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.     

Anticardiolipin antibodies and risk of thromboembolic disease in young Jamaican women

BACKGROUND: Anticardiolipin antibodies (aCL) are a heterogeneous group of antiphospholipid antibodies that are associated with arterial and venous thrombosis. We measured aCL in women, aged 15-49 years, to determine if they are an independent risk factor for thromboembolic disease. STUDY DESIGN: Case--control study METHODS: Fifty cases were studied including venous thromboembolism (n=29), stroke and myocardial infarction (n=21), along with 148 age-matched controls. Serum samples were assayed for aCL and anti-beta2 glycoprotein 1 antibodies using the enzyme-linked immunosorbent assay (ELISA). Information on other risk factors was obtained by a standardized questionnaire. RESULTS: aCL were present in 16/50 (32%) of cases compared with 25/148 (17%) of controls (P[?]=[?]0.02). Unadjusted odds ratio (OR) and 95% confidence interval (95% CI) for thromboembolic disease associated with aCL was 2.32 (1.10--4.87). Other risk factors were hypertension, 2.93 (1.20--7.17) and a history of other heart diseases, 12.78 (1.32--123.60). Adjustment for hypertension, diabetes, oral contraceptive use, smoking, alcohol use, varicose veins, a family history of cardiovascular disease and a history of other heart diseases yielded OR (95%CI) 2.99 (1.32--6.80). beta2 glycoprotein 1-dependent aCL were also an independent risk factor, OR 4.56 (1.76--17.83). Subgroup analysis was carried out separately for cases of MI and stroke and for venous thrombosis. Adjusted OR (95% CI) associated with aCL in cases of MI and stroke was 1.76 (0.46--6.73) and 3.32 (1.15--9.54) for venous thromboembolism. CONCLUSION: aCL are a risk factor for thromboembolic disease in young Jamaican women. They confer a strong independent risk for venous thromboembolism.     

Prevalence of factor V Leiden and prothrombin variant G20210A in patients age <50 years with no significant stenoses at angiography three to four weeks after myocardial infarction

OBJECTIVES: We sought to determine the frequencies of factor V Leiden and prothrombin variant G20210A in patients age <50 years with no significant coronary stenoses three to four weeks after myocardial infarction (MI). BACKGROUND: Factor V Leiden and prothrombin variant G20210A occur frequently in patients with venous thromboembolism. However, the contribution of these mutations to the development of MI requires clarification. METHODS: The frequencies of factor V Leiden and prothrombin variant G20210A were determined in 41 patients age <50 years who had "normal" or "near normal" coronary arteries (no stenosis >50%) at angiography three to four weeks after MI (the study group) and compared with those in 114 patients who had at least one angiographic stenosis >50% after MI (the control group). Patients age > or =50 years with, or without, stenoses were also studied. RESULTS: The frequency of factor V Leiden was 14.6% in patients age <50 years in the study group compared with 3.6% in patients in the control group (odds ratio [OR] 4.7 [95% confidence interval (CI) 1.3-17.7], p = 0.02). The frequency of the prothrombin variant G20210A was 7.3% in the study group compared with 1.8% in the control group (OR 4.4 [95% CI 0.7-27.5], p = 0.12). One or both mutations were present in 8 of the 41 patients (19.5%) age <50 years in the study group compared with 6 of the 114 patients (5.5%) in the control group (OR 4.4 [95% CI 1.4-13.5], p = 0.01). In all 271 patients (irrespective of age) with normal arteries, the frequency of factor V Leiden was 11.7% (7/60) compared with 4.3% (9/211) in patients with at least one >50% stenosis (OR 2.9 [95% CI 1.1-8.3], p = 0.04), and the frequency of prothrombin variant G20210A was 6.7% (4/60) compared with 1.4% (3/211) (OR 4.9 [95% CI 1.1-22.8], p = 0.04), respectively. CONCLUSIONS: The frequencies of factor V Leiden and/or prothrombin variant G20210A are increased in patients age <50 years with normal or near normal coronary arteries after MI.     

Lower contribution of factor V Leiden or G202104 mutations to ischemic stroke in patients with clinical risk factors: pair-matched case-control study.

It was suggested that factor V Leiden and prothrombin G20210A mutations increase the risk of ischemic stroke only in combination with clinical risk factors of arterial ischemic disease. In these studies the controls were derived from the general population, with fewer clinical risk factors, which might have produced biased results. The factor V Leiden and prothrombin G20210A mutations were examined by polymerase chain reaction technique in 120 ischemic stroke patients and 120 controls younger than 65 years of age. Each patient had his own control, tightly matched in clinical risk factors. The prevalences of factor V Leiden and prothrombin G20210A mutations in patients were 8.3% (P = 0.02) and 7.5% (P = 0.04), respectively, and 2.5% for controls for both mutations. All carriers were single heterozygotes. In patients, but not in controls, the carriers of either mutation were mostly women and with fewer clinical risk factors for arterial ischemic events. In particular, considering both mutations as a single coagulation deficit, their presence increased the likelihood of ischemic stroke (odds ratio [OR] = 3.6; 95% confidence interval [CI] 1.4-9.3), especially among women (OR = 4.6; 95% CI: 1.2-17.8), normotensive persons (OR = 9.2; 95% CI: 1.1-17.8) and those having normal cholesterol (OR = 5.9; 95% CI: 1.6-21.2) and triglyceride serum concentrations (OR = 4.3; 95% CI: 1.5-12.8). In the studied sample of adult North Mediterranean population younger than 65 years the prevalences of factor V Leiden and prothrombin G20210A mutations were greater in patients with ischemic stroke than in matched controls. Unlike in studies with unmatched controls, we observed an apparently negative interaction of these mutations with clinical risk factors.     

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.     

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.     

Coagulation factors II, V, VII, and X, prothrombin gene 20210G-->A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction

Increased levels of hemostatic factors and genetic mutations of proteins involved in coagulation may play a role in the pathogenesis of coronary artery disease. We investigated clotting activity of factors II (FII:C), V (FV:C), VII (FVII:C), and X (FX:C), the prothrombin gene 20210G-->A transition, and the factor V Leiden mutation in 200 survivors of myocardial infarction and in 100 healthy controls. FV:C (P<0.0001) and FVII:C (P<0.0001) were found to be independent risk factors for myocardial infarction. High FV:C or high FVII:C combined with smoking or arterial hypertension increased the relative risk for myocardial infarction up to 50-fold. One of 177 patients (0.6%) and 4 of 89 controls (4.5%) had the prothrombin 20210 AG genotype. Eleven of 177 patients (6.2%) and 6 of 89 controls (6.7%) were heterozygous for the factor V Leiden mutation. No homozygous carrier for these mutations was found. Neither the prothrombin gene 20210G-->A transition (odds ratio [OR], 0.1; 95% confidence interval [CI], 0.01 to 1.1) nor the factor V Leiden mutation (OR, 1.0; 95% CI, 0.4 to 2.8) were associated with an increased relative risk for myocardial infarction. In conclusion, our data indicate that neither the prothrombin gene 20210G-->A transition nor the factor V Leiden mutation are risk factors for myocardial infarction. High FVII:C was confirmed to be an independent risk factor for myocardial infarction. Moreover, we describe for the first time that high FV:C is an independent risk factor for myocardial infarction.     

The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors

BACKGROUND AND OBJECTIVES. The modulation of disease severity in hemophilia A (HA) patients may be related to the co-inheritance of mutations in genes with a known thrombotic effect such as factor V Leiden (FVL) and prothrombin. In the Spanish population, the prothrombin 20210A (PT20210A) allele is the most prevalent genetic risk factor for venous thromboembolism. DESIGN AND METHODS. We investigated the presence of both mutations in a cohort of 265 hemophiliac patients divided into two groups: I) 140 unrelated patients with moderate and mild HA and II) 125 unrelated patients with severe HA (83 carrying an inversion of intron 22). RESULTS. In group I, 4 patients had the FVL (2.8% vs. 2.98% controls) and 5 had the PT20210A (3.6% vs. 6.46% controls). In group II, two patients with inversion had the FVL (1.6%) and PT20210A was found in 10 patients (8%), five of them with inversion of intron 22 without inhibitors. One of these patients had the FVL and PT20210A mutations concomitantly. In the subgroup of patients with inversion who were carriers of the PT20210A, three parameters i.e. spontaneous bleeding (p=0.008), factor VIII utilization (p=0.016) and number of hemophilic arthropathies (p<0.0005) were significantly lower than in a subgroup of 11 age-matched non-PT20210A severe HA patients with inversion and without inhibitors. INTERPRETATION AND CONCLUSIONS. These results indicate that the inheritance of PT20210A could be a protective factor that mitigates the clinical severity of HA.     

Autoantibodies to the atheroma component beta2-glycoprotein I and risk of symptomatic peripheral artery disease

Peripheral artery disease (PAD) is mostly related to atherosclerosis. Autoimmunity and, in particular, antibodies to cardiolipin (aCL) and phospholipid cofactors such as beta2-glycoprotein I (beta2-gpI) might influence the development of atheroma. Beta2-glycoprotein I (beta2-gpI) has been found in atheroma. It has previously been shown that immunoglobulin A (IgA) anti-beta2-gpI antibodies are associated with a risk of cerebral ischemia and myocardial infarction. This case control study aimed to determine whether elevated levels of aCL/anti-beta2-gpI antibodies are associated with a risk of symptomatic PAD (sPAD). Cases comprised a nonselected population of patients with sPAD (intermittent claudication or critical ischemia). Patient recruitment was based on arteriography changes. Controls were selected from patients admitted to orthopedic wards as a result of fractures or muscle-ligamentous disorders. Age, sex, race, hypertension, smoking, diabetes mellitus, and hypercholesterolemia were evaluated as risk factors in both groups. IgG/IgM/IgA aCL and anti-beta2-gpI were detected by enzyme-linked immunoabsorbant assays (ELISA). To estimate the grade of association of antibodies with sPAD, odds ratios (OR) were calculated. Logistic regression was utilized for adjustment of confounding factors. Seventy-seven cases and 93 controls were studied. The mean age was 61.5 years for cases and 47.5 years for controls (p <0.001). Among the risk factors evaluated, the presence of hypertension showed the strongest association with sPAD (OR 12.1; 95%CI 5.8-30). The presence of IgA anti-beta2-gpI was independently associated with sPAD (OR 5.4; 95%CI 1.8-15.8; p = 0.01). IgA aCL was strongly associated with the outcome (nonadjusted OR 11.5 after Agresti correction). IgA aCL and IgA anti-beta2-gpI antibodies were not associated with any known risk factors for sPAD or with arteriography changes. The occurrence of these autoantibodies might represent one of the links between autoimmunity and atherosclerosis in patients with sPAD.     

Prothrombotic gene mutations and Crohn's disease; is there any association?

BACKGROUND/AIMS: Patients with inflammatory bowel disease have an increased tendency for thromboembolism. In this study we aimed to determine the frequency of FV gene and Prothrombin G20210A gene mutations in a group of patients with Crohn's Disease (CD) and estimate its correlation with disease activity and clinical subtype. METHODOLOGY: Forty-four CD patients and 43 healthy controls were included in the study. Twenty-three of the patients had inflammatory CD, while 11 had fibrostenotic and 10 had fistulizing CD. Only one patient had a history of deep vein thrombosis. Polymorphism Light Cycler FV Leiden mutation detection kit and Light Cycler prothrombin (G20210A) mutation detection kit were used for the detection of mutations in DNA samples. RESULTS: Forty of the CD patients had normal factor V genotype, three (6.8%) patients showed a heterozygous, and one (2.3%) patient homozygous pattern. Two (4.7%) of the 43 controls showed heterozygous factor V mutation and 41 had normal FV genotype. Two (4.6%) CD patients had heterozygous prothrombin G20210A mutation, and there was only one (2.3%) homozygous mutation in the control group. There was no significant difference between controls and CD patients neither for factor V mutation (p > 0.05) nor for prothrombin G20210A mutations (p > 0.05). No correlation was found between disease activity and both gene mutations (p > 0.05), as well as between disease subtype and gene mutations (p > 0.05). CONCLUSIONS: The prevalence of prothrombin G20210A gene and factor V Leiden gene mutations were found to be statistically insignificant among CD patients and control group.     

Inherited thrombophilic risk factors and venous thromboembolism: distinct role in peripheral deep venous thrombosis and pulmonary embolism

STUDY OBJECTIVES: To investigate whether the FII A(20210) mutation is associated with isolated pulmonary embolism (PE). DESIGN: Case-control study. SETTING: Five thrombosis centers in southern Italy. PATIENTS: Six hundred forty-seven consecutive referred patients with objectively documented venous thrombosis and 1,329 control subjects. Measurements and results: Medical histories were collected. The G-to-A transition at nucleotide 1691 within the factor V gene (FV Leiden) and the G-to-A transition at nucleotide position 20210 within the prothrombin gene locus (FII A(20210)), levels of anticoagulant factors, and levels of antiphospholipid antibodies were determined by standard techniques. Patients with deep venous thrombosis (DVT) of the lower extremities (n = 346) or with additional PEs (n = 175) showed similar prevalences of FV Leiden mutation (24.3% and 16.6%, respectively) and FII A(20210) mutation (14.2% and 12.6%, respectively), and similar deficiencies of natural anticoagulants (4.9% and 2.3%, respectively). In both groups, the frequencies of FV Leiden and/or FII A(20210) mutation were higher than those observed among 1,329 apparently healthy control subjects (4.8% and 4.4%, respectively; p < 0.0001). Among patients with isolated PE (n = 126), prevalences of FV Leiden (7.1%) and FII A(20210) mutation (8.7%) were similar to those of control subjects. Inherited thrombophilic abnormalities were less frequent among patients with PE only (15.6%) than among those with DVT only (37.0%; p < 0.001) or whose conditions were complicated by PE (28. 0%; p = 0.020). Adjusting for age and sex, FV Leiden mutation, FII A(20210) mutation, or both mutations were associated with DVT with PE (FV Leiden mutation: odds ratio [OR], 3.0; 95% confidence interval [CI], 1.6 to 5.5; FII A(20210) mutation: OR, 2.6; 95% CI, 1. 3 to 5.2; and both mutations: OR, 82.1; 95% CI, 7.5 to 901.2) or without PE (FV Leiden mutation: OR, 6.1; 95% CI, 4.0 to 9.3; FII A(20210) mutation: OR, 2.8; 95% CI, 1.7 to 4.8; and both mutations: OR, 167.5; 95% CI, 21.6 to 1,297.7), but not with isolated PE (FV Leiden mutation: OR, 1.2; 95% CI, 0.5 to 2.8; FII A(20210) mutation: OR, 1.2; 95% CI, 0.5 to 3.1; and both mutations: OR, 22.1; 95% CI, 1. 3 to 370.2). CONCLUSIONS: FII A(20210) mutation is associated with DVT in the lower extremities alone or when complicated by PE, but it is not associated with isolated PE.     

Antiphospholipid syndrome and antiphospholipid antibodies as a risk factors of ischaemic heart disease and myocardial infarction in patients with systemic lupus erythematosus

Ischemic heart disease and myocardial infarction in patients with SLE--are usually secondary to early coronary atherosclerosis. Estimation if antiphospholipid syndrome and antiphospholipid antibodies are the risk factor for myocardial infarction and ischemic heart disease in patients with TRU. We examined 129 patients with SLE (114 women and 15 men). All the patients underwent comprehensive physical examination. ECG, ultrasound heart examinations were performed. They were followed by heart scintygraphic examination if indicated. Routine biochemical and hematological laboratory tests were performed including fasting glucose level, concentration of homocysteine, uric acid and lipids. Wide range of immunological essays were performed, testing for antinuclear antibodies (ANA), extractable nuclear antigen antibodies (ENA), antiphospholipid antibodies (anticardiolipin antibodies--aCL, lupus anticoagulant--LA, antiprothrombine antibodies aPT, anti-beta2glicoprotein-I antibodies), anti-dsDNA antibodies, anti-nucleosome antibodies, antihistone antibodies, antineutrophil cytoplasmic antibodies (ANCA) and antiendothelial antibodies (AECA). Statistical analysis was performed with chi2 Yates, chi2 Pearson and R rang Spearman tests. Multivariate regression analysis was also done. Ischemic heart disease was found in 20 (15.5%) SLE patients, myocardial infarctions were diagnosed in 9 (6.97%). Ischemic heart disease and myocardial infarction were significantly related to presence of secondary antiphospholipid syndrome (SAPS), OR: 4.21, p = 0.008 and OR: 12.8; p = 0.02 respectively). They were also related to high activity of SLE, OR: 7.18; p = 0.012 and OR: 27.3; p = 0.006 respectively. Ischemic heart disease was significantly more common in older patients (52.75 years versus 42.15 years; p = 0.0008) and in patients with hypertension (p < 0.05). Impaired glucose tolerance (OR: 8.44; p = 0.03), presence of aCL IgG (OR; 2.93; p = 0.05) and p-ANCA anti-MPO (OR: 6.08; p = 0.036) were found to be risk factors of ischemic heart disease. Myocardial infarction was significantly associated with high uric acid level (OR: 5.01; p = 0.052) and impaired glucose tolerance (OR: 7.42; p = 0.047) and with presence of the following antibodies: aCL IgG and/or aCL IgM (OR: 5.61; p = 0.039), ANCA in the indirect immunofluorescence essay (OR: 5.78; p = 0.035), anti-MPO antibodies (OR: 6.58; p = 0.051) and AECA (OR: 11.10; p = 0.026). Presence of antiphospholipid antibodies and SAPS are significant risk factors of ischemic heart disease and myocardial infarction in SLE patients. The risk factors of ischemic heart disease and myocardial infarction in SLE patients significantly differ from the ones in general population.     

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.     

Brachial endothelial function is impaired in patients with systemic lupus erythematosus

OBJECTIVE: To verify if endothelial function is impaired in pre-menopausal women with systemic lupus erythematosus (SLE) and whether endothelial dysfunction is related to disease duration, cumulative prednisone dose, antimalarial use, anticardiolipin antibody (aCL), hypertension, Raynaud's phenomenon, disease activity score, and vasculitis. METHODS: Using high-resolution ultrasound, we measured the diameter of brachial artery at rest, during reactive hyperemia, and after glyceryl trinitrate (GTN). We compared 69 pre-menopausal female patients with SLE (mean age 29 +/- 8 years) with 35 age and sex-matched controls (mean age 29 +/- 6 years), The mean disease duration was 72 months. RESULTS: There was no significant difference in baseline brachial artery diameter. The flow-mediated dilation (endothelial dependent dilation) was significantly impaired in SLE patients when compared to controls (5.0 +/- 5.0% vs 12.0 +/- 6.0%, p < 0.001), even in the subgroup of patients without coronary artery disease risk factor (4.5 +/- 4.0% vs 12.0 +/- 6.0%, p < 0.001). The GTN induced dilation (endothelial independent dilation) was significantly lower in the aCL positive SLE patients when compared to the controls (11.9 +/- 4.0% vs 16.3 +/- 6.0%, p < 0.05). The endothelium-dependent dilation was not related to disease duration, cumulative prednisone dose, antimalarial use, anticardiolipin antibody, hypertension history, Raynaud's phenomenon, SLE disease activity score or vasculitis. CONCLUSION: This is the first study using brachial artery ultrasound imaging to evaluate endothelium function in SLE. Patients with SLE presented lower flow mediated dilation (endothelium dependent dilation) than sex and age-matched controls, even in patients without traditional cardiovascular risk factors and this may represent an early atherosclerotic process.     

Potential thrombophilic mutations/polymorphisms in patients with no flow-limiting stenosis after myocardial infarction

Background Although inherited thrombophilias are more common in patients with venous thromboembolism, their influence on the development of myocardial infarction (MI) requires clarification.Methods and Results To determine whether there are increased frequencies of mutations/polymorphisms in 14 genes potentially causing thrombophilia in patients with no flow-limiting stenoses after MI compared with patients with ≥1 flow-limiting stenosis of >50%, we studied 395 patients (60 with no flow-limiting stenosis) who underwent angiography at approximately 1 month. The mutations/polymorphisms studied included Factor V Leiden, prothrombin variant G20210A, β-fibrinogen 448 (G/A), endothelial protein C receptor (23-base pair insertion), methyl tetrahydrofolate reductase 677 (C/T), platelet glycoprotein IIIa PlA1/A2, plasminogen activator inhibitor-1 4G/5G, angiotensin II type 1 receptor (A/C), hemochromatosis gene 282 (G/A), nitric oxide synthase (NOS) (3 forms: eNOS, eNOS3, eNOS4), p22 phox of NADPH oxidase C242T, and angiotensin-converting enzyme insertion/deletion polymorphism. The frequencies of Factor V Leiden and the β-fibrinogen 448 A allele were higher in patients with no flow-limiting stenosis than in patients with ≥1 stenosis (11.7% vs 3.6%, odds ratio [OR] 3.6, 95% CI 1.3-9.4, P = .015; and 42% vs 27%, OR 2.0, 95% CI 1.1-3.5, P = .018, respectively), and there was a trend toward an increased frequency of prothrombin variant G20210A (6.7% vs 2.1%, OR 3.4, 95% CI 0.95-11.8, P = .069). However, in patients with no flow-limiting stenosis after MI the frequencies of the other gene mutations/polymorphisms were not increased. Also, there were no significant interactions between any of these 14 mutation/polymorphisms, major cardiovascular risk factors, and the absence of any flow-limiting stenosis, except for Factor V Leiden and hypertension (OR 6.34, 95% CI 2.67-100, P = .004).Conclusions Patients with no flow-limiting stenosis after MI had increased frequencies of 2 inherited thrombophilias (Factor V Leiden and β-fibrinogen 448 A allele), and there was a trend toward an increased frequency of prothrombin variant G20210A compared with patients with ≥1 stenosis. These data suggest that polymorphisms/mutations in some gene products influencing coagulation may influence the pathogenesis of MI. (Am Heart J 2003;145:118-24.)     

Prothrombin 20210GA and factor V Leiden mutations in patients less than 55 years old with myocardial infarction

Several studies claim that prothrombin 20210GA and factor V Leiden mutations are related to arterial thrombosis. We investigated the frequencies of these mutations and their significance in the development of early atherosclerosis in acute myocardial infarction (AMI) patients younger than 55 years of age. We investigated 96 patients with AMI and 77 control subjects. The diagnosis of AMI was established by typical chest pain and ST elevations on the presentation electrocardiogram and characteristic cardiac enzyme elevations. None of the control subjects had evidence of cardiovascular disease. DNA samples were isolated from all subjects and prothrombin 20210GA and factor V Leiden mutations were determined by the RealTime PCR technique with the aid of a Light Cycler device. The prevalence of factor V Leiden mutation was 6.3% and 5.2% in the patient and control groups, respectively (OR 0.6 [95% CI 0.1- 3.9], P = 0.6), whereas the prevalence of prothrombin G20210A mutation was 4.2% and 2.6% in the patient and control groups, respectively (OR 2.8 [95% CI 0.2 - 32.2], P = 0.4). None of the patients had both mutations. Prothrombin 20210GA and factor V Leiden mutations are not significant risk factors for the development of myocardial infarction in patients less than 55 years old in Southern Turkey.     

Complement factor H Y402H gene polymorphism, C-reactive protein, and risk of incident myocardial infarction, ischaemic stroke, and venous thromboembolism: a nested case-control study

OBJECTIVES: An exonic polymorphism (Y402H) in the complement factor H (CFH) gene, which locates within the binding sites for heparin and C-reactive protein, has recently been described and hypothesized to play an important role in atherothrombosis. METHODS: We, therefore, evaluated the CFH genetic variant Y402H amongst 685 Caucasian individuals who subsequently developed arterial or venous thrombotic event (incident myocardial infarction (MI), ischaemic stroke, or venous thromboembolism) and amongst 685 age- and smoking-matched Caucasian individuals who remained free of reported vascular disease during follow-up (controls) within the Physicians' Health Study cohort. RESULTS: Genotype distribution for the polymorphism tested was in Hardy-Weinberg equilibrium in the control group. In contrast to expected results, we found no association of Y402H polymorphism with risk of atherothrombosis (adjusted: myocardial infarction, OR=1.09, 95%CI 0.88-1.36, p=0.43; ischaemic stroke, OR=1.11, 95%CI 0.81-1.54, p=0.52; venous thromboembolism, OR=1.41, 95%CI 0.88-2.24, p=0.15), nor with baseline plasma C-reactive protein levels [median (interquartile range) mg/L: YY, 1.39 (0.70-2.60); YH, 1.10 (0.57-2.16); HH, 1.00 (0.48-1.79); p=0.14]. CONCLUSIONS: In this large, prospective cohort of apparently healthy Caucasian men, we found no association of the complement factor H Y402H gene polymorphism with risk of incident thromboembolic events, nor with baseline levels of C-reactive protein.     

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.     

Survey of factor V leiden and prothrombin gene mutations in systemic lupus erythematosus

The two most common hereditary risk factors for thrombosis are factor V Leiden mutation and a prothrombin gene mutation. There is indeed a thrombotic tendency in patients with systemic lupus erythematosis (SLE) and it is not always associated with antiphospholipid antibodies. We aimed to determine the relationship between both factor V Leiden and prothrombin gene mutations and SLE. Using polymerase chain reaction (PCR) the factor V Leiden and prothrombin gene mutations were evaluated in 55 patients (20 children and 35 adults) with SLE. Although seven patients were found to have factor V Leiden mutation in the heterozygous state, two had the heterozygous G→A (20210) prothrombin gene mutation. Although one had these two mutations concurrently, these two patients did not have thrombosis. The factor V Leiden mutation frequency (12.7%) was higher than that of our general population (7.1%). On the other hand, seven of the patients with SLE had a thrombotic event. Although of these seven, four (57%) had factor V Leiden mutation, three (43%) had no mutation. Of 48 patients with no thrombotic history, only three had the factor V mutation (6.25%). The prevalence of the factor V Leiden mutation in SLE patients with and without thrombosis was significantly different by Fisher’s exact test (p<0.05). The risk of venous thrombosis in patients with factor V Leiden increased threefold compared to that in those without factor V Leiden mutation (odds ratio 20.1; CI 2.99–133.6). Although factor V Leiden mutation seems to play a role in the development of venous thrombosis in SLE, the development of thrombosis in SLE is multifactorial. Received: 1 August 2000 / Accepted: 9 March 2001     

Sex-specific effect of serum urate levels on coronary heart disease and myocardial infarction prevention: A Mendelian randomization study

Background and aimsObservational studies have examined serum urate levels in relation to coronary heart disease (CHD) and myocardial infarction (MI). Whether these associations are causal remains controversial, due to confounding factors and reverse causality. We aim to investigate the causality of these associations using Mendelian randomization method.Methods and resultsInstrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. Summary statistics were from CARDIoGRAMplusC4D consortium (60,801 CHD cases; 43,676 MI cases), FinnGen (21,012 CHD cases; 12,801 MI cases), UK Biobank (10,157 CHD cases; 7018 MI cases), and Biobank Japan (29,319 CHD cases). Inverse-variance weighted method was applied as the main results. Other statistical methods and reverse MR analysis were conducted in the supplementary analyses. Elevated genetically determined serum urate levels were associated with increased risks of CHD and MI. The association pattern remained for the datasets in FinnGen, the combined results of three independent data sources (CHD: odds ratio (OR), 1.10; 95%CI, 1.06–1.15; p = 4.2 × 10^?6; MI: OR, 1.12; 95%CI, 1.07–1.18; p = 2.7 × 10^?6), and East Asian population. Interestingly, sex-specific subgroup analyses revealed that these associations kept in men only, but not among women in individuals of European ancestry. No consistent evidence was found for the causal effect of CHD or MI on serum urate levels.ConclusionWe provide consistent evidence for the causal effect of genetically predicted serum urate levels on CHD and MI, but not the reverse effect. Urate-lowering therapy may be of cardiovascular benefit in the prevention of CHD and MI, especially for men.