were included in the study, with blood sampling done on the morning following admission to hospital, as well as after delivery (mean duration 4.8 days). Two global haemostatic assays-endogenous thrombin potential (ETP) and assay of overall haemostatic potential (OHP)-were employed, including fibrin clot turbidity measurements and scanning electron microscopy (SEM) of representative samples. RESULTS: Three thrombin generation parameters (ETP, t_lag and peak height) and OHP were significantly increased in pre-eclampsia compared with controls, whereas overall fibrinolytic potential (OFP-determined as a parameter of the OHP assay) had significantly lower values. Clot lysis time was significantly prolonged in patients with pre-eclampsia. In the pre-eclamptic group after delivery, we observed a significant elevation in the peak height and a reduction in the time to peak and OFP compared with values before delivery. Pre-eclamptic patients with renal complications had significantly higher values for ETP, peak height and D-dimer. Turbidity measurements and SEM revealed dense fibrin structure in patients with pre-eclampsia. CONCLUSION: Patients with pre-eclampsia have enhanced coagulation and impaired fibrinolysis before, and even after, delivery. In particular, the presence of multi-organ dysfunction, such as renal dysfunction, may be associated with increased thrombin generation in pre-eclampsia.

The Silence Speaks, but We Do Not Listen: Synonymous c.1824C>T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor.

BACKGROUND: Thrombosis is a major global disease burden with almost 60% of cases related to underlying heredity and most cases still idiopathic. Synonymous single nucleotide polymorphisms (sSNPs) are considered silent and phenotypically neutral. Our previous study revealed a novel synonymous FII c.1824C>T variant as a potential risk factor for pregnancy loss, but it has not yet been associated with thrombotic diseases. METHODS: To determine the frequency of the FII c.1824C>T variant we have sequenced patients' DNA. Prothrombin RNA expression was measured by quantitative PCR. Functional analyses included routine hemostasis tests, western blotting and ELISA to determine prothrombin levels in plasma, and global hemostasis assays for thrombin and fibrin generation in carriers of the FII c.1824C>T variant. Scanning electron microscopy was used to examine the structure of fibrin clots. RESULTS: Frequency of the FII c.1824C>T variant was significantly increased in patients with venous thromboembolism and cerebrovascular insult. Examination in vitro demonstrated increased expression of prothrombin mRNA in FII c.1824T transfected cells. Our ex vivo study of FII c.1824C>T carriers showed that the presence of this variant was associated with hyperprothrombinemia, hypofibrinolysis, and formation of densely packed fibrin clots resistant to fibrinolysis. CONCLUSION: Our data indicate that FII c.1824C>T, although a synonymous variant, leads to the development of a prothrombotic phenotype and could represent a new prothrombotic risk factor. As a silent variant, FII c.1824C>T would probably be overlooked during genetic screening, and our results show that it could not be detected in routine laboratory tests.

Rationale and design of two prospective, multicenter, observational studies on reproductive outcome in women with recurrent failures after spontaneous or assisted conception: OTTILIA and FIRST registries.

BACKGROUND: Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences. Although 50-60% of all cases remains unexplained, various predisposing factors, including thrombophilias, have been identified. Thus, the potential benefit of a prophylaxis with low-molecular-weight heparins in improving outcomes has been often investigated over the years. However, the majority of studies are observational and results from randomized clinical trials (RCTs) are inconclusive, probably due to heterogeneity and limited sample size. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we designed these multicenter registries. METHODS: OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss) and FIRST (recurrent Failures in assIsted Reproductive Techniques) registries are two prospective, multicenter, observational studies to evaluate pregnancy or ART outcomes in consecutive women with previous reproductive failures after spontaneous or assisted conception, respectively. All enrolled women are observed from their first visit after positive pregnancy test (OTTILIA) or before commencing a new ART cycle (FIRST) until the end of pregnancy or ART procedure (negative pregnancy test/end of pregnancy, if successful cycle), respectively. Data are collected by means of questionnaires and recorded in a central database. Follow-up investigations are performed during hospital stay, routine clinical follow-up visits or telephone interviews. Primary outcome is live birth rate in the OTTILIA register and clinical pregnancy rate in the FIRST. DISCUSSION: Although RCTs are the 'gold standard' for evaluating treatment outcomes, we believe that our registries represent a valid alternative in improving knowledge on mechanisms involved in reproductive failures and supporting future clinical decisions. TRIAL REGISTRATION: NCT02385461 , retrospectively registered 5 March 2015 (OTTILIA); NCT02685800 , registered 10 February 2016 (FIRST).

Genotype phenotype correlation in a pediatric population with antithrombin deficiency.

Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the AT gene (SERPINC1). Considering that the genotype phenotype relationship in AT deficiency patients remains unclear, especially in pediatric patients, the aim of our study was to evaluate genotype phenotype correlation in a Serbian pediatric population. A retrospective cohort study included 19 children younger than 18 years, from 15 Serbian families, with newly diagnosed AT deficiency. In 21% of the recruited families, mutations affecting exon 4, 5, and 6 of the SERPINC1 gene that causes type I AT deficiency were detected. In the remaining families, the mutation in exon 2 causing type II HBS (AT Budapest 3) was found. Thrombosis events were observed in 1 (33%) of those with type I, 11 (85%) of those with AT Budapest 3 in the homozygous respectively, and 1(33%) in the heterozygous form. Recurrent thrombosis was observed only in AT Budapest 3 in the homozygous form, in 27% during initial treatment of the first thrombotic event. Abdominal venous thrombosis and arterial ischemic stroke, observed in almost half of the children from the group with AT Budapest 3 in the homozygous form, were unprovoked in all cases.Conclusion: Type II HBS (AT Budapest 3) in the homozygous form is a strong risk factor for arterial and venous thrombosis in pediatric patients. What is Known: • Inherited AT deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1gene. • The genotype phenotype correlation in AT deficiency patients remains unclear, especially in pediatric patients. What is New: • The genetic results for our paediatric population predominantly showed the presence of a single specific mutation in exon 2, that causes type II HBS deficiency (AT Budapest 3). • In this group thrombosis mostly occurred as unprovoked, in almost half of them as abdominal thrombosis or stroke with high incidence of recurrent thrombosis, in 27% during initial treatment.

The influence of specific mutations in the AT gene (SERPINC1) on the type of pregnancy related complications.

BACKGROUND: Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1 gene. The most common clinical presentation in AT deficient patients includes venous thrombosis and pulmonary embolism, while the association of AT deficiency and its effect on the development of pregnancy complications has been less studied. The aim of our research was to evaluate the effect of AT deficiency types, determined by genotyping, on pregnancy outcomes. METHODS: A retrospective cohort study included 28 women with AT deficiency, and their 64 pregnancies were analyzed. RESULTS: With regard to live birth rate, a significant difference was observed among women who were carriers of different SERPINC1 mutations, as the rate varied from 100% in cases of type I to the extremely low rate of 8% for women with type II HBS (AT Budapest 3) in the homozygous variant, P = 0.0005. All pregnancies from the type I group, even untreated ones, resulted in live births. In women with AT Budapest 3 in homozygous variant the overall live birth rate increased to 28.5% in the treated pregnancies. In this group the highest incidence of fetal death was observed of 62%; repeated fetal losses in 30%; fetal growth restriction in 22% and placental abruption in 7% of all pregnancies. CONCLUSION: Our study results indicate a difference between type I and type II AT deficiency. The risk of pregnancy related VTE was equally present in both groups, except for AT Budapest 3 in the heterozygous variant, while adverse pregnancy outcomes were strictly related to type II, especially AT Budapest 3 in the homozygous variant.

Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center.

INTRODUCTION: Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays. PATIENTS AND METHODS: Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored. RESULTS: Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I. CONCLUSION: Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.

Are Prothrombotic Mutations a Time-to-Event Risk Factor?

BACKGROUND: Deep vein thrombosis (DVT) represents a common disorder involving genetic and acquired risk factors. It has been proposed that acquired risk factors are more important with aging than genetic factors, indicating different prevalence of prothrombotic mutations throughout the lifespan. OBJECTIVE: To determine the role of the most frequent prothrombotic genetic risk factors (Factor V [FV] Leiden and Factor II [FII] G20210A mutations) in first-time DVT etiology in patients of different ages. METHOD: This retrospective study included 701 patients living in Serbia with diagnosed DVT as a first-time thrombotic event. RESULTS: Risk assessment for mutations as age-related markers showed no statistical difference (FV Leiden mutation-OR, 1.027; 95% confidence interval [CI], .87-1.22; P = .76 and FII G20210A mutation-OR, 0.940, 95% CI, .74-1.19; P = .61). Our results show similar mutation prevalence regardless of how old the patients were at the time of the first DVT occurrence. CONCLUSION: Our results indicate that these 2 mutations cannot be used as prognostic marker for time-to-event first DVT in the Serbian population; however, further studies are required.

Early onset of abdominal venous thrombosis in a newborn with homozygous type II heparin-binding site antithrombin deficiency.

: The overall incidence of thromboembolic events in the neonatal period is 5 per 100 000 births, wherein more than 40% of all such manifestations are symptomatic renal vein thromboses. We describe the case of a newborn female who developed extensive thrombosis, which filled the inferior vena cava and renal vein and was diagnosed in the first weeks of life. A homozygous type II heparin-binding site antithrombin deficiency (c. 391C>T, p. Leu131Phe) was detected in the background. Despite the timely diagnosis and appropriate treatment, clinical signs of renal insufficiency, because of left kidney atrophy and arterial hypertension, were observed. Our case demonstrates the seriousness of the consequences arising after early onset of venous thrombosis caused by homozygous type II heparin-binding site antithrombin deficiency. In addition to prompt diagnosis, of huge importance is the determination of inherited thrombophilia, as it significantly affects therapeutic treatment and indicates that long-term follow-up is mandatory.

Clopidogrel High On-Treatment Platelet Reactivity in Patients with Carotid Artery Stenosis Undergoing Endarterectomy. A Pilot Study.

OBJECTIVES: A considerable number of patients do not achieve an adequate response to clopidogrel. Our study aimed to evaluate genetic and non-genetic factors as possible risks for clopidogrel high on-treatment platelet reactivity (HTPR) in patients (n=112) with carotid artery stenosis undergoing endarterectomy (CEA). METHODS: Using multiple-electrode impedance aggregometry (MEA) the antiplatelet effectiveness of clopidogrel was measured after 24 h, 7 and 30 days of clopidogrel treatment, which was introduced after elective CEA at a dose of 75 mg daily, for at least 30 days. RESULTS: HTPR was observed among 25% patients after clopidogrel therapy for 30 days. Further analysis showed that 53.3% of patients carrying the CYP2C19*2 gene variant had clopidogrel-HTPR, while in the wild type group there were 14.6% (p<0.001). Multivariate logistic regression analysis identified the CYP2C19*2 variant allele (OR 4.384; 95% CI 1.296-14.833, p=0.017) and high total cholesterol level (OR 2.090; 95% CI 1.263-3.459, p=0.004) as the only independent risk factors for clopidogrel-HTPR. CONCLUSION: The CYP2C19*2 gene variant and high total cholesterol level were major factors for clopidogrel- HTPR in patients with carotid artery stenosis undergoing CEA.