Factor V Leiden and prothrombin gene G20210A mutation in children with cerebral thromboembolism

We investigated whether there is an association between factor V Leiden (FVL) and/or prothrombin gene G20210A mutation (PT20210A) and cerebral thromboembolism in a pediatric Argentinean population. From May 1992 to January 2002, 44 consecutive children with arterial ischemic stroke (AIS) and 23 children with cerebral sinovenous thrombosis (SVT) were prospectively studied at a single center. The prevalence of both mutations was compared with a 102 age-matched controls. In children with AIS, the frequencies (patients vs. controls), odds ratio (OR), and 95% confidence interval (95% CI) for the presence of FVL were as follows: 2.3% vs. 2%, OR/95% CI, 1.16/0.2 to 13.2; P value = 0.99. No cases of PT20210A were found in this group. In children with SVT, the frequencies (patients vs. controls), OR, and 95% CI were as follows: FVL (4.3% vs. 2%, OR/95% CI, 2.27/0.22 to 6.2; P value = 0.99) and PT20210A (4.3% vs. 1%; OR/95% CI, 4.6/0.3 to 76.3; P value = 0.3354). One child with PT20210A also had an inherited protein C deficiency. In 12 (18%) out of the 67 children with cerebral thromboembolism, without the aforementioned mutations, other prothrombotic disorders were detected. Although a multi-center prospective study with a large number of Argentinean pediatric patients is needed to obtain considerable evidence, no association between factor V Leiden and/or prothrombin gene G20210A mutation and cerebral thromboembolism was found in this pediatric series.     

Prevalence of factor V Leiden (G1691A) and prothrombin (G20210A) among Kurdish population from Western Iran

BACKGROUND: The mutation in factor V (FV) G1691A, known as factor V Leiden, and prothrombin (FII) gene G20210A are the two most prevalent causes of inherited thrombophilia. The present study reports the prevalence of factor V Leiden and the prothrombin G20210A gene mutations among healthy individuals of Kurdish ethnic background in Western Iran. METHODS: Four hundred thirty-four healthy unrelated individuals, 255 male and 179 female, with a mean age of 28.7+/-15.5 from the Kermanshah Province of Iran were studied for prothrombin G20210A mutation. The factor V Leiden mutation was studied in 404 healthy individuals, of whom 232 were male and 172 were female. The factor V Leiden and prothrombin G20210A were detected by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) method using Mnl I and Hind III restriction enzymes, respectively. RESULTS: Among 434 individuals studied for prothrombin G20210A mutation seven carried this mutation as heterozygous (four female subjects and three male), giving a prevalence of 1.6% [95% confidence intervals (CI) 0.5-2.7) and an allele frequency of 0.8%. No homozygous prothrombin 20210AA was found. Factor V G1691A mutation was detected as heterozygous in 11 of 404 healthy individuals (five female and six male) and as homozygous in one male indicating a prevalence of 2.97% (95% CI 1.3-4.6) and allele frequency of 1.6%. CONCLUSIONS: Our results indicated that the factor V Leiden and prothrombin G20210A mutations are not rare among populations of Western Iran and that the relationship between venous thrombophilia and these mutations have to be further studied in Western Iran population, which, in turn, may suggest a causal effect.     

Prevalence of factor V Leiden and prothrombin G20210A in patients with gastric cancer

AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrom-bin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS: Among the 121 cancer patients, factor V Leiden was found in 4 cases (GA genotype: 3.3%) and prothrombin G20210A in 10 cases (GA genotype: 8.3%). Of the 130 control subjects, factor V Leiden was detected in 6 cases (GA genotype: 4.6%) and prothrombin G20210A in 8 cases (GA genotype: 6.1%). No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION: Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.     

Association between adverse pregnancy outcomes and maternal factor V G1691A (Leiden) and prothrombin G20210A genotypes in women with a history of recurrent idiopathic miscarriages

Thrombophilia was implicated in the development of pregnancy complications, including recurrent idiopathic pregnancy loss, and is aggravated in women who are carriers of factor V G1691A (FV Leiden) and prothrombin (PRT) G20210A single-nucleotide polymorphisms (SNPs). Previous studies examined the role of FV-Leiden and PRT G20210A in recurrent pregnancy loss with conflicting results. Here we examined the prevalence of FV Leiden and PRT G20210A SNPs, in 200 women with 3 or more consecutive early (n = 87), late (n = 41), or early-late (n = 72) recurrent pregnancy losses, and 200 age-matched fertile parous control women. APC resistance (APCR) was detected functionally (measuring the activated clotting time triggered by activated factor X in presence of a fixed amount of purified APC), and FV-Leiden and PRT G20210A genotypes were assessed by PCR. The frequency of the mutant FV (0.1400 vs. 0.0276; P < 0.001) but not PRT 20210 (0.0100 vs. 0.0225; P = 0.159) allele was higher in patients than controls, respectively. APC resistance with factor V Leiden was seen in 27% of patients compared to 11.5% of controls, while APC resistance without factor V Leiden was seen in 12.5% of patients compared to 9.5% of controls. Regression analysis demonstrated that the significant predictors for early abortion was FV Leiden; those for late abortion were oral contraceptive, APCR, and FV Leiden; and predictors for early-late abortions were oral contraceptives, obesity, FV Leiden, and smoking. APC resistance and FV Leiden, as well as combination of both, are common thrombotic defects seen in women with idiopathic recurrent pregnancy loss, thus testing for these is recommended in women who have experienced recurrent miscarriages.     

Factor V Leiden, prothrombin 20210A and the risk of venous thrombosis among cancer patients

Cancer patients have an increased risk of venous thrombosis (VT). The association of factor V Leiden (FVL) and the prothrombin 20210A variant with VT in cancer patients is not established. We genotyped 101 cancer patients with VT and 101 cancer patients without VT for these polymorphisms. Five cases and three controls were heterozygous for FVL, yielding an odds ratio of 1.7 (95% confidence interval (CI) 0.3-10.7). Five cases and no controls were heterozygous for prothrombin 20210A, for an odds ratio of 6.7 (95% CI 0.9-infinity). Prothrombin 20210A may be associated with VT risk among cancer patients.     

Varied Prevalence of Factor V G1691A (Leiden) and Prothrombin G20210A Single Nucleotide Polymorphisms Among Arabs

Background: Factor V G1691A (FV-Leiden) and prothrombin (PRT) G20210A single nucleotide polymorphisms (SNPs) are major inherited risk factors of venous thromboembolism. In view of the heterogeneity in their world distribution and lack of sufficient information about their distribution among Arabs, we addressed the prevalence of both SNPs in 4 distinct Arab populations (Lebanon, Tunisia, Bahrain, and Saudi Arabia). Methods: Study subjects comprised 698 Lebanese, 313 Tunisian, 194 Bahraini, and 149 Saudi Arabian healthy subjects; genotyping was done by PCR-RFLP using Mnl I and Hind III for FV-Leiden and PRT G20210A, respectively. Results: The prevalence of the mutant A alleles of FV-Leiden and PRT G20210A were significantly higher among Lebanese (0.0788 and 0.0136) and Tunisians (0.0351 and 0.0128), as compared to Bahraini (0.0155 and 0.0052) and Saudi (0.0101 and 0.000) subjects. Higher frequency of the FV-Leiden G/A and A/A genotypes were seen in Lebanon (13.8 and 1.0%), followed by Tunisia (5.8 and 0.6%), Bahrain (3.1 and 0.0%) and Saudi Arabia ((2.0 and 0.0%). All PRT G20210A positive cases were in the heterozygote (G/A) state, and these comprised 3.6% for Lebanon, 2.6% for Tunisia, 1.0% for Bahrain. The carrier rate of FV-Leiden was significantly higher among Lebanese compared to the other populations (p < 0.001), while the difference in the prevalence of FV-Leiden between the other populations was not statistically different. With the exception of Lebanese-Saudi (p = 0.038), the prevalence of PRT G20210A was similar among the study communities. Furthermore, the overall average genetic differentiation between populations (estimated with the F_ST) was 0.0022 for FV-Leiden and 0.005 for PRT G20210A. Conclusions: These results further confirm the heterogeneity in FV-Leiden and PRT G20210A distribution among Arabs, and recommend potential institution of prophylactic measures for carriers of either or both SNPs.     

Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: an international case series of 100 individuals

The risk of thrombosis in individuals with rare compound thrombophilias, homozygous factor V Leiden (FVL) plus heterozygous prothrombin G20210A (PTM), homozygous PTM plus heterozygous FVL, and homozygous FVL plus homozygous PTM, is unknown. We identified, worldwide, individuals with these compound thrombophilias, predominantly through mailing members of the International Society on Thrombosis and Haemostasis. Physicians were sent a clinical questionnaire. Confirmatory copies of the genetic results were obtained. One hundred individuals were enrolled; 58% were female. Seventy‐one individuals had a venous thrombosis (includes superficial and deep vein thrombosis, and pulmonary embolism), 4 had an arterial thrombosis and 6 had both. Nineteen individuals had never had a thrombotic event. Thrombosis‐free survival curves demonstrated that 50% of individuals had experienced a thrombotic event by 35 yrs of age, while 50% had a first venous thromboembolic event (VTE; includes all venous thrombosis except superficial thrombosis) by 41 yrs of age; 38.2% of first VTEs were unprovoked. 37% of patients had at least one VTE recurrence. Seventy percent of first pregnancies carried to term and not treated with anticoagulation were thrombosis‐free. In conclusion, patients with these rare compound thrombophilias are not exceedingly thrombogenic, even though they have a substantial risk for VTE.     

Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism

We determined the prevalence of factor V Leiden and of prothrombin G20210A mutations in a cohort of unselected outpatients (n = 748) referred for suspected deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and a pooled analysis of similar studies was also performed. Based on the clinical presentation, the prevalence of factor V Leiden was 15.7% in the 83 patients with DVT and 14.1% in the 99 patients with PE compared with 5.3% in patients without DVT and/or PE (control group). The prevalence of the prothrombin G20210A mutation did not differ among the three groups (3.9% for controls, 4. 8% for DVT and 3.9% for PE patients). We then divided the 99 patients with PE by separately analysing those with PE but without DVT (n = 57) and those with PE and DVT (n = 42). Compared with the control group, the prevalence of factor V Leiden was 10.5%, odds ratio (OR) 2.10 [95% confidence interval (95% CI) 0.68-5.45] in patients with primary PE and 19.1%, OR 4.20 (95% CI 1.54-10.30) in patients with DVT and PE. For the prothrombin G20210A mutation, no statistically significant differences were found between the control group and the three other groups. In conclusion, our data and the pooled analysis indicate that patients with primary PE are less often affected by the factor V Leiden mutation. No statistically significant differences were observed between patients and controls for the prothrombin G20210A mutation.     

Two common genetic thrombotic risk factors: factor V Leiden and prothrombin G20210A in adult Turkish patients with thrombosis

The prevalence of genetic risk factors for thrombosis varies greatly in different parts of the world, both in patients with thrombosis and in the general population. Factor V Leiden (FVL) and prothrombin G20210A (PT G20210A) mutations are the most common genetic defects leading to thrombosis. We have previously reported that those two thrombotic risk alleles are frequently found in Turkish children with thrombosis. The aim of the present study was to investigate the frequency of FVL and PT G20210A and their clinical manifestations in adult Turkish patients with thrombosis. Between January 1997 and February 2000, 146 patients with documented thrombosis were investigated in our center for the presence of the FVL and PT G20210A mutations. Forty-five of 146 patients with thrombosis (30.8%) were detected to have FVL mutation. Among those cases with the FVL mutation, seven (4.8%) had homozygote and 38 (26%) had heterozygote mutation. The PT G20210A mutation was detected in 10 of the 146 patients with thrombosis (6.8%). Another six cases (4.1%) had both FVL and PT G20210A mutations. The overall frequency of these two common risk alleles in our adult population with thrombosis was 41.6%. Our findings reveal that FVL and PT G20210A mutations are significant genetic risk factors contributing to the pathophysiology of thrombosis in the Turkish population.     

Effect of the MTHFRC677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations

Odds ratios for the MTHFR C677T variant were determined in a large case–control study of 558 unselected patients with venous thromboembolism and 500 control subjects. The odds ratios for MTHFR C677T heterozygosity and homozygosity were 1.07 (95%CI 0.84–1.36) and 0.71 (95%CI 0.48–1.03). In patients with the factor V Leiden or the F2 G20210A mutations there was no apparent increase in risk of venous thromboembolism due to the MTHFR C677T polymorphism.
Thrombophilia testing should not include genotyping for the MTHFR C677T polymorphism.     

Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly suggesting that at least the FII G20210A polymorphism might be considered an important risk factor for acute myocardial infarction in aged patients (55–80 years old). On the other hand, in spite of a not different genotypic and allelic distribution for the Leiden FV G1691A mutation, the presence of one or both the two polymorphisms is significantly higher among cases than in controls. In conclusion, our data suggest that FII G20210A and/or Leiden FV might be involved as risk factor for arterial disorders in about 5% of old subjects, justifying the opportunity of a genetic screening and an eventual preventive treatment, in particular in old subjects in which other and major risk factors, as hypertension and atherosclerosis, are detected.     

Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: data from the southeast of Turkey

Factor V Leiden (FV-Leiden) and prothrombin gene mutations (FII G20210A) are well-established independent risk factors for thrombosis. In the recent years, many studies have suggested that these mutations are associated with an increased risk of recurrent pregnancy loss (RPL). We aimed to investigate the prevalence of these molecular defects in subjects with a history of early RPL. One hundred and fourteen women with three or more consecutive unexplained first-trimester miscarriages were compared to 185 parous women with uncomplicated pregnancies from the same ethnic origin. The presence of FV-Leiden and FII G20210A mutations was assessed by polymerase chain reaction analysis. Overall, 11 out of the 114 women with early RPL (9.6%) had either FV-Leiden or FII G20210A mutation, as compared with 16 out of the 185 women with normal pregnancies (8.6%; p = 0.756). The prevalence of FV-Leiden mutation was 7.9% (9/114) in patient group, compared with 7% (13/185) in control group (p = 0.780). One hundred and two patients were primary and 12 were secondary aborters. All FV-Leiden positive cases were primary aborters (8.8%; 9/102, p = 0.584). Concerning the FII G20210A, two out of 114 (1.7%) were first-trimester RPL (primary aborters) and three out of 185 (1.6%) controls were carriers of the FII G20210A mutation (1.7 vs 1.6%, p = 0.931). The results obtained from patients with first-trimester RPL and the control group have no statistical significant differences in the prevalence of FV-Leiden and FII G20210A mutations. These results suggest that mutations have no role in etiology of first-trimester recurrent abortions.     

Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease

Mild hyperhomocysteinaemia is an established risk factor for deep vein thrombosis (DVT); few data concerning its potential interaction with thrombophilic genotypes are available at the present time. We investigated 121 thrombosis-free individuals and 111 patients with at least one objectively confirmed episode of DVT. A thrombophilic condition (deficiency in antithrombin, protein C and S, factor V Leiden, prothrombin G20210A) was detected in 25.2% of the patients; mutant factor V or prothrombin genotypes were present in 6.6% of the controls. Hyperhomocysteinaemia was found in 14.4% of patients and 3. 3% of the controls, with a 3.7-fold increase in risk for DVT (95% CI 1.1-12.3). Adoption of different cut-off levels for definition of hyperhomocysteinaemia did not substantially change the magnitude of the risk. Carriership of both hyperhomocysteinaemia and factor V Leiden or prothrombin G20210A was detected in 2.7% of patients for each combination and in none of the controls. An approximate estimate of 30-fold increased risk in carriers of both hyperhomocysteinaemia and factor V Leiden and 50-fold increased risk in carriers of both hyperhomocysteinaemia and prothrombin G20210A was calculated, suggesting a synergistic interaction between hyperhomocysteinaemia and such thrombophilic genotypes. Yet statistical analysis is highly unstable due to the small number of individuals with combined defects. Further investigations on large series of patients are needed.     

An overview of methods for detection of factor V Leiden and the prothrombin G20210A mutations

Venous thromboembolism, represented by deep venous thrombosis and pulmonary embolism, is a common disease with high mortality and morbidity. Within the last 25 years, risk factors for venous thromboembolism have been linked to mutations in the genes of the coagulation/anticoagulation system. Factor V Leiden and the prothrombin G20210A mutations are the most prevalent inherited risk factors predisposing to venous thromboembolism in the Western world. Tests to detect these mutations are carried out when investigating a personal or family history of venous thromboembolism. At the present, there are several different methods available for the detection of these mutations in the laboratory. The choice of the method will depend on many variables. This article is aimed at reviewing the available methods for the detection of factor V Leiden and prothrombin G20210A mutations, their principle, applicability, advantages and disadvantages of use.     

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in Mediterranean area

Background. Thromboembolism has been reported to be associated with inflammatory bowel disease.Aim. To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events.Patients and methods. A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls.Results. One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively.Conclusions. Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.     

Contribution of the glycoprotein Ia 807TT, methylene tetrahydrofolate reductase 677TT and prothrombin 20210GA genotypes to prothrombotic risk among factor V 1691GA (Leiden) carriers

The cooperative effects of the GPIa 807TT, MTHFR 677TT and prothrombin 20210GA genotypes with the FV Leiden 1691GA (FVL) genotype were evaluated by comparing these genotype frequencies in 77 asymptomatic and 156 symptomatic heterozygous FVL carriers. The GPIa 807TT and MTHFR 677TT genotypes did not segregate within the symptomatic FVL carrier group and did not contribute to venous thrombotic risk in this patient cohort. There was no difference in the prothrombin 20210GA genotype frequency between asymptomatic FVL carriers and a random Caucasian control group; however, the prothrombin 20210GA genotype was nearly 5 times as prevalent (19/156 v 2/77; P < 0.02) in the symptomatic FVL carriers (odds ratio 5.21; 95% confidence interval 1.20-47.62), demonstrating that this important prothrombotic risk factor acts synergistically with FVL.     

Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone

The risk of venous thromboembolism (VTE) in the absence of prophylaxis was evaluated in a retrospective study of 47 women (84 pregnancies) with combined thrombophilia [heterozygous factor V Leiden (FVL) plus prothrombin (FII) 20210A mutation (group I)] and in 82 women (193 pregnancies) with the FII alone (group II). VTE was more frequent in group I than in group II [17.8% versus 6.2%, P = 0.003, relative risk (RR) 2.9, 95% confidence interval (CI) 1.4-5.9], ante partum (7.1% and 2.1%) and post partum (11.5% and 4.2%). The risk was higher in index cases than in family members (RR 2.5, 95% CI 1.2-5.2 and RR 2.1, 95% CI 0.2-22.3 respectively) Even women who had no history of VTE before pregnancy had an increased risk (RR 2.2, 95% CI 1.0-4.8). Our results suggest that, during ante partum, prophylaxis is indicated in women with combined thrombophilia and with a VTE before pregnancy. In those without VTE before pregnancy, prophylaxis might be decided for each individual case, taking into consideration all risk factors. In women with the FII mutation alone, the low risk may not justify prophylaxis in the absence of previous VTE. In post partum, prophylaxis is indicated in all cases.     

Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family

We analysed the clinical and analytical features of 18 subjects from a Spanish family who bear several combinations of two prothrombotic mutations, factor V Leiden (FVL) and prothrombin 20210A. We identified three subjects homozygous for the 20210A prothrombin mutation which additionally were heterozygous for FVL. The combination of both mutations increases the risk of developing venous thrombotic episodes at the earlier age. However, even in association with FVL, the homozygous condition of the prothrombin 20210A mutation requires additional risk factors to induce a thrombotic event. Finally, the plasma level of factor II showed a significant relationship with the prothrombin genotype.     

Factor V Leiden and prothrombin gene G20210A mutations in Italian patients with Behçet's disease and deep vein thrombosis

Objective

To evaluate the frequency and type of vascular lesions and to study the association of factor V gene G1691A (Leiden) and prothrombin gene G20210A polymorphisms with venous thrombosis in Italian patients with Behçet's disease (BD).

Methods

Included were 118 consecutive Italian BD patients followed over a 3‐year period (1997–1999) who satisfied the International Study Group criteria for BD. The control group consisted of 132 healthy Italian blood donors. All BD patients and controls were genotyped by polymerase chain reaction and allele‐specific restriction enzyme techniques for factor V Leiden and prothrombin gene G20210A polymorphisms.

Results

Vascular lesions were observed in 37 (31.4%) patients. The 2 most common lesions were subcutaneous thrombophlebitis (10.2%) and deep vein thrombosis (DVT) of the legs (22.8%). No significant demographic and clinical differences between patients with and without DVT were present. The distribution of allele and genotype frequencies of prothrombin gene G20210A and factor V Leiden polymorphisms did not differ significantly between BD patients and healthy controls. The frequencies of carriage rates of prothrombin gene G20210A and factor V Leiden polymorphisms in BD patients with and without DVT were similar. However, the frequency of 20210A allele was significantly higher in BD patients with ocular disease than in those without, particularly in the patients with posterior uveitis/retinal vasculitis.

Conclusions

The frequency and types of vascular lesions in Italian BD patients were similar to those reported in studies from other countries. No association between factor V Leiden mutation and G20210A mutation in the 3′‐untranslated region of the prothrombin gene with DVT was found. However, a prothrombin gene G20210A mutation may influence the development and severity of ocular involvement in BD.