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Background/Aim. Coagulation Factor II G20210A and Factor V G1691A variants are moderately associated with coronary artery disease. Polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene C677T is associated with myocardial infarction (MI) in some ethnical groups. At the present time there are rare studies which try to differentiate two forms of MI, ST-elevation MI (STEMI) and non ST-elevation MI (NSTEMI) according to the genetic background. The aim of the study was investigate the association of polymorphisms of Factor II G20210A, Factor V G1691A and MTHFR C677T with different forms of MI: STEMI and NSTEMI. Methods. The study included 82 patients, divided into two cohorts: patients with STEMI (49 patients) and NSTEMI (33 patients). Genetic factors that would be different in those two entities, included in response to plaque rupture and occlusion of coronary artery, were examined. The peripheral blood lymphocytes were used as DNA source. Genotypes were determined on the polymerase chain reaction (PCR) based methodology. Results. The frequency of MTHFR C677T CT genotype was higher in the patients with NSTEMI in comparison with the patients with STEMI [odds ratio (OR) 3.33; 95% confidence interval (CI) 1.22?9.15; p = 0.02]. Logistic regression analysis shows MTHFR CT genotype as an independent prognostic factor for development of NSTEMI (OR 3.15; 95% CI 1.20?8.29; p = 0.02). There were no differences between two patients groups in frequency of Factor II G20210A and Factor V G1691A gene polymorphism. Conclusion. MTHFR C677T CT genotype was significantly associated with the NSTEMI development examined patients.

Thrombophilia may be anticipated by single or combined hereditary defects in encoding genes factor V, Prothrombin, and MTHFR. The aim of this study was to determine the prevalence and associated risks of V Leiden (G1691A), Prothrombin (G20210A), and MTHFR (C677T) mutations in Saudi women with Deep Vein Thrombosis (DVT) and women with recurrent pregnancy loss (RPL). Protein C and protein S activity were measured to determine combined effects, if any. We examined 60 women with a history of DVT and 60 with RPL, extracted DNA from EDTA blood and determined three mutations by using multiplex PCR reactions followed by Strip Assay KIT. Pro C Global assay was used to determine the cutoff value [PCATNR = 0.80]. Protein C/S chromogenic assay was used to estimate protein C and S percentages. Frequency of Factor V Leiden G/A genotype in patients with DVT 7 (11.6%) had a significant association for DVT χ2 (OR = 5.1, P = 0.03). In women with RPL the three mutations did not show any significant association, levels of Protein C, protein S and PCAT-NR in patient groups not different from controls (P > 0.05). In conclusion, we recommend expanding on these data to provide larger-scale studies.

Background: Ischemic stroke (IS) is a complex multifactorial and polygenic disease. Studies on association between Factor V G1691A gene polymorphism and ischemic stroke have shown conflicting results. To address this issue, we conducted a meta-analysis to determine the precise role of Factor V gene polymorphism with risk of ischemic stroke Materials and Methods: We searched electronic databases PubMed, Trip Data Base, Medline, EMBASE and Google Scholar (last search dated March 2017). Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Results: Forty case-control studies fulfilled our inclusion criteria comprising 6860 patients and 18025 controls. 19 studies were conducted in young adults (mean age < or = 40 years), 17 studies were conducted in the subjects with old onset of stroke (mean age > 40) years and 5 studies did not report the mean age at recruitment. The significant associations between Factor V G1691A gene polymorphism and risk of ischemic stroke were observed in dominant model (odds ratio [OR] 1.40; 95% CI:1.22 to 1.62, P-value = 40 years). Across all the included studies, Factor V heterozygous state was observed in 423 of 6860 cases (6.1%) and 1069 of 18025 controls (5.9%), yielding a fixed effect odds ratio of 1.40 (95% CI: 1.22 to 1.62). Conclusion: Factor V G1691A genetic polymorphism was associated with risk of ischemic stroke mainly in young adults. Further prospective studies are needed to validate these findings. Keywords: Factor V gene polymorphism, Meta-analysis,Ischemic stroke, Cardiovascular Disorder, Stroke

WOS: 000297962900009, PubMed ID: 27264588, Objective: The aim of this study was to examine Factor V G1691A (Leiden) (FVL) and prothrombin G20210A (PT) gene mutation status, and their relationship with thrombosis in patients with chronic myeloproliferative disorders (CMPDs). Materials and Methods: The study included 160 patients with a CMPD that were regularly followed-up between 1993 and 2009. FVL and PT mutation status was established based on blood samples analyzed via PCR using specific primers. Results: The frequency of FVL and PT mutation was 12.5% and 4.4%, respectively. In total, 27 episodes of thrombosis occurred in 24 (15%) of the patients, and there wasn't an association between the observed thrombotic events, and FVL or PT mutations. Hepatic vein thrombosis was noted in 3 patients that had FVL mutation, of which 1 also had PT mutation. Conclusion: We did not observe a relationship between thrombosis, and FVL or PT mutations in CMPD patients; however, 3 of the patients that had hepatic vein thrombosis also had FVL mutation. Larger studies are needed to more clearly determine if all CMPD patients with hepatic vein thrombosis need be investigated for FVL and PT mutation. (Turk J Hematol 2011; 28: 306-11)

Atherosclerosis, the major cause of coronary artery disease (CAD), has a very long asymptomatic development phase, which begins in childhood. In this study, we describe the factor V G1691A, factor V H1299R and prothrombin G20210A gene polymorphisms in children with a family history of premature CAD. Evidence of these polymorphisms in these children may predict the probability of having atherosclerosis in the future. Our study included a total of 140 children, 72 males and 68 females between the ages of 4.9 and 15.7 years. Among these children, 73 had a parental history of premature CAD and the remaining 67 belonged to our control group. The participants were screened for the mutations factor V G1691A, factor V H1299R and prothrombin G20210A by polymerase chain reaction amplified DNA products with specific oligonucleotide probes. Our results suggested that frequencies of the mutated allele of factor V G1691A and prothrombin G20210A are higher in children with a parental history of premature CAD. In conclusion, factor V G1691A and prothrombin G20210A polymorphisms which were detected in higher frequencies in children with a parental history of premature CAD may indicate a risk for developing atherosclerosis and might be useful in screening for CAD in children; however, large population-based research is necessary to investigate further genetic risk assessment for CAD.

OBJECTIVE To investigate the association of two common prothrombotic mutations, factor V G1691A (FV G1691A) and prothrombin G20210A (PT G20210A), in neonates with thrombosis. METHODS Twenty-six neonates with thrombosis were assessed with the spectrum of assays for thrombophilia, including the two DNA-based prothrombotic factors. RESULTS Eight patients (31%) had the FV G1691A mutation in heterozygous state. PT G20210A mutation was detected in four patients (15%). Overall, two common prothrombotic factors were detected in 12 neonates (46%) and an underlying disease or a triggering event in 18 neonates (69%). Thrombosis was considered to be idiopathic in five neonates (19%). CONCLUSIONS The pathogenesis of thrombosis in neonates is multi-factorial. Along with underlying diseases or triggering events, congenital prothrombotic factors (FV G1691A and PT G20210A) showed a trend toward a higher frequency in neonates with thrombosis. These data indicate that mutations associated with underlying disorders in neonates may contribute to the development of thromboembolic disease.

Intravascular coagulation is considered a major pathogenetic mechanism for nontraumatic osteonecrosis. The aim of our study was to evaluate the association of thrombophilic factor V G1691A mutation (factor V Leiden) and G20210A prothrombin mutation with the disease. Mutation presence was investigate

WOS: 000314289700012 Objectives: The aim of our study was to evaluate the possible roles of factor V Leiden, prothrombin G20120A mutations, factor XIIIA and B, methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C and apolipoprotein (Apo) E polymorphisms in the development of coronary artery disease (CAD). Methods: A total of 442 subjects (234 CAD and 208 non-CAD) were included in the study according to their coronary angiography. Polymerase chain reaction (PCR), real-time PCR and restriction enzyme analysis (REA) were carried out in the study. Results: Logistic regression analysis showed that when the biochemical variables and genetic risk factors were placed in a model, the most important variables were smoking, alcohol, Diabetes Mellitus (DM), factor V G1691A, MTHFR A1298C, factor XIIIA Val34Leu and XIIIB His95Arg. We showed that smoking, DM, factor V G1691A, MTHFR A1298C increased the risk of CAD 3.19, 2.27, 3.32, 1.97-fold, respectively. On the other hand, alcohol, factor XIIIA Val34Leu and XIIIB His95Arg decreased the risk of CAD 0.44, 0.46 and 0.17-fold, respectively. Apo E polymorphisms were not found important statistically in our study. Conclusions: It is concluded that presence of Leu allele at factor XIIIA Val34Leu and Arg allele at factor XIIIB His95Arg is protective against CAD. In addition, Factor V G1691A mutation, MTHFR 1298 AC genotype could have an important role in the progression of CAD. Research Foundation of Cukurova UniversityCukurova University [SBE-02YL17] We thank Dr. Ilker Unal for expert assistance in statistical analysis. This study was supported by the Research Foundation of Cukurova University (SBE-02YL17).

Single point mutations in the genes coding for factor V [G1691A; Leiden], prothrombin [PRT; G20210A], and methylenetetrahydrofolate reductase [MTHFR, C677T] were shown to be major inherited predisposing factors for venous thromboembolism. However, their contribution in the development of coronary artery disease [CAD] remains controversial. The aim of the study was to examine the association of these mutations in CAD.A total of 96 patients with angiographically-demonstrated CAD [mean age 55.3 +/- 11.3], and 404 healthy subjects [mean age 50.7 +/- 8.9] were recruited into the study. Fasting plasma homocysteine was determined by HPLC, and genotype analysis was assessed by PCR-RFLP.The carrier frequency of factor V-Leiden (14.6% vs. 15.1%, p = 0.617) and PRT G20210A (3.1% vs. 3.0%; p = 0.936) were similar between patients and controls, respectively. In contrast, the frequency of the MTHFR variant C677T was 71.9% among patients compared with 45.5% in controls (p0.001), of which the T/T genotype was significantly higher among patients (31.3%) than controls (4.5%; p0.001). Significantly higher homocysteine levels were seen among T/T genotype in both groups compared to non-T/T carriers (p0.05), and among patients compared with controls (18.47 +/- 3.73 micromol/L vs. 16.28 +/- 4.16 micromol/L). In addition, the coexistence of MTHFR C677T with FV-Leiden was seen in 10.4% of CAD patients compared 6.9% of controls (p = 0.001).While results from this study clearly demonstrate a strong association of hyperhomocysteinemia and homozygosity of the MTHFR C677T, but not FV-Leiden or PRT G20210A, mutations with confirmed CAD, they also suggest a potential role for factor V-Leiden in MTHFR C677T carriers.

Two G-to-A mutations at positions 1691 of the factor V (FV) gene and 20210 of the prothrombin (FII) gene have been associated with an increased risk of venous thromboembolism. We report a thrombosis-prone family in which one subject – the propositus who exhibited combined heterozygous FV G1691A and FII G20210A mutations – showed spontaneous and early clinical onset (at 23 years), recurrences of deep-vein thrombosis and pulmonary embolism. His asymptomatic father carried the FII G20210A substitution and his mother, characterized by an isolated thrombotic episode on occasion of surgery (at 48 years), carried the FV G1691A substitution. In the maternal lineage, one of the propositus’ uncles had thrombosis on occasion of a bone fracture (at 65 years) despite the absence of known prothrombotic defects. A sister of the propositus carried the FII G20210A and the brother the FV G1691A mutation. They have been asymptomatic until now. The propositus’ two children, 20 and 16 years old, both carry the FV G1691A substitution and have been asymptomatic until now. The plasma levels of FII were higher in carriers of the FII G20210A allele if compared with noncarriers, and the activated protein C resistance phenotype, associated with the FV Leiden mutation, showed a complete correlation with the FV G1691A mutation. Despite the very limited number of thrombotic cases involved in this survey, which does not allow statistically sound conclusions, the data obtained from this family suggest that the synergy of inherited factors and transient risk conditions could play a key role in the occurrence of thrombotic accidents.

Abstract 2234 It has been reported that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V (FV) G1691A mutation and that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors, namely the FV or the factor II (FII) G20210A variant, is significantly later in life than in non-carriers. Until today many factors, such as a positive family history, the use of recombinant FVIII [rFVIII] concentrates, or high dose FVIII administration, are included as potential risk factors for inhibitor development. The present non-concurrent Israeli-German database study was performed to investigate the impact of FV and FII mutations on clinical meaningful inhibitor development (outcome variable) in patients with severe HA. 272 patients with HA < 1% consecutively ascertained from Israel (n=88) and four different German catchment areas (n=184) born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. To avoid family cluster effects [inhibitor; IT] in both countries only the first HA patient who presented for diagnosis at the treatment center was included in the present study. From the entire cohort 80% were tested for thrombophilia [IT]. 32 of 216 children (14.8%) carried either the FV or the FII variant. During the follow-up period of 200 exposure days 54 of 216 (26%) developed a clinical meaningful inhibitor: 14 out of 32 carriers of IT (44%) compared with 40 of 184 (22%) without IT [Hazard ratio [HR]/95% confidence intervals [CIs] 2.1/1.16–3.9]. In addition, univariate Cox regression analysis for patients treated with rFVIII products compared with plasma-derived [pdFVIII] showed a significant increased risk for inhibitor development [HR/CI: 2.1/1.3–3.6]. Multivariate analysis adjusted for patient's individual median single FVIII dose, administered during the first three months, first-line use of pdFVIII (n=82) versus rFVIII concentrations (n=134) and treatment periods [1980–2011] revealed that the presence of IT independently increases the risk of inhibitor development to a hazard of 2.5 [CI: 1.1–5.8]. In addition, the increase of FVIII per one IU/kgbw was significantly associated with the risk to develop a high responding inhibitor [HR/CI: 1.2/1.04–1.1]. In multivariate analysis neither rFVIII products, nor treatment periods showed a statistically significant influence on clinical important inhibitor development. Data presented here suggest that clinical meaningful inhibitor development is of multifactorial origin and that apart from a positive family history also FV and FII mutations should be included in the aetiology research. Disclosures: No relevant conflicts of interest to declare.

Prevalence of Two Thrombophilia Predisposing Mutations: Factor V G1691A (R506Q; Leiden) and Prothrombin G20210A, among Healthy Lebanese

It has been recently shown that the first bleeding onset in children with severe hemophilia A (HA) carrying prothrombotic risk factors is significantly later in life than in non-carriers.1 The present multicenter study was performed to determine whether the factor (F) V G1691A or the F II G20210A are associated with decreased annual bleeding episodes (ABE) in 106 pediatric PUP patients with severe HA (Intron 22 58.6%) consecutively admitted to German pediatric hemophilia treatment centers. Treatment was initiated according to the frequency of bleedings, and most patients received on demand therapy with a switch over to prophylactic therapy 3x/week (40–60 IU/kgKG factor VIIII concentrate) when more than three bleedings (range 2–6) had occurred into the same joint (n=49). Prospective median(range) patient follow-up was 14(4–35) years. Heterozygosity of the FV mutation was found in 8 subjects, homozygosity in one, and 5 children carried the FII mutation once combined with protein C-deficiency. Carriers of the FV and FII mutations had significantly fewer ABE than non-carriers (p=0.004). 66 of 106 PUP patients developed at least one target joint with a median(range) Pettersson score of 1(0–12) available in 57 patients clearly dependent on age (p=0.039) as well as ABE (p=0.037). The “Nuss” joint score available in 33 subjects highly correlated with the Pettersson score (p=0.007). Data presented here give evidence that the clinical expression of severe HA in children is influenced by the co-expression of the FV and FII mutation.

Factor V G1691A, apo E4 Allele, Hyperhomocysteinemia and MTHFR C677T in a Young Patient with Myocardial Infarction