Pregnancy complications in G20210A mutation carriers associated with high prothrombin activity.

OBJECTIVE: To study the association between high activity of Factor II (prothrombin) in blood plasma with G20210A mutation and the development of great obstetrical syndromes. MATERIAL AND METHODS: A prospective clinical cohort study was conducted on 290 pregnant women (average age 31.7 ± 4.7 years old). The main group was made up of 140 G20210A patients, while the control group comprised 150 women with the wild G20210G type. The aim was to evaluate the activity of Factor II in the venous blood plasma during the stages of pregnancy with regard to trophoblast invasion waves. As per results, association analysis of Factor II activity value and gestational complications was carried out. RESULTS: In the control group, the median (Me) of Factor II activity ranged from 108% (preconception period) to 144% (pregnancy) [95% CI 130-150]. In patients with the GA type, the value was significantly higher in related periods, ranging from 149 to 181% [95% CI 142-195], p < 0.0001. With Factor II activity ranging from 148.5 to 180.6%, pregnancies in the main group had no complications. Higher levels of Factor II activity were associated with the development of early and/or severe preeclampsia (PE) and fetal growth retardation (FGR). CONCLUSION: The data obtained regarding Factor II activity in blood plasma, juxtaposed with the development of great obstetrical syndromes, allow to assume that manifestation of G20210A in early and/or severe PE and FGR is associated with this coagulation factor's level of activity. Threshold value of the Factor II activity with G20210A mutation, allowing to predict the development of PE, comprised 171.0% at the preconception stage (AUC - 0.86; p < 0.0001) and within 7-8 weeks of gestation it was 181.3% (AUC - 0.84; p < 0.0001).

MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin G20210A mutation in arterial ischemic stroke among young tunisian adults.

Arterial ischemic stroke (AIS) in young adults is less common in older adults, but the underlying pathogenesis and risk factors are more multi-faceted. The role of inherited thrombophilia such as 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, (C677T and A1298C), factor V of Leiden (FVL) polymorphism, and the prothrombin G20210A mutations remains unclear. This study aims to evaluate the role of prothrombin genetic factor in AIS among young adults in Tunisia and to assess the synergistic effect between thrombogenic mutations in the pathogenesis of AIS. In this case-control study, blood samples were collected from patients and healthy controls, all matched for age and gender. The difference between them is evaluated by using the chi-square test. The odds ratio (OR) was carried out to evaluate the associations between each polymorphism and AIS risk using a binary logistic regression model. Values were considered statistically significant when p < 0.05. Patients carrying simultaneously the MTHFR polymorphisms (677T and 1298C) have a higher risk to develop AIS compared to controls. The heterozygous variants FVL increased the risk of AIS only when it is associated with MTHFR C677T or MTHFR A1298C polymorphisms. In conclusion, our study confirmed the involvement of MTHFR polymorphisms as AIS's important risk factors. The existence of FVL polymorphism or prothrombin G20210A mutation alone doesn't correlate with the occurrence of stroke. We assume that the presence of both MTHFR and FVL polymorphisms has a synergistic effect and increased the risk of the AIS.

Interaction of thrombophilic SNPs in patients with unexplained infertility-multifactor dimensionality reduction (MDR) model analysis.

PURPOSE: Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis. METHODS: A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed. RESULTS: There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02). CONCLUSION: The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

Factor V Leiden is associated with increased sperm count.

STUDY QUESTION: Is the thrombophilia mutation factor V Leiden (FVL) associated with an increased total sperm count? SUMMARY ANSWER: Carriers of FVL have a higher total sperm count than non-FVL-carriers, which could not be explained by genetic linkage or by observations in a FVL-mouse model. WHAT IS KNOWN ALREADY: FVL has a high prevalence in Caucasians despite detrimental health effects. Carriers have been shown to have higher fecundity, which might partly explain this evolutionary paradox. STUDY DESIGN, SIZE, DURATION: We determined FVL status in two cohorts (Dutch, n = 627; Danish, n = 854) of consecutively included men without known causes for spermatogenic failure, and performed an individual patient data meta-analysis of these two cohorts together with one previously published (Dutch, n = 908) cohort. We explored possible biological underpinnings for the relation between sperm count and FVL, by use of a FVL-mouse model and investigations of genetic linkage. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were male partners of subfertile couples (two Dutch cohorts) and young men from the general population (Danish cohort): FVL carrier rate was 4.0%, 4.6% and 7.3%, respectively. There were differences in smoking, abstinence time and age between the cohorts. We corrected for these in the primary analysis, which consisted of a mixed linear effects model, also incorporating unobjectified population differences. In public haplotype data from subjects of European descent, we explored linkage disequilibrium of FVL with all known single nucleotide polymorphisms in a 1.5 MB region around the F5 gene with an R2 cutoff of 0.8. We sequenced exons of four candidate genes hypothesized to be linked to FVL in a subgroup of FVL carriers with extreme sperm count values. The animal studies consisted of never mated 15-18-week-old C57BL/J6 mice heterozygous and homozygous for FVL and wild-type mice. We compared spermatogenesis parameters (normalized internal genitalia weights, epididymis sperm content and sperm motility) between FVL and wild-type mice. MAIN RESULTS AND THE ROLE OF CHANCE: Human FVL carriers have a higher total sperm count than non-carriers, with an adjusted mean difference of 31 × 106 (95%CI 0.2-61.7; P = 0.048). Mice with the FVL mutation do not have increased spermatogenesis as compared to wildtype mice. None of the studied polymorphisms was in linkage disequilibrium, either in the public databases or in a subgroup of FVL carriers with extremely high sperm counts. LIMITATIONS, REASONS FOR CAUTION: The difference in total sperm count would benefit from confirmation in other cohorts. The finding of higher count in carriers was consistent however, with no heterogeneity between the cohorts. The lack of effect of murine FVL might suggest there is no direct causality. The exploratory efforts on genetic linkage do not rule out that the association is a reflection of FVL co-inheritance with a non-studied causative polymorphism. WIDER IMPLICATIONS OF THE FINDINGS: A high sperm count in FVL-carrying males contributes to understanding the high prevalence of this otherwise disadvantageous mutation. The findings might provide directions for future research on male fertility. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest. Research was conducted with funding from the Netherlands Organisation for Scientific Research (NWO, VIDI innovative research grant 016.126.364 awarded to S. Middeldorp). The Danish cohort was supported by the Innovation Fund Denmark (InnovationsFonden, grant no. 14-2013-4), The Danish Ministry of Health and the Danish Environmental Protection Agency. TRIAL REGISTRATION NUMBER: Not applicable.

The Contribution of Inherited Thrombophilia to Venous Thromboembolism in Cancer Patients.

Although the relationship between venous thromboembolism (VTE) and cancer has been a subject of study, knowledge of the contribution of thrombophilia to thrombosis in patients with cancer is still very limited. The aim of this article is to collect present knowledge on the contribution of inherited thrombophilia to VTE in cancer patients. We performed a search in Google Scholar and PubMed and selected 21 from 76 returned articles. Then we made a narrative review of the selected articles. We describe 11 studies on the contribution of inherited thrombophilia to VTE in cancer patients in general and 10 on that contribution in specific types of cancer: 1 in colorectal cancer, 4 in breast cancer, 1 in gynecologic cancer and 4 in hematopoietic malignancies. All studies investigate the relation of factor V Leiden (FVL) to VTE, 13 that of the prothrombin G20210A mutation (PTG20210A) and 7 studies also investigate other inherited thrombophilias, such methylenetetrahydrofolate reductase gene mutations, although only 2 investigate the contribution of deficiencies of the natural anticoagulants. Studies are very heterogeneous, in design and sample size and conclusions differ considerably. There is no consensus on the contribution of inherited thrombophilia to VTE in cancer patients except for acute lymphoblastic leukemia in children. Probably, that contribution is not the same for all types of cancer and more studies are needed to bring more knowledge on this subject.

Maternal factor V Leiden and prothrombin mutations do not seem to contribute to the occurrence of two or more than two consecutive miscarriages in Caucasian patients.

BACKGROUND: We analysed the prevalence of the most common hereditary thrombophilia (hTP) - factor V Leiden (FVL) mutation, prothrombin 20210 G>A substitution (PT) - and the 677 C>T replacement in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in Caucasian patients with a history of two and more consecutive recurrent miscarriages (RMs) as compared to healthy controls with an identical ethnic background and at least one live birth. METHODS: A multicenter analysis of three hTP was performed in 641 RM patients identically screened at specialized university centres. RESULTS: The study groups consisted of 240 patients with 2 (1) and 401 patients with >2 miscarriages (2) and were compared with 157 controls. There was no significant difference in the prevalence of the hTP between RM patients and controls nor within the two study groups. Subgroup analysis showed that the homozygous MTHFR polymorphism was significantly more prevalent in the study group 2 as compared to study group 1 (13.9 versus 7.9%, P = 0.02). CONCLUSION: In Caucasians, maternal FVL or PT mutations do not seem to contribute to the pathophysiology of RM, irrespective of the number of miscarriages. However, the role of the homozygous MTHFR polymorphism merits further investigation.

Deep venous thromboembolism after a trauma in a football player double heterozygous for factor V Leiden and prothrombin G20210A mutation: The role of genetic testing in sport.

Traumatic vascular injuries to the lower limb are frequent in athletes, particularly in sports characterized by high-speed collisions. However, the diagnosis is not always straightforward, for the lack of clearly visible abnormalities without provocative testing or appropriate imaging. The failure of an early diagnosis can lead to devastating consequences. In these subjects, it may be useful to investigate the personal susceptibility to thrombotic events such as the presence of a hereditary hypercoagulable state. We experienced a case of a soccer player with progressive swelling and severe pain of the calf after a trauma during a football match 3 days previously, who came to our hospital for suspected deep vein thrombosis, confirmed by echo-Doppler ultrasound. A thrombophilia screening detected a double heterozygosity for factor V Leiden and prothrombin G20210A mutation in the presence of a strong family history for thromboembolism. Immediate treatment with elastic stocking compression and enoxaparin was started. The patient was discharged on warfarin therapy maintained for six months, with the warning to avoid trauma activities during anticoagulation. Thrombotic genetic testing in athletes who experience episodes of deep vein thrombosis might offer important opportunities for patient management, such as prolonged anticoagulant therapy or avoidance of risk factors such as trauma-related sports.

Nonarteritic anterior ischemic optic neuropathy and double thrombophilic defect: a new observation.

WE REPORT THE FIRST CASE OF NONARTERITIC ANTERIOR ISCHEMIC NEUROPATHY (NAION) ASSOCIATED WITH DOUBLE THROMBOPHILIA: protein S deficiency and prothrombin G20210A mutation. A 58-year-old man is presented including the clinical and laboratory findings, cardiovascular profile and thrombophilia screening. The patient presented with 3/10 vision and an inferior altitudinal defect in the right eye. Funduscopic examination of the right eye revealed a hyperemic optic disk with blurred superior optic disk border and sectoral nerve fiber layer edema. Complete blood count, erythrocyte sedimentation rate and C-reactive protein were normal, suggesting a NAION. A workup of cardiovascular risk factors revealed hyperlipidemia, arterial hypertension and high-risk asymptomatic coronary artery disease. Due to the family history of deep vein thrombosis in the patient's daughter, a thrombophilia screening was additionally performed. The results revealed a double thrombophilic defect, namely congenital protein S deficiency and heterozygosity for prothrombin G20210A mutation, which were also identified in the patient's daughter. Anticoagulant warfarin therapy was initiated and the patient underwent a triple bypass surgery. At three-month follow-up, the right optic disk edema had resolved, leaving a pale superior optic nerve head. Visual acuity in the right eye had slightly improved to 4/10; however, the dense inferior altitudinal field defect had remained unchanged. The patient is currently treated with warfarin, atorvastatin, irbesartan and metoprolol. This case suggests that the first line of investigation in all patients with NAION involves assessment of cardiovascular risk factors. However, careful history taking will identify NAION patients who are eligible for additional thrombophilia screening: young patients without vasculopathic risk factors, bilateral or recurrent NAION, idiopathic or recurrent venous thromboembolism (VTE), positive family history of VTE, and VTE in young age or in unusual sites (e.g. cerebral, hepatic, mesenteric, or renal vein).

Low prevalence of Factor V Leiden and the prothrombin G20210A mutation in a healthy population from the central-south region of Chile / Baixa prevalência do Fator V Leiden e da mutação da protrombina G20210A em uma população sã da região centro-sul do Chile

Thrombosis is a result of the interaction between predisposing genetic polymorphisms and acquired risk factors. The two prothrombotic polymorphisms which are most frequently associated with thrombosis are factor V (FV) Leiden and the prothrombin (PT) G20210A mutation. The objective of this work was to investigate the prevalence of both factors in the central-south region of Chile. Determination of the frequency was carried out by means of a genetic analysis of 1200 healthy, non-native individuals. The mutation of FV Leiden was found in 1.25 percent of the population and the PT G20210A mutation in 1.33 percent. None of the individuals were homozygosis or had both polymorphisms. The prevalences of FV Leiden and the PT G20210A mutation are less common in the healthy population.

A trombose pode ser o resultado da interação de polimorfismo genético e fatores de riscos adquiridos. Os polimosfirmos protrombóticos mais frequentes são fator V (FV) Leiden e a mutação da protrombina (PT) G20210A. O objetivo deste trabalho foi investigar a prevalência de ambos os polimorfismos na região centro-sul do Chile. Foram realizadas análises genéticas (PCR RFLP) de 1.200 pessoas saudáveis, não nativas da região. Foram encontrados 1,25 por cento de mutação do Fator V Leiden e 1,33 por cento da mutação da protrombina G20210A. Não foi detectada homozigose em ambos os polimorfismos. A prevalência de FV Leiden e da mutação G20210A é baixa na população estudada.

Mutação G20210A no gene da protrombina, fator V de Leiden e anticorpos anticardiolipina não influenciam a sobrevida do enxerto renal após o transplante / Prothrombin G20210A gene mutation, factor V Leiden and anticardiolipin antibodies do not influence renal graft survival after transplantation

Introdução: Complicações tromboembólicas são importantes fatores de risco para perda do enxerto e pior evolução após o transplante renal. pacientes com defeito trombofílico apresentam maior risco de complicações tromboembólicas. Foram analisados, entre receptores de transplante renal, a prevalência de defeito trombofílico e o risco atribuído a esta condição para a perda do enxerto e para o desenvolvimento de tromboses intravasculares. Métodos: estudo do tipo coorte incluindo 388 receptores adultos analisados quanto à presença de trombofilia de acordo com a pesquisa de anticorpos anticardiolipidina (aCL) por ELISA e das mutações G1691A no gene do fator V (FV) e G20210A no gene da protrombina (PT) por PCR multiplex. Resultados: Defeito trombofílico foi identificado em 25,8% dos pacientes. As taxas de sobrevida de 2 anos do enxerto foram semelhantes entre os pacientes com e sem defeito trombofílico (94%, p=0,53), bem como a sobrevida dos enxertos livres de tromboses intravasculares (97% versus 97%, p=0,83). pacientes com defeito trombofílico apresentaram prevalência de tromboses intravasculares semelhante à do grupo-controle (3% versus 3,5%, p=0,82). O transplante renal anterior foi associado a maior risco de perda de enxerto (OR 20,8, p<0,001) e de ocorrência de trombose intravasculares (OR 6,8, p=0,008). Conclusões: As prevalências das mutações FVG1691A e PTG20210A na população estudada foram semelhantes às da população geral não transplantada, e a prevalência de anticorpos aCL superou a observada entre os indivíduos sadios. Não houve associação entre os marcadores de trombofilia estudados e a sobrevida em médio prazo do transplante renal.

Introduction: Thromboembolic complications are important risk factors for graft loss and poor outcome after renal transplantation. patients with thrombophilic defects are at increased risk of thromboembolic complications. Were analyzed, among kidney transplant recipients, the prevalence of thrombophilic defects and the risk attributed to this condition for graft loss and the development of intravascular thrombosis. Methods: A cohort study including 388 adult recipients analyzed for the presence of thrombophilia according to anticardiolipidina antibodies (aCL) by ELISA and gene mutations G1691A in factor V (FV) and prothrombin gene G20210A (PT) by multiplex PCR. Results: thrombophilic defect was identified in 25.8% of patients. The survival rates of two years of the graft were similar between patients with and without thrombophilic defect (94%, p = 0.53), and the survival of free grafts of intravascular thrombosis (97% versus 97%, p = 0 , 83). patients with an increased prevalence of thrombophilic defect intravascular thrombosis similar to the control group (3% versus 3.5%, p = 0.82). Previous renal transplantation was associated with increased risk of graft loss (OR 20.8, p <0.001) and intravascular thrombosis (OR 6.8, p = 0.008). Conclusions: The prevalence of mutations and FVG1691A PTG20210A in this study were similar to those of the general population not transplanted, and the prevalence of aCL antibodies exceeded that observed among healthy individuals. There was no association between markers of thrombophilia studied and medium-term survival in renal transplantation.