PAI-1 4G-4G and MTHFR 677TT in non-hepatitis C virus/hepatitis B virus-related liver cirrhosis

AIM: To evaluate the different roles of thrombophilia in patients with and without viral etiology. The thrombophilic genetic factors(THRGFs), PAI-1 4G-4G, MTHFR 677 TT, V Leiden 506 Q and prothrombin 20210 A, were studied as risk factors in 1079 patients with liver cirrhosis(LC), enrolled from January 2000 to January 2014. METHODS: All Caucasian LC patients consecutively observed in a seven year period were included; the presence of portal vein thrombosis(PVT) and Budd Chiari syndrome(BCS) was registered. The differences between the proportions of each THRGF with regard to the presence or absence of viral etiology and the frequencies of the THRGF genotypes with those predicted in a population by the Hardy-Weinberg equilibrium were registered.RESULTS: Four hundred and seventeen/one thousand and seventy-six patients(38.6%) showed thrombophilia: 217 PAI-1 4G-4G, 176 MTHFR C677 TT, 71 V Leiden factor and 41 prothrombin G20210 A, 84 with more than 1 THRGF; 350 presented with no viral liver cirrhosis(NVLC) and 729 with, called viral liver cirrhosis(VLC), of whom 56 patients were hepatitis C virus + hepatitis B virus. PAI-1 4G-4G, MTHFR C677 TT, the presence of at least one TRHGF and the presence of 1 THRGF, were statistically more frequent in patients with NVLC vs patients with VLC: All χ~2 3.85 and P 0.05. Patients with PVT and/or BCS with at least one TRHGF were 189/352(53.7%). The Hardy-Weinberg of PAI-1 and MTHFR 677 genotypes deviated from that expected from a population in equilibrium in patients with NVLC(respectively χ~2 = 39.3; P 0.000 and χ~2 = 27.94; P 0.05), whereas the equilibrium was respected in VLC.CONCLUSION: MTHFR 677 TT was nearly twofold and PAI-1 4G-4G more than threefold more frequently found in NVLC vs patients with VLC; the Hardy-Weinberg equilibrium of these two polymorphisms confirms this data in NVLC. We suggest that PAI-1 4G-4G and MTHFR677 TT could be considered as factors of fibrosis and thrombosis mechanisms, increasing the inflammation response, and causing the hepatic fibrosis and augmented intrahepatic vascular resistance typical of LC. PAI-1 4G-4G and MTHFR 677 TT screening of LC patients could be useful, mainly in those with NVLC, to identify patients in which new drug therapies based on the attenuation of the hepatic stellate cells activation or other mechanisms could be more easily evaluated.     

Factor V Leiden G1691A, prothrombin G20210A, and MTHFR C677T mutations in Turkish inflammatory bowel disease patients

BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) have an increased risk for thromboembolic complications. We investigated the incidence of factor V Leiden G1691A, methylene tetrahydrofolate reductase (MTHFR) C677T, and prothrombin G20210A mutation in 27 Turkish IBD patients with no history of thromboembolic disease. METHODOLOGY: Twenty-seven patients, 22 with ulcerative colitis (UC) and 5 with Crohn's disease (CD), and 47 healthy were included to the study. The DNAs were obtained from peripheral blood by using pure polymerase chain kit. Then, factor V Leiden G1691A, which active protein C resistance positive, prothrombin G20210A and MTHFR C677T mutations were investigated in DNA by using LightCycler-Factor V Leiden G1691A mutation, Prothrombin G20210A and MTHFR C677T estimate kits. RESULTS: The heterozygote factor V Leiden G1691A mutation was detected in 3 (11.1%) patients with IBD and 2 (4.3%) controls (p > 0.05). The homozygote factor V Leiden G1691A mutation was not estimated among patients and controls. Heterozygote prothrombin G20210A mutation was detected in 2 (7.4%) patients with IBD and in 0 (0%) controls (p > 0.05). There was no homozygote prothrombin G20210A mutation in IBD and controls. Heterozygote MTHFR C677T mutation was 10 of 27 (37%) patients with IBD while 15 of 47 (32%) controls (p > 0.05). Homozygote MTHFR C677T mutation was detected in 4 patients (14.9%) with IBD and 3 (6.3%) controls (p > 0.05). CONCLUSIONS: Our study did not reveal any association between IBD and the most common hereditary thrombophilic factors and these mutations interfere with neither disease manifestations nor the thrombotic complications.     

Prevalence of factor V Leiden, prothrombin G20210A, and MTHFR G677A among 594 thrombotic Jordanian patients.

Venous thromboembolism develops as the result of multiple interactions between non-genetic and genetic risk factors. In order to estimate the frequency of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in Jordanian thrombotic patients, we studied 594 patients admitted to the King Hussein Medical Center for thrombophilia assessment. Polymerase chain reaction detected 25.7% (20.7% heterozygous, 5% homozygous), 6% (5.8% heterozygous, 0.2% homozygous) and 31.7% (25% heterozygous, 6.7% homozygous) for factor V Leiden, prothrombin G20210A and MTHFR C677T mutations, respectively. A one-stage clotting assay was used to measure prothrombin activity. None of the prothrombin G20210A mutant patients had high prothrombin activity. The high prevalence found among our study group of factor V Leiden and prothrombin G20210A confirms the importance of thrombophilia screening for patients with venous thrombosis with family history and those with additional risk factors. On the contrary, the high prevalence of the MTHFR C677T mutation among arterial thrombosis patients shows its importance in screening in arterial thrombosis patients. These results, which are close to the prevalence found by other studies in the region, suggests that the Eastern Mediterranean region is probably the area of origin of these mutations, especially factor V Leiden. The knowledge of these frequencies in the Middle East region through population-based studies will contribute to a better understanding of the interaction between genetic and environmental risk factors underlying the mentioned mutations.     

Familial thrombophilia and the occurrence of fetal growth restriction

BACKGROUND AND OBJECTIVES: To evaluate the association between unexplained or gestational-hypertension-associated fetal growth restriction (FGR) and factor V Leiden, prothrombin A20210 mutations, and methylenetetrahydrofolate reductase (MTHFR) TT 677 genotype. DESIGN AND METHODS: Sixty-one women with a previous history of FGR and 93 parous women with uneventful pregnancies from the same ethnic background were investigated for the presence of factor V (FV) Leiden, prothrombin A20210 mutations, and MTHFR TT 677 genotype. Moreover, antiphospholipid antibodies, antithrombin, protein C, and total and free protein S antigen were determined in all patients. RESULTS: Among the controls, 2 (2.2%) carried the FV Leiden mutation, 19 (20.4%) were TT MTHFR homozygotes and 1 (1.6%) carried the prothrombin A20210 allele. The FV Leiden mutation was present in 8 women with FGR (13.1%, OR: 6.9, 95%CI 1.4-33.5), the TT MTHFR homozygosity in 17 (27.8%, OR: 1.5, 95%CI 0.7-3.2) and the A20210 prothrombin allele in 7 (11.5%, OR: 5.9, 95%CI 1.2-29.4). In six cases (9.8%) there was coexistence of more than one mutation (2 had the FV Leiden and the TT MTHFR genotype and 4 carried the A20210 prothrombin allele and TT MTHFR genotype). A logistic regression analysis showed that FV Leiden and A20210 prothrombin mutations were independently associated with the occurrence of FGR. INTERPRETATION AND CONCLUSIONS: Present data indicate an association between prothrombotic genetic factors and FGR.     

Primary thrombophilia in Mexico. II. Factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase C677T polymorphism in thrombophilic Mexican mestizos.

We have shown that in Mexican mestizo patients with clinical features of primary thrombophilia, 39% have activated protein C resistance phenotype, 5% protein C deficiency, and 2% protein S deficiency. In the present study, in a group of 37 thrombophilic Mexicans and 50 normal controls, we assessed the factor V G1691A (Leiden), the prothrombin G20210A, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphisms. Four patients were found to be heterozygous for factor V Leiden, 5 heterozygous for the prothrombin 20210, 16 heterozygous, and 6 homozygous for the MTHFR 677. There were four individuals with co-segregation of alleles: two heterozygotes for the factor V Leiden/prothrombin 20210, one heterozygote for prothrombin 20210/MTHFR 677, and one heterozygote for prothrombin 20210/homozygote for MTHFR 677. For factor V Leiden, prothrombin 20210, and MTHFR 677 mutations, the allele frequencies were respectively 1% (+/-0.2%, alpha = 0.05), <1% and 51% (+/-5%, alpha = 0.05), with calculated relative risks for thrombosis of 5.94 (P = 0.08), >7.66 (P < 0.05), and 0.44 (P NS), respectively. In Mexican mestizo thrombophilic patients, the low prevalence of the factor V Leiden mutation (10.8%) and the high prevalence of the prothrombin 20210 mutation (13.5%) contrast with those identified in Caucasian thrombophilic patients (21% and 6%, respectively; P < 0.01). On the other hand, the high prevalence of the MTHFR 677 mutation gene both in normal controls (78%) and thrombophilic patients (61%) does not support a role of this mutation in the thrombogenesis of Mexican mestizo patients.     

Factor V-Leiden, prothrombin G20210A, and MTHFR C677T mutations among patients with sickle cell disease in Eastern Saudi Arabia

The prevalence of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations were investigated among 87 Saudi sickle cell disease (SCD) patients (38 males and 49 females) and 105 healthy controls (65 males and 40 females). The prevalences of factor V Leiden (P = 0.174) and PRT G20210A (P = 0.397) were not different between patients and controls, thereby giving no support to an association of either single-point mutation with SCD. However, an increased prevalence of the MTHFR 677 T/T genotype was seen among patients (8/87) compared to controls (4/105), but this was not statistically significant (P = 0.217; OR = 2.56). This suggested a low impact of inherited hypercoagulability risk factors in the pathogenesis of SCD and/or its complications.     

Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis

The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with cirrhosis without hepatocellular carcinoma are not clearly defined. The role of thrombophilic genetic factors is well established in other venous thrombotic diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin [PTHR A(20210)], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR C677-->T]) have been identified and associated with increased risk of venous thrombosis. The aim of our study was to investigate the role of these thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty-three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons served as controls. The FVL, PTHR A(20210), and MTHFR C(677)-->T genotypes were identified by a polymerase chain reaction and restriction analysis. The frequencies of FVL, PTHR A(20210) mutation, and homozygous MTHFR C(677)-->T were 13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in cirrhotic patients without PVT, respectively. Five patients in the former group had associated defects. A thrombophilic genotype was detected in 69.5% of the patients with PVT. Identification of this high-risk group may have implications in patients who are candidates for major surgery or liver transplantation, and may influence the duration of oral anticoagulation.     

Risk of recurrent venous thrombosis in patients with G20210A mutation in the prothrombin gene or factor V Leiden mutation.

The impact of the G20210A prothrombin mutation, factor V Leiden and 677T mutation of methylene tetrahydrofalate reductase (MTHFR) in recurrent deep venous thrombosis (DVT) is not so clear. We have prospectively monitored 259 patients following a first episode of DVT in order to determine which factors influence the development of a recurrent event. Several clinical and biological factors together with the genetic polymorphisms of factor V Leiden, G20210A prothrombin and 677T MTHFR were assessed. During a median follow-up of 786 patient-years, 27 patients (14%) developed one objective episode of recurrent venous thrombosis. The carriers of a double defect, homozygous or double heterozygous for factor V Leiden and G20210A, had an increased risk after a first episode of DVT, while patients who were isolated heterozygous for factor V Leiden or G20210 had a risk of recurrent DVT similar to patients who had neither mutation (annual incidence of 12.1, 3.1, 2.9 and 2.8%). The 677T MTHFR mutation alone or combined with hyperhomocysteinemia was not associated with an increased risk of recurrent events. The development of proximal DVT (P=0.01) and the presence of a double defect (P=0.01) were the only two risk factors independently associated with a high recurrence ratio in the multivariate analysis. Thus, the annual incidence of DVT recurrence in patients without any of these two risk factors was only 0.6% (95% confidence interval, 0.2-0.9). We have identified a group of patients with DVT but at very low risk of re-thrombosis in whom an extended secondary thromboprophylaxis should be carefully considered.     

Posterior ocular involvement in Behçet's disease and thrombophilic mutations

It is not well established whether there is an association among common inherited gene defects, Factor V (FV) Leiden, the prothrombin (PT) G20210A mutation, C677T methylene tetrahydrofolate reductase (MTHFR) and ocular Beh?et's disease (BD). We aimed to evaluate the association of these mutations with posterior ocular involvement in 89 BD patients from eastern Spain (48 men and 41 women) of whom 23 had posterior ocular involvement and 66 did not. None of the 23 BD patients with posterior ocular involvement was a carrier of either FV Leiden or the PTG20210A mutation. Only 1 patient was a carrier of the 677TT MTHFR mutation, whereas 4 patients carried FV Leiden, 3 the PTG20210A mutation and 10 the 677TT MTHFR mutation in the group without posterior ocular involvement (p = 0.227, p = 0.556, p = 0.144), respectively. In our geographical area, the commonest thrombophilic mutations do not seem to be related with posterior ocular involvement in BD patients.     

Prevalence of factor V Leiden G1691A, MTHFR C677T, and prothrombin G20210A among Asian Indian sickle cell patients

The prevalence of factor V (FV) Leiden G1691A, prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T mutations were investigated among 90 sickle trait, 61 sickle homozygous, 75 sickle beta thalassemia, and 15 HbSD Asian Indian sickle cell patients. In all, 297 healthy controls were evaluated to compare the polymorphism frequency. The prevalence of FV Leiden heterozygous G>A were significant in the group (P = .02), while PRT G20210A polymorphism was not seen among patients as well as controls. However, an increased frequency of the MTHFR 677 C>T genotype was seen among patients as well as controls, but this was not statistically significant (P = .13). This suggested a low impact of inherited hypercoagulability risk factors in the pathogenesis of sickle cell disease and/or its complications.     

The frequency of factor V Leiden and concomitance of factor V Leiden with prothrombin G20210A mutation and methylene tetrahydrofolate reductase C677T gene mutation in healthy population of Denizli, Aegean region of Turkey.

Factor V Leiden causing activated protein C resistance is the most common inherited form of thrombophilia leading to thrombosis. Its frequency shows great ethnic and geographic variations. The aim of this study was to determine the frequency of FV Leiden and coinheritance of FV Leiden with two other frequent hereditary thrombophilia causes, namely, prothrombin G20210A and methylene-tetrahydrofolate reductase (MTHFR) C677T mutation in the Aegean region of Turkey. The study population consisted of 1030 (500 men and 530 women) apparently healthy subjects. Functional resistance to activated protein C (APC) was measured by using the test kit STA staclot APC-R ((Diagnostica Stago, Asnieres, France, Cat. No. 00721). In subjects with APC resistance, molecular analyses of FV Leiden and of prothrombin G20210A and MTHFR C677T mutation were performed by using FV-PTH-MTHFR StripA (Vienna Lab, Labordiagnostika GmbH, Austria) kit, which was based on hybridization of polymerase chain reaction (PCR) amplified DNA products with mutation-specific oligonucleotide probes. Functional APC resistance was present in 93 subjects (9%). FV Leiden mutation was found in 87 of 93 subjects with APC resistance by PCR method. The FV Leiden carrier frequency was found to be 8.4% (87/1030). Seventy-six individuals were heterozygous (7.3%), and 11 were homozygous (1.06%). Among the 87 subjects with FV Leiden mutation, 45 subjects had MTHFR C677T gene mutation (7 homozygous, 38 heterozygous) and 4 subjects had heterozygote prothrombin G20210A gene mutation. A combination of FV Leiden and prothrombin G20210A and MTHFR C677T gene mutation was detected in 3 subjects. The results indicate that FV Leiden prevalence is quite high and coexistence of FV Leiden with other hereditary causes of thrombosis such as prothrombin G20210A mutation and MTHFR enzyme defect is not rare in healthy population of Aegean region of Turkey.     

Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: a meta-analysis of published studies

Background

The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial.

Methods

We performed a MEDLINE search to identify published case-control and cohort studies correlating the factor V Leiden, prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T (TT genotype) mutations with myocardial infarction, ischemic stroke, or peripheral vascular disease. Studies were included only when they adhered to specific diagnostic criteria for ischemic events and met the published methodological criteria. Odds ratios (ORs) with accompanying 95% CIs were calculated for each mutation and clinical end points with a random-effects model (DerSimonian and Laird method).

Results

The association between inherited gene mutations and arterial ischemic events was modest: factor V Leiden mutation (OR, 1.21; 95% CI, 0.99-1.49), PT G20210A mutation (OR, 1.32; 95% CI, 1.03-1.69), and MTHFR TT mutation (OR, 1.20; 95% CI, 1.02-1.41). Subgroup analyses of younger patients (<55 years old) and of women revealed slightly stronger associations overall.

Conclusions

Genetic abnormalities specific to factor V, prothrombin ,and homocysteine metabolism increase the risk for myocardial infarction and ischemic stroke, particularly among younger patients and women. Because the overall association is only modest, screening studies should be limited to carefully selected patient populations. The individual propensity for arterial and venous thrombosis is likely influenced by differing local mechanisms, systemic mechanisms, or both.     

High prevalence of thrombophilic genotypes in patients with acute mesenteric vein thrombosis

OBJECTIVES: Mesenteric vein thrombosis is a rare but severe abdominal emergency, often requiring intestinal resection. New genetic prothrombotic defects such as factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype have been described in association with venous thrombosis. Our goal was to assess prevalence and clinical significance of genetic thrombophilia in mesenteric vein thrombosis. METHODS: Twelve patients with acute mesenteric vein thrombosis were compared with 431 healthy people from the same geographical area. The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype were identified by polymerase chain reaction and restriction analysis. RESULTS: A thrombophilic genotype was present in 9 patients (75%): the methylenetetrahydrofolate reductase TT677 genotype was present in 6 (50%), the factor V Leiden in 3 (25%), and the prothrombin transition G20210A in 3 (25%). Combined mutations were present in 4 (33%) patients. CONCLUSIONS: The factor V Leiden, the prothrombin transition G20210A, and the methylenetetrahydrofolate reductase TT677 genotype are important predisposing factors in the pathogenesis of mesenteric vein thrombosis. Their identification bears strong clinical implications for management of patients with mesenteric vein thrombosis.     

Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischemic stroke in childhood

Ischemic stroke is a rare event in childhood. In approximately one third of cases no obvious underlying cause or disorder can be detected. We investigated the importance of genetic risk factors of venous thromboembolism in childhood or stroke in adulthood as risk factors for spontaneous ischemic stroke in children. One hundred forty-eight Caucasian infants and children (aged 0.5 to 16 years) with stroke and 296 age-matched controls from the same geographic areas as the patients were analyzed for increased lipoprotein (a) [Lp(a)] levels >30 mg/dL; for the presence of the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, and the TT677 genotype of methylenetetrahydrofolate reductase (MTHFR); and deficiencies of protein C, protein S, and antithrombin. The following frequencies (patients v controls), odds ratios (ORs), and confidence intervals (CIs) of single risk factors were found: Lp(a) >30 mg/dL (26.4% v 4.7%; OR/CI, 7.2/3.8 to 13.8; P <.0001), FV G1691A (20.2% v 4%; OR/CI, 6/2.97 to 12.1; P <.0001), protein C deficiency (6% v 0.67%; OR/CI, 9.5/2 to 44.6; P =.001), PT G20210A (6% v 1.3%; OR/CI, 4.7/1.4 to 15.6; P =.01), and the MTHFR TT677 genotype (23.6% v 10.4%; OR/CI, 2.4/1.53 to 4.5; P <.0001). A combination of the heterozygous FV G1691A mutation with increased Lp(a) (n = 11) or the MTHFR TT677 genotype (n = 5) was found in 10. 8% of cases, but only 0.3% of controls (OR/CI, 35.75/4.7 to 272; P <. 0001). Increased Lp (a) levels, the FV G1691A mutation, protein C deficiency, the prothrombin G20210A variant, and the MTHFR TT677 are important risk factors for spontaneous ischemic stroke in childhood.     

Coexistence of prothrombic risk factors and its relation to left ventricular thrombus in acute myocardial infarction

OBJECTIVE: Within the last few years a number of thrombophilic mutations have been identified. Pre-symptomatic testing for these established genetic risk factors identifies individuals predisposed to a disease and often allows to select suitable prophylactic interventions in time. We investigated whether or not the prothrombin G20210A allele, the factor V Leiden G1691A, and MTHFR C677T allele are risk factors for left ventricular thrombus (LV) in patients with myocardial infarction (AMI) or not. METHODS AND RESULTS: We analysed clinical, echocardiographic and biochemical data in 183 consecutive patients (aged 58 +/- 12 years; 34 women) with a first anterior acute myocardial infarction. Two-dimensional echocardiographic examination was performed on days 1, 3, 7, 15, and 30. LV thrombi were detected in 42 (23%) of the 183 patients with acute myocardial infarction. We have used multiplex assays based on PCR and DNA hybridization in microtitre plates for the simultaneous analysis of three mutations (FV Leiden G1691A, prothrombin G20210A, and MTHFR C677T). No significant differences in allele frequencies of FV Leiden G1691A (9.5% vs. 8.5%, p = 0.75), prothrombin G20210A (9.5% vs 7.1%, p = 0.74) and MTHFR C677T (47.6% vs. 50.3%, p = 0.74) were found in patients with LV thrombus when compared with those without LV thrombus. No significant differences in haemostatic factor levels were found in patients with LV thrombus when compared with those without LV thrombus. CONCLUSION: FV Leiden, prothrombin 20210 variant, and MTHFR mutation are no risk factors for left ventricular thrombus in patients with myocardial infarction.The presence of multiple mutations did not influence the development and outcome of LV thrombus in patients with myocardial infarction     

Prevalence of thrombotic risk factors among β-thalassemia patients from Western Iran

Background There is evidence for increased risk of thrombosis in patients with β-thalassemia intermedia and β-thalassemia major. The present study investigated the prevalence of thromboembolic risk factors of prothrombin G20210A, factor V Leiden G1691A and methylentetrahydrofolate reductase (MTHFR) C677T, as well as the hematological and clinical profiles in β-thalassemia major and intermedia patients from Western Iran. Methods Patients consisted of 158 β-thalassemia patients, 151 β-thalassemia major and 7 β-thalassemia intermedia patients, including 82 males and 76 females aged 13.6 ± 6.3 years. The control group were 180 healthy blood donors and school students, consisting of 103 males and 77 females aged 16.8 ± 2.1. Genotyping was done by PCR-RFLP using Mnl I, Hind III and Hinf I for factor V Leiden and prothrombin G20210A and MTHFR, respectively. Results The prevalence of prothrombin G20210A variant in patients and healthy individuals were 1.3 and 3.3%, respectively. Factor V Leiden G1691A was insignificantly higher in β-thalassemia patients (prevalence 5.7% and allele frequency 3.2%) compared to healthy individuals (2.8%). This mutation was found in eight β-thalassemia major (5.3%) and one β-thalassemia intermedia (14.3%) patients. The prevalence of MTHFR C677T polymorphism was slightly higher in patients (50%) compared to healthy individuals (48.3%). Around 71% of β-thalassemia intermedia and 38.4% of β-thalassemia major patients had undergone splenectomy. In β-thalassemia major patients, 5.3% had insulin dependent diabetes mellitus (IDDM) and 6.6% had HCV antibodies. All patients with IDDM were splenectomized and in one of them the prothrombin G20210A variant was found. Two patients, a 7-year-old boy with β-thalassemia intermedia receiving regularly blood transfusion and a β-thalassemia major patient (a 22-year-old splenectomized female), were found to be homozygous for MTHFR 677TT and heterozygous for factor V Leiden G1691A. Double heterozygosity for factor V Leiden G1691A and MTHFR C677T and also homozygous factor V Leiden 1691AA were found in two β-thalassemia major patients. No thromboembolic event has been recorded in the files of patients. Conclusions The results of present study establish the prevalence of biological risk factors of thrombosis in β-thalassemia patients from Western Iran. It seems that thrombophilic mutations may not be associated with thrombotic events in thalassemic patients, which needs to be confirmed by the study of larger sample sizes.     

Genetic polymorphisms associated with acute pulmonary embolism and deep venous thrombosis.

Frequently an inherited predisposition to thrombosis remains clinically silent until an additional environmental factor intervenes. The present study aimed to assess distribution of inherited risk factors of venous thrombosis in patients with venous thromboembolism (VTE). The prevalences of factor V Leiden (FV Leiden), prothrombin factor II G20210A (FII G20210A), C677T and A1298C of methylenetetrahydrofolate reductase (MTHFR) mutations were studied in 149 VTE patients and 100 controls. The following key risks were established: previous deep venous thrombosis or pulmonary embolism (23.5%), bed rest (34.2%), immobilisation of lower limb (10.1%), hospitalisation (30.9%) and obesity (28.9%). In 29 (19%) patients and in three (3%) controls FV Leiden was found. A significant association between VTE and FV Leiden was established. There were six (4%) carriers of the FII G20210A among VTE patients and one in the controls. No associations between VTE and MTHFR polymorphisms (C677T, A1298C) were found. In three of 149 patients both FV Leiden and FII G20210A polymorphisms were observed. The mean protein C activity was slightly, though nonsignificantly, smaller in VTE patients. In conclusion, there was a positive association between venous thromboembolism and factor V Leiden. Only a weak trend favouring a relationship between prothrombin factor II G20210A and venous thrombolism was present. No associations between common polymorphisms of methylenetetrahydrofolate reductase and venous thromboembolism were found.     

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.     

Abdominal venous thrombosis in neonates and infants: role of prothrombotic risk factors - a multicentre case-control study. For the Childhood Thrombophilia Study Group

The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, together with fasting homocysteine (HCY) concentration, lipoprotein (Lp)(a), anti-thrombin (AT), protein C (PC), protein S (PS) and anti-cardiolipin antibodies were investigated in 65 consecutively recruited infants (neonate to < 12 months) with renal venous thrombosis (RVT; n = 31), portal vein thrombosis (PVT; n = 24) or hepatic vein thrombosis (HVT n = 10), and 100 age- and sex-matched healthy controls. FV G1691A was found in 14 babies (heterozygous: RVT n = 9, PVT n = 4; homozygous HVT n = 1) and five controls, the MTHFR TT677 genotype together with increased HCY in four infants with thrombosis (RVT n = 2; PVT n = 1; HVT n = 1) compared with one control, and the PT G20210A variant was present in one control only. PC type I deficiency was diagnosed in three patients (RVT n = 2; PVT n = 1) and AT deficiency in two patients (RVT n = 1; PVT n = 1). Three neonates with spontaneous thrombosis showed FV G1691A combined with Lp(a) and the FV G1691A was combined with the PT G20210A genotype in two infants. Additional triggering factors were reported in 27 patients (41.5%). The overall odds ratios (ORs) and 95% confidence intervals (CIs) with respect to the different thrombosis locations were: RVT (OR/CI: 10.9/3.85-31.1; P < 0.0001), PVT (5.47/1.7-17.6; P < 0.0007) and HVT (3.3/0.58-18.7; P = 0.18). The data presented here suggest that genetic prothrombotic risk factors also play an important role in abdominal venous thrombosis during infancy.     

Factor V Leiden and prothrombin gene G20210A mutations are uncommon in portal vein thrombosis in India.

BACKGROUND: Extra-hepatic portal vein obstruction due to portal vein thrombosis (PVT) is an important cause of portal hypertension in several regions including India. The cause of thrombosis in these patients remains unclear. We studied the frequency of mutations in genes for coagulation factors V and II (prothrombin) in 61 Indian patients with PVT and 49 healthy control subjects. METHODS: The presence of factor V Leiden mutation and of G20210A prothrombin gene mutation was determined using polymerase chain reaction followed by restriction fragment length polymorphism. Chi-squared test was used to compare patients and controls. RESULTS: Of the 61 patients (median age 11 years; 47 male) studied, 49 were children. One of 61 (1.6%) patients with PVT was heterozygous for factor V Leiden mutation and none had the G20210 prothrombin gene mutation. The frequencies of these mutations were not different from those in control subjects (2/49 and 0/46, respectively). CONCLUSION: Factor V Leiden and G20210 prothrombin gene mutations are infrequent in Indian patients with PVT. Thus, these mutations are unlikely to be responsible for PVT in the Indian population.