Interaction between hyperhomocysteinemia,mutated methylenetetrahydrofolatereductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis

Venous thrombosis is a multicausal disease involving acquired and genetic factors. In this study we investigated a possible interaction between hyperhomocysteinemia (fasting or postload) and factor V Leiden or prothrombin G20210A on the risk of recurrent venous thrombosis. We also looked at the risk due to mutations in the MTHFR-gene (C677T and A1298C). We performed a case-control study in 171 patients with a history of recurrent venous thrombosis and 461 control subjects from the general population. Hyperhomocysteinemia (fasting or 6 h after an oral methionine load) was defined as a homocysteine concentration above the 90th percentile of the distributions in the control group. The odds ratio (adjusted for age and sex) for recurrent venous thrombosis was 1.8 (95% CI: 1.1 to 3.0) for fasting hyperhomocysteinemia, 5.1 (95% CI: 3.0 to 8.6) for factor V Leiden and 1.8 (95% CI: 0.7 to 4.2) for prothrombin G20210A. We found 14 patients and 3 controls with both hyperhomocysteinemia and factor V Leiden, which yielded an odds ratio of 11.6 (95% CI: 3.2 to 42.5). We found no interaction between hyperhomocysteinemia and prothrombin G20210A. The relative risk for MTHFR 677CT was 1.6 (95% CI: 1.1 to 2.4) and for MTHFR 677TT was 1.4 (95% CI: 0.7 to 2.8). The combined risk for MTHFR 677TT and factor V Leiden was 18.7 (95% CI: 3.3 to 108). We conclude that hyperhomocysteinemia and factor V Leiden are risk factors for recurrent venous thrombosis. The risk of thrombosis appeared high for individuals who had both risk factors.     

Thrombin generation in first-degree relatives of patients with venous thromboembolism who have factor V Leiden. A pilot study

The thrombin generation test appears to be a highly sensitive and specific test in the detection of thrombophilia in patients with venous thromboembolism. We aimed to determine the accuracy of the thrombin generation test to detect factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden. Sixty-two first-degree relatives of 21 index cases were tested for factor V Leiden, the G20210A prothrombin gene mutation and thrombin generation. Information about oestrogen therapy and previous VTE was also collected. The normalized Thrombomodulin sensitivity ratio (n-TMsr) was defined as the ratio of endogenous thrombin potential determined in the presence and absence of thrombomodulin which was normalized against the same ratio determined in normal control plasma. The mean n-TMsr was 1.37 (+/- 0.33) in the 45 relatives with one or more prothrombotic state (factor V Leiden, G20210A prothrombin mutation, oestrogen therapy or hormonal therapy) and 1.02 (+/- 0.34) in the 17 relatives without prothrombotic state (p = 0.001). The positive predictive value was 90.3 (95%CI, 73.1-97.4). In relatives with an abnormal n-TMsr, the adjusted odds ratio for having a prothrombotic state was 8.3 (95%CI, 1.9-36.9) and the adjusted odds ratio for having the factor V Leiden was 14.3 (95%CI, 2.9-71.2). An abnormal thrombin generation test appears highly predictive for having factor V Leiden and/or other prothrombotic states in first-degree relatives of patients with venous thromboembolism and factor V Leiden.     

Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels.

To find genetic causes of high plasma prothrombin levels, an established prothrombotic risk factor. we searched for sequence variations in the prothrombin gene. We selected subjects with the 20210-GG genotype (since the 20210-A allele is already known to be associated with high levels) and elevated prothrombin levels (> or = 130 U/dl) from the Leiden Thrombophilia Study (LETS). No mutations were found in the 1 kb promoter region of the prothrombin gene in seven individuals with an isolated high prothrombin level. Comparison of the allelic frequencies of four different polymorphisms in the prothrombin gene in healthy volunteers and in the control subjects among the selected LETS individuals indicated a higher frequency of the 19911-G allele in the latter group (allele frequency 52 vs. 78%, respectively). Homozygous carriers of the 19911-G allele had 8 U/dl higher plasma prothrombin levels than 19911-AA carriers. This difference in prothrombin levels did not affect the thrombotic risk in 20210-GG carriers. In heterozygous 20210-A carriers the odds ratio increased from 1.6 (95% CI: 0.6-4.3) in subjects with 19911-A to 4.7 (1.6-14.0) in subjects with 19911-G on the other prothrombin allele.     

Prevalence of prothrombin G20210A, factor V G1691A (Leiden), and methylenetetrahydrofolate reductase (MTHFR) C677T in seven different populations determined by multiplex allele-specific PCR.

Individuals belonging to six racial groups (African American, Asian Indian, Caucasian, Hispanic, Korean, Native American), and a seventh group comprised of referred patients with thrombosis were genotyped for the prothrombin G20210A mutation, the factor V G1691A (Leiden) mutation, and the methylenetetrahydrofolate reductase (MTHFR) C677T mutation by multiplexed allele-specific PCR. The prothrombin 20210A and factor V 1691A allele frequencies in the thrombosis patients, 3.2% and 9.5%, were significantly higher than those in the random Caucasians, 1.3% and 1.8%, (p = 0.043 and p <0.001, respectively). The relative risk of venous thrombosis was determined to be 2.4-fold for carriers of the prothrombin 20210A allele (odds ratio = 2.54; 95% confidence interval = 0.94, 6.82) and 4.5-fold for carriers of the factor V 1691A allele (odds ratio = 5.06; 95% confidence interval = 2.25, 11.36). Among the seven populations, significant differences were observed in the MTHFR 677T allele distribution, however this mutation was not determined to be a risk factor for venous thrombosis in the patient group studied, either alone or in combination with the prothrombin 20210A and/or the factor V 1691A allele(s).     

The role of prothrombotic mutations in patients with Buerger's disease

Thromboangiitis obliterans (TAO), or Buerger's disease, is a segmental occlusive inflammatory disorder of the arteries and veins, and etiopathogenesis is still obscure. In the present study we investigated the prevalence of prothrombin 20210 G-->A, factor V 1691 G-->A (Factor V Leiden), and factor V 4070 A-->G (His 1299 Arg) mutations, found to be associated with increased risk for vascular thrombosis, in 36 patients with TAO. We performed a case-control study of these mutations. The odds ratio for prothrombin 20210 A allele compared with G allele was 7.98 (95% confidence intervals 2. 45-25.93). Only this prothrombotic genetic factor was associated with the risk of TAO (p=0.032). In conclusion, carrying the prothrombin 20210 G-->A may be an important prothrombotic risk factor of TAO. This genetic predisposition must be screened in these patients routinely, and clinical importance must be supported by further investigations.     

Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism

Factor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.     

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.     

Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium

Venous thromboembolism is a rare but threatening complication of pregnancy. Little conclusive information is available on the actual risk of venous thromboembolism during pregnancy or puerperium in women with inherited thrombophilia, particularly in carriers of factor V Leiden and of the G20210A prothrombin gene mutation. To determine the pregnancy-related and puerperium-related risk of venous thromboembolism in women with inherited thrombophilia, we performed a case-control study on 119 women who had a first episode of deep vein thrombosis and/or pulmonary embolism during pregnancy or puerperium and 232 healthy women who had at least one pregnancy without thrombosis. Inherited thrombophilia was diagnosed in 47 patients (39.5%) and 15 controls (6.5%). The relative risk of venous thromboembolism was 10.6 (95% CI, 5.6-20.4) for heterozygous carriers of factor V Leiden, 2.9 (95% CI, 1.0-8.6) for heterozygous carriers of the prothrombin mutation and 13.1 (95% CI, 5.0-34.2) for those with antithrombin, protein C or protein S deficiency taken together. Sixty-eight of the 119 women (57%) had thrombosis after delivery, confirming the puerperium as a particularly high-risk period. When women were divided into two groups of those with antenatal or postnatal thrombosis. the relative risks associated with each type of inherited thrombophilia were of similar magnitude. In conclusion, women with inherited thrombophilia have an increased risk of venous thromboembolism during pregnancy. Among thrombophilic abnormalities, the prothrombin mutation was the weakest risk factor. Thrombosis occurred more frequently in puerperium than in pregnancy, whether or not thrombophilia was diagnosed.     

Interrelation of hyperhomocysteinemia and inherited risk factors for venous thromboembolism. Results from the E.D.I.TH. study: a hospital-based case-control study

BACKGROUND: Moderate hyperhomocysteinemia and factor V Leiden mutation are among the most prevalent risk factors for venous thromboembolism (VTE). The hypothesis of an interaction between those risks has been raised and conflicting results were reported. METHODS: We designed a hospital-based case-control study to test the interaction between Factor V Leiden and fasting serum total homocysteine (tHcy). We have also analysed the G20210A prothrombin gene variant. This study enrolled 904 hospitalised patients who had an objectively proven deep vein thrombosis and/or pulmonary embolism as well as 904 hospitalised control patients matched for gender, age and major acquired risk factor for VTE. RESULTS: Our data did not detect any multiplicative interaction between hyperhomocysteinemia (>15 mumol/L) and factor V Leiden mutation or G20210A prothrombin gene variant. Odds ratios (95% CI) were 4.0 (1.5-11) and 6.0 (1.3-27) for the combined effect of hyperhomocysteinemia with either factor V Leiden mutation or G20210A prothrombin gene variant, respectively. CONCLUSIONS: Current data provide further knowledge in relationship between hyperhomocysteinemia and inherited risk factors, such as factor V Leiden mutation and G20210A prothrombin gene variant. As those risk factors are not so rare among Caucasians, a better estimate of the risk related to double exposure might help to optimise venous thromboembolism prevention.     

D-dimer as a risk factor for deep vein thrombosis: the Leiden Thrombophilia Study

We studied the association of D-dimer with the risk of deep vein thrombosis (DVT). D-dimer was measured in 474 patients more than 6 months after diagnosis of a first DVT and in 474 age- and sex-matched controls. For D-dimer above the 70th percentile (130.5 ng/ml), the odds ratio (OR) for DVT was 2.2 (95% CI, 1.6-2.9). The association was unchanged with adjustment for other risk factors. Excluding participants with Factor V Leiden, prothrombin 20210A, or factors VIIIc or IX above the 90th percentile, the OR was 1.6 (95% CI, 1.1-2.3). The risks of DVT with the joint presence of high D-dimer and either factor V Leiden or prothrombin 20210A were increased 12.4-fold (95% CI 5.6-27.7) and 7.2-fold (95% CI 2.1-25.1), respectively. Higher D-dimer concentration was associated with the risk of DVT, and was supra-additive to the risks associated with factor V Leiden and the prothrombin 20210A variant. Persistence of this association in the absence of other hemostatic risk factors for DVT suggests that high D-dimer may be related to other, as yet unknown, risk factors for venous thrombosis. Confirmation of these findings is desirable.     

Clinical characteristics of patients with factor V Leiden or prothrombin G20210A and a first episode of venous thromboembolism. Findings from the RIETE Registry

Background

The clinical characteristics of patients with factor V Leiden or prothrombin G20210A presenting with a first episode of venous thromboembolism (VTE) have not been thoroughly studied.

Methods

RIETE is an ongoing registry of consecutive patients with acute VTE. We compared the clinical characteristics of patients with factor V Leiden, prothrombin G20210A, or no thrombophilia, at presentation with a first episode of VTE.

Results

As of May 2009, 22428 patients had been enrolled with a first episode of VTE. Of these, 345 had factor V Leiden, 261 had prothrombin G20210A, and 2399 tested negative. Sixty-two percent of the VTE episodes in women with factor V Leiden or prothrombin G20210A (40% in men) were associated with an acquired risk factor. Among women, pregnancy or contraceptive use accounted for 63% and 67% of such risk factors. Patients with factor V Leiden presented with pulmonary embolism (PE) less likely than those with prothrombin G20210A (31% vs. 51%; p < 0.001) or with negative testing (31% vs. 45%, p < 0.001). In addition, PE patients with Factor V Leiden presented with hypoxaemia (Sat O₂ levels < 90%) less likely than those with prothrombin G20210A (4.5% vs. 17%; p < 0.001) or with no thrombophilia (4.5% vs. 20%; p < 0.001).

Conclusions

Most VTE episodes in women (not men) with factor V Leiden or prothrombin G20210A were associated with an acquired risk factor (mostly pregnancy or contraceptive use). Only 4.5% of patients with factor V Leiden presenting with acute PE had hypoxaemia.     

In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband

The utility of laboratory investigation of relatives of individuals with inherited thrombophilia is uncertain. To assess the risk of venous thromboembolism (VTE) among the carriers, we investigated a family cohort of 1,720 relatives of probands with thrombophilia who were evaluated because of VTE (n=1,088), premature arterial thrombosis (n=113), obstetric complication (n=257), or universal screening before pregnancy or hormonal contraception or therapy (n=262); 968 relatives were carriers of thrombophilia. A first deep venous thrombosis (DVT) occurred in 44 carriers and 10 non-carriers during 37,688 and 29,548 observation-years from birth, respectively. The risk of DVT among the carriers compared with non-carriers was estimated as a hazard ratio (HR). If the proband had VTE and factor V Leiden (FVL) and/or prothrombin (PT)20210A, the HR for DVT was 2.77 (95%CI 1.21-4.82) in the carriers overall, and 5.54 (95%CI 3.20-187.00) in those homozygous or double heterozygous for FVL and PT20210A. If the proband had VTE and a deficiency of antithrombin (AT), protein C or S, the HR for DVT was 5.14 (95%CI 0.88-10.03) in the carriers overall, and 12.86 (95%CI 2.46-59.90) in those with AT deficiency. No increase in risk was found among the carriers who were relatives of the probands who were evaluated for reasons other than VTE. In conclusion, familial investigation for inherited thrombophilia seems justified for probands with previous VTE, but appears of doubtful utility for the relatives of probands without VTE. This should be taken with caution regarding families with deficiency of natural anticoagulants, given the low number of cases analysed.     

The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels

A common G to A transition at nucleotide 20210 of the prothrombin gene is associated with an increased risk for deep-vein thrombosis (DVT) and high plasma levels of prothrombin. We calculated the prevalences of prothrombin G20210A, factor V G1691A (also associated with high risk for DVT) and homozygous methylenetetrahydrofolate reductase (MTHFR) C677T (associated with increased susceptibility to develop hyperhomocysteinemia) in 118 patients with a first episode of DVT and in 416 healthy controls. 15.9% of the patients and 2.3% of the controls had prothrombin G20210A (odds ratio [OR]: 8.7, 95% C.I.: 3.8-21.4); 21.1% of the patients and 3.2% of the controls had factor V G1691A (OR 7.8, 3.9-17.1); 20.5% of the patients and 21% of the controls had homozygous MTHFR C677T (OR: 1.0, 0.7-1.2). Exclusion of patients with other hereditary risk factors for DVT did not substantially modify the results. Mutant factor V and prothrombin coexisted in three patients but in no control. The concomitant presence of the MTHFR mutation did not increase the thrombotic risk associated with prothrombin G20210A. 63.2% of individuals with prothrombin G20210A had plasma levels of prothrombin in the upper quartile of distribution. After adjustment for age and sex, subjects with prothrombin levels in the upper quartile carried a slightly higher risk for thrombosis than those with lower prothrombin concentrations (OR: 1.9, 1.1-3.2). In conclusion, we found that prothrombin G20210A is relatively common in Italy and is associated with high prothrombin levels and an 8.7-fold increase in the risk for DVT. Such risk is independent of the coexistence of other known inherited risk factors for thrombosis and increases in patients with associated mutant factor V. Whether it is due to the associated increase in plasma prothrombin levels remains to be established.     

Prothrombin G20210A mutation,but not factor V Leiden,is a risk factor in patients with persistent foramen ovale and otherwise unexplained cerebral ischemia

BACKGROUND: Paradoxical embolism via persistent foramen ovale (PFO) is suspected to be a frequent cause of stroke in younger patients. We investigated whether the prevalence of the risk factors for venous thrombosis factor V Leiden (FVL) and prothrombin G20210A mutation (PT G20210A) is increased in this group of patients. METHODS: We examined FVL and PT G20210A mutation in 220 patients (group 1) with cerebral ischemia associated with a PFO and without other etiology, in 196 patients with cerebral ischemia of an etiology other than PFO (group 2), and in 362 healthy subjects (group 3) from the same region in Germany. RESULTS: Heterozygosity for the PT G20210A mutation was more common in group 1 (5.0%) than in group 3 (1.4%; sex- and age-adjusted odds ratio 3.66; 95% CI 1.25-10.75; p = 0.01). By contrast, the mutation was not more common in group 2 (2.6%; odds ratio 1.50; 95% CI 0.42-5.41; p = 0.5). Prevalences of FVL were not different between groups. CONCLUSIONS: We identified PT G20210A but not FVL - the strongest genetic risk factor for deep venous thrombosis - to be significantly associated with stroke attributed to PFO. These findings rise doubts about the concept of paradoxical brain embolism as the dominating mechanism in stroke associated with PFO.     

Thrombophilic risk factors and homocysteine levels in Behçet's disease in eastern Spain and their association with thrombotic events

Beh?et's disease (BD) is a chronic inflammatory disorder in which thrombosis occurs in about 30% of patients. The prothrombotic mechanisms are unknown. Thrombophilic defects and hyperhomocysteinaemia may be involved in the pathogenesis of thrombotic events, although results have been controversial. Moreover, no information is available on this issue for eastern Spain. We studied the prevalence of inherited and acquired thrombophilic risk factors in 79 patients with BD (43 men, 36 women) who had (n = 23) or did not have (n = 56) thrombosis, and in 84 healthy control subjects (42 men, 42 women). Risk factors examined were antithrombin, protein C and protein S levels, factor V Leiden, the prothrombin G20210A mutation, the methylenetetrahydrofolate reductase C677T polymorphism, and acquired thrombophilic risk factors, including anticardiolipin antibodies, lupus anticoagulant, and serum homocysteine levels. There were no differences between patients and controls in any of the parameters studied. When we studied BD patients with and without thrombotic events, the only thrombophilic defect that differed was the prothrombin G20210A mutation: Three out of 23 patients with thrombosis were carriers, compared with none of 56 patients without thrombosis (p = 0.022). Two of the three carriers developed catastrophic or recurrent thrombotic episodes; one was a homozygous carrier of the G20210A prothrombin mutation and the other was doubly heterozygous for the G20210A prothrombin mutation and factor V Leiden. A meta-analysis demonstrated an association of factor V Leiden and prothrombin mutation with thrombosis in BD. When studies from Turkey were excluded from the meta-analysis, only the prothrombin G20210A mutation was associated with thrombosis.     

The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia

It is uncertain whether the presence of inherited thrombophilia influences the risk of developing symptomatic pulmonary embolism (PE) and whether different thrombophilic alterations are associated with different risks of symptomatic PE. To investigate such issue, we retrospectively studied 920 patients with proximal deep vein thrombosis (DVT) of the legs with or without symptomatic PE referred for thrombophilia screening; patients with overt cancer or antiphospholipid antibodies had been excluded. Three hundred fifty-four patients (38.5%) had deficiency of antithrombin (AT, n = 16), protein C (PC, n = 26), protein S (PS, n = 22), factor V Leiden (FVL, n = 168), prothrombin G20210A (PT-GA, n = 87), or multiple abnormalities (n = 35), and 566 had none of the studied thrombophilic abnormalities. Symptomatic PE complicated the first DVT in 242 patients (26%); the risk of PE was increased in patients with AT deficiency (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6-3.6) or with PT-GA (RR 1.5, 95%CI 1.1-2.0) and decreased in those with FVL (RR 0.7, 95%CI 0.5-1.0) in comparison with those with unknown inherited defect. These data suggest that patients with proximal DVT have different risks of symptomatic PE according to the type of inherited thrombophilia.     

Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adults

INTRODUCTION: Several recent studies have analyzed a possible effect of thrombophilia risk factors such as factor V Leiden, the prothrombin variant (allele 20210 A), and homozygosity for thermolabile methylenetetrahydrofolate reductase (MTHFR-T) on the development of ischemic stroke (IS). In the present study, we determined the role of these prothrombotic polymorphisms in the early onset of arterial IS or cerebral venous thrombosis (CVT) in a group of young Brazilian adults of Caucasian and African descent. MATERIALS AND METHODS: We conducted a cross-sectional study of 167 survivors of IS (153 patients with arterial IS and 14 cases of CVT; 66 men: 101 women; 124 of Caucasian and 43 of African origin; median age: 32.6 years; range: 15 to 45 years) and compared the prevalence of inherited thrombophilia risk factors with a control group of 225 sex and age matched individuals of the same ethnic background. To determine the interaction with atherogenic risk factors, the following diagnoses were considered: hypertension, hyperlipoproteinemia, diabetes mellitus, smoking status and use of oral contraceptives. RESULTS: In the arterial IS group, no significant variation was found between patients and controls of Caucasian origin regarding the prevalence of factor V Leiden (P = 0.92), the prothrombin variant (P = 0.13) or homozygosity for MTHFR-T (P = 0.61). Among Brazilians of African descent, 10.3% were homozygous for MTHFR-T, which was significantly elevated, odds ratio of 5.9 (95% CI: 0.88 to 49.15). In the CVT group, two Caucasian patients (20%) were heterozygous for the prothrombin variant, odds ratio of 9.7 (95% CI: 0.95 to 89.71) and one patient was carrier of factor V Leiden (P = 0.49). No prothrombotic polymorphism was identified in patients with CVT of African descent. All women in the CVT group were in use of oral contraceptives or in the post-partum state. DISCUSSION: Inherited thrombophilia risk factors were not found to increase the risk of arterial IS among young patients of Caucasian descent. However, a potential role of homozygosity for MTHFR-T was observed in a small group of patients of African origin. The analysis of patients with CVT revealed an increased risk due to the prothrombin gene variant or oral contraceptive use. Further studies including all incoming patients with IS are necessary to evaluate the impact of inherited thrombophilia risk factors on early mortality.     

Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan

The relative risks (odds ratio, OR) of various risk factors for venous thrombophilia, including sex, antithrombin III, protein C (PC), protein S (PS) and plasminogen deficiencies, and C677T homozygous mutation of methylenetetrahydrofolate reductase gene were assessed using age matched (+/-5 years) conditional logistic regression analysis in 116 Chinese venous thrombophilic patients (58 males; 58 females; mean age 47.5+/-17.7 [SD] years) and 125 healthy controls (67 males; 58 females; mean age 45.5+/-15.7 years). None of the patients had prothrombin G20210A and factor V Leiden mutation or an activated PC sensitivity ratio of less than 2. One hundred and five age-matched patients and 105 controls were entered in this analysis. Only PC and PS deficiencies were significantly associated with increased risk for the development of thrombosis with an OR of 10.6 and 6.7, respectively. The findings of this study suggest that PC deficiency and PS deficiency are the most important risk factors for thrombosis in Chinese venous thrombophilic patients.     

Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium

In a retrospective study of 190 women with a first history of venous thromboembolism during pregnancy and the puerperium and 190 age-matched women with at least one prior pregnancy and no history of venous thromboembolism, the individual probability of thrombosis was determined. Assuming an overall risk of 1 in 1500 pregnancies, the probability of pregnancy-related thrombosis in carriers of homozygous factor V Leiden was 1 in 80 (odds ratio 20.6, p=0.005) and among carriers of combined heterozygous factor V Leiden and heterozygous G20210A mutation in the prothrombin gene 1 in 20 (odds ratio 88, p<0.001). The probability of thrombosis per pregnancy among women with elevated levels of factor VIII:C (>172 % activity) was 1 in 385 (odds ratio 4.5, p<0.001) and among those with increased levels of von Willebrand factor antigen (>190 %) 1 in 435 (odds ratio 4.0, p=0.002), independent of elevated factor VIII:C levels. The high prevalence of combined and homozygous defects of hemostatic components (21.6%) in patients as compared with normal women (0.86%) supports the concept that venous thromboembolism is a multicausal disorder.     

The G20210A prothrombin polymorphism is not associated with increased thromboembolic risk in a large protein C deficient kindred

Likelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 +/- 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 +/- 0.130 NS). Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 +/- 2% to 124 +/- 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (approximately 2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.