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.     

Effects of second and third generation oral contraceptives and their respective progestagens on the coagulation system in the absence or presence of the factor V Leiden mutation

Compared to second generation, the use of third generation oral contraceptives has been associated with an increased risk of venous thrombosis especially in women with the factor V Leiden mutation. To find an explanation for these risk differences we investigated the effects of desogestrel- and levonorgestrel-containing oral contraceptives as well as their progestagens separately on the coagulation system in the absence or presence of the factor V Leiden mutation. In a single center, double blind trial, 51 women without and 35 women with the factor V Leiden mutation were randomized to either a second generation (30 microg ethinylestradiol/150 microg levonorgestrel) or a third generation (30 microg ethinylestradiol/150 microg desogestrel) oral contraceptive. After two cycles of use and a wash-out period of 2 menstrual cycles, the participants received the corresponding progestagen-only preparation containing 150 microg levonorgestrel or 150 microg desogestrel. In plasmas of the participating women fragment 1+2, factor V, VII, VIII, IX, X and XI were determined. Both combined oral contraceptives induced a decrease in factor V, whereas the levels of all other coagulant parameters increased. However, in women without the factor V Leiden mutation the effects of desogestrel-containing preparations were significantly different compared to levonorgestrel-containing oral contraceptives for factor V (-8.0; 95% CI -13.4 to -2.6), factor VII (26.8; 95% CI 15.5 to 38.0) and factor IX (-9.6; 95% CI -16.2 to -3.2). When these women used progestagen-only pills, a differential effect between desogestrel and levonorgestrel was only found for factor IX (-6.5; 95% CI -11.4 to -1.5). In carriers of the factor V Leiden mutation desogestrel-containing oral contraceptives induced more pronounced changes in factor V (-14.2; 95% CI -22.4 to -6.0) and factor VII (36.1; 95% CI 19.7 to 52.6) compared to levonorgestrel-containing oral contraceptives. Comparing desogestrel- and levonorgestrel-only, only for factor V a differential effect was found in these women (-9.5; 95% CI -18.3 to -0.6). It appears that desogestrel-containing oral contraceptives have a more pronounced effect on the coagulation system than levonorgestrel-containing oral contraceptives which may be explained by a less effective compensation of the thrombotic effect of ethinylestradiol by desogestrel.     

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.     

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.     

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.     

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.     

Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis

The magnitude of the association of factor V Leiden mutation with pregnancy-related venous thrombosis remains unclear. Our objective was to undertake a systematic review and a metaanalysis of the literature to estimate precisely the association of factorV Leiden mutation with the risk of first, or recurrent, pregnancy-related venous thromboembolism. Studies published before October 2005 were identified by Medline((R)). Using both fixed and random effect models, odds ratios (OR) with accompanying 95% confidential intervals (CI) were calculated for the factor V Leiden mutation and the clinical end-point (Yusuf-Peto adaptation of the Mantel-Haenszel, DerSimonian and Laird method). We identified 13 studies including 7 cohorts and 6 casecontrol studies relating to factor V Leiden and pregnancy-related venous thrombosis. The results from the cohorts showed a pooled OR of 4.46 (95% CI, 1.82-10.94; 7,879 pooled women), with no evidence of statistical heterogeneity (p = 0.36), for the risk of a first venous thromboembolism during pregnancy or the postpartum period associated with the factor V Leiden mutation. Case-control studies revealed a higher risk (OR 8.6, 95% CI, 5.85-12.63; 1,433 [corrected] pooled women) with significant heterogeneity (p < 0.005). Because of insufficient data, an analysis for the risk of recurrence could not be performed. Our findings emphasize the fact that limited data are available on this topic. This meta-analysis provides clinicians with an estimate of the average risk of a first thrombosis occurring during pregnancy in women carrying the factor V Leiden to assist the management of such women.     

Factor V gene A4070G mutation and the risk of cerebral veno-sinus thrombosis occurring during puerperium

INTRODUCTION: Cerebral veno-sinus thrombosis (CVT) occurring during puerperium is a common form of stroke in young women in India, associated with high mortality and morbidity. Genetic polymorphisms involving coagulation factors are considered to be risk factors for thrombosis. A recently identified polymorphism in factor V gene, A4070G (R2 allele), has been reported as a risk factor for venous thrombosis in some studies. Moreover, the R2 allele has been reported to increase factor V Leiden-related thrombosis risk in doubly heterozygous individuals. The risk associated with the R2 allele has not yet been evaluated in CVT. Our aim was to determine the prevalence of factor V A4070G mutation in Indians and examine its role as a possible risk factor for CVT occurring during puerperium. MATERIALS AND METHODS: We investigated 50 patients with puerperal CVT and 100 healthy women with no post-partum complications for factor V A4070G and G1691A (factor V Leiden) polymorphisms using polymerase chain reaction and restriction fragment length polymorphism. RESULTS AND CONCLUSION: Among cases, 6 (12%) were heterozygous for the factor V A4070G mutation and none were homozygous. In the control group, 9 (9%) were heterozygous and 3 (3%) were homozygous. The odds ratio was 1.00 (95% CI: 0.31-3.13, p=1.000), suggesting that the risk for CVT was not increased in the presence of the R2 allele. There was no co-inheritance of factor V A4070G with factor V G1691A in any of the subjects. Our study shows that the A4070G mutation in factor V though highly prevalent in the Indian population is not associated with an increased risk of CVT occurring during puerperium in Indian women.     

Effect of prothrombin 19911 A>G polymorphism on the risk of cerebral sinus‐venous thrombosis

Background and Purpose: The A>G polymorphism at position 19911 of the prothrombin gene is associated with a mildly increased risk of venous thromboembolism, alone or in association with such common thrombophilia mutations as factor V Leiden and prothrombin 20210 GA. Its role in cerebral sinus‐venous thrombosis (CSVT) is not known. Methods: The presence of prothrombin 19911 A>G was investigated in a case–control study of 107 patients with cerebral thrombosis and factor V Leiden (n = 25), prothrombin 20210 GA (n = 47), without known thrombophilia (n = 35) and 842 healthy individuals with the corresponding coagulation profile. Results: Prothrombin 19911 A>G did not increase the risk of CSVT in carriers of factor V Leiden (adjusted odds ratio 1.6, 95%CI 0.6–4.7), prothrombin 20210 GA (odds ratio 1.1, 95%CI 0.6–2.2), nor in patients without known thrombophilia (odds ratio 1.3, 95%CI 0.5–3.1). Conclusions: Prothrombin 19911 A>G polymorphism does not appear to be a risk factor for CSVT, alone or in association with factor V Leiden or prothrombin 20210GA.     

Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors

Previous studies have shown an increased risk of retinal vein occlusion (RVO) in patients with hypertension, hypercholesterolemia and diabetes mellitus. Literature on the association between thrombophilic factors and RVO consists of small studies and case reports. The objective was to determine the relationship between thrombophilic risk factors and RVO. Thrombophilic risk factors analyzed were hyperhomocysteinemia, MTHFR gene mutation, factor V Leiden mutation, protein C and S deficiency, antithrombin deficiency, prothrombin gene mutation, anticardiolipin antibodies and lupus anticoagulant. For all currently known thrombophilic risk factors odds ratios for RVO were calculated as estimates of relative risk. The odds ratios were 8.9 (95% CI 5.7 - 13.7) for hyperhomocysteinemia, 3.9 (95% CI 2.3 - 6.7) for anticardiolipin antibodies, 1.2 (95% CI 0.9 - 1.6) for MTHFR, 1.5 (95% CI 1.0 - 2.2) for factor V Leiden mutation and 1.6 (95% CI 0.8 - 3.2) for prothrombin gene mutation. In conclusion, regarding thrombophilic risk factors and RVO there is only evidence for an association with hyperhomocysteinemia and anticardiolipin antibodies, factors that are known as risk factors for venous thrombosis as well as for arterial vascular disease. The minor effect of factor V Leiden mutation and the protrombin gene mutation (risk factors for venous thrombosis only) suggests that atherosclerosis might be an important factor in the development of CRVO.     

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.     

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.     

Is the prevalence of the factor V Leiden mutation in patients with pulmonary embolism and deep vein thrombosis really different?

INTRODUCTION: Previous investigations have suggested a lower prevalence of the factor V Leiden mutation in patients with pulmonary embolism, as compared to patients with deep leg vein thrombosis. METHODS: We studied unselected patients with pulmonary embolism, in whom we also assessed the presence of deep vein thrombosis by ultrasonography. We assessed the prevalence of heterozygosity for the factor V Leiden mutation and compared the outcome of patients with a normal ultrasound (primary pulmonary embolism) to those with an abnormal ultrasound (combined form of venous thromboembolism). Furthermore, we performed a literature search to identify all articles regarding the prevalence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and a combined form of venous thromboembolism. We calculated a (common) odds ratio for these 3 manifestations of venous thromboembolism, including the current findings. RESULTS: In 92 patients with proven pulmonary embolism, 25 (27%) had also an abnormal ultrasound. In these patients, the prevalence of the factor V Leiden mutation was 24% (95% CI 9%-45%), whereas the mutation was present in 5 of 67 patients with primary pulmonary embolism (7%; 95% CI 2%-16%). The literature analysis indicated the common odds ratio for the presence of heterozygous factor V Leiden mutation in patients with primary deep vein thrombosis, primary pulmonary embolism and the combined form of venous thromboembolism to be 7.9 (95% CI 5-12), 3.5 (95% CI 2-6) and 6.8 (95% CI 3-14), respectively. CONCLUSION: In patients with primary pulmonary embolism the prevalence of the factor V Leiden mutation appears to be half of that reported in patients with primary deep vein thrombosis. The mechanism remains unclear.     

Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism

Tissue factor pathway inhibitor (TFPI) regulates factor X activation. Low TFPI is a risk factor for a first venous thrombosis. We evaluated whether low TFPI confers an increased risk of recurrent venous thromboembolism (VTE). TFPI-free antigen was measured in 611 patients with a first spontaneous VTE, and who were prospectively followed after withdrawal of anticoagulation. The endpoint was symptomatic recurrent VTE. The relative risk (RR) of recurrence increased from 1.0 (95% CI 0.4-2.6) in patients with TFPI levels < or = 5th percentile to 2.7 (95% CI 1.0-7.4) in patients with levels < or = 2nd percentile as compared with higher levels. At five years, the probability of recurrence was 48.6% (95th CI 19.0-78.1) among patients with TFPI < or = 2nd percentile and 16.8% (95th CI 13.8-19.8) among those with higher levels (p=0.04). Compared to patients with wild type factor V and high TFPI, the RR of recurrence was 1.1 (95% CI 0.7-1.7) in patients with factor V Leiden and high TFPI, 2.3 (95% CI 0.6-9.5) in patients with wild type factor V and low TFPI and 3.5 (95% CI 0.9-14.3) in patients with factor V Leiden and low TFPI. In a multivariate analysis,the high risk of recurrence in carriers of factor V Leiden and low TFPI slightly decreased [RR 2.8 (95% CI 0.6-9.5)]. We conclude that thrombosis patients with low levels of free TFPI are at an increased risk of recurrent VTE.     

The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels

Elevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 3951C/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P<0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 1241E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.     

Cerebral venous thrombosis: Incidence in prothrombotic states

Cerebral venous thrombosis (CVT) is a rare clotting event with a highly variable clinical presentation. Local and systemic infections, collagen vascular disorders, malignancies, pregnancy and puerperium, and the use of oral contraceptives (OC) have been strongly associated with CVT. It is clear that a minority of individuals with the above conditions develop CVT. Therefore, inherited or acquired prothrombotic states may play a key role in the development of this disease.In recent years, the discovery of new thrombophilic risk factors such as factor V Leiden and the prothrombin gene mutation has contributed to the understanding of the environment-gene interaction in the development of thrombosis. Several studies have found factor V Leiden to be the most common coagulation abnormality in patients with CVT, with a prevalence of 20% to 25%. Immobilization, puerperium, or the use of oral contraceptives, factors considered to increase the risk of developing thromboses, were present in the majority of the cases.The odds ratio for CVT in women heterozygous for the prothrombin gene mutation taking OC was 150, with an odds ratio of 10 for carriers of the mutation and 22 for OC users, respectively. Hence, the inherited or acquired hypercoagulable states establish the conditions for thrombosis to develop when certain factors are present. Numerous cases of factor V Leiden and prothrombin gene mutation in patients with CVT during pregnancy and puerperium have been reported, and the prevalence of prothrombotic risk factors appears to be similar to the ones in patients with extracerebral thrombosis during the same period.CVT in neonates and young infants is a rare, but well-recognized disorder with a high morbidity rate. The prevalence of congenital and inherited prothrombotic risk factors in children with CVT is comparable or even higher than in the adult population.Although advances have been made in the characterization of prothrombotic risk factors in patients with CVT, many cases still are considered idiopathic. Larger, well-designed, prospective studies will allow practitioners to determine the population at risk for CVT. Therefore, adequate measures can be taken in order to prevent this severe thrombotic disorder.     

The risk of fetal loss in family members of probands with factor V Leiden mutation.

In order to investigate the risk of fetal loss in carriers of factor V Leiden who are family members of probands with this mutation, we performed a retrospective cohort study including 109 women who had been pregnant at least once and were family members of 61 probands with venous thromboembolism and a single identified factor V Leiden mutation. The rate of pregnancies ending in unexplained fetal loss, early miscarriage, late miscarriage or stillbirth in women with the factor V Leiden was compared with that of women with normal genotype. In the 65 women who were carriers of factor V Leiden 31 of the 191 pregnancies (16.2% per pregnancy) resulted in unexplained fetal loss, as compared to 13 of the 121 pregnancies (10.7% per pregnancy) in the 44 non-carriers (relative risk, 1.5; 95% CI, 0.8-3.2). After the first trimester of pregnancy, 25 pregnancies (13.1% per pregnancy) among carriers of factor V Leiden ended in fetal loss, as compared to 7 (5.8% per pregnancy) among females with normal genotype (relative risk, 2.3; 95% CI, 1.01 to 5.1). We conclude that carriers of factor V Leiden who are family members of probands with this mutation have a statistically significant and clinically important risk of late miscarriage or stillbirth. Studies addressing the benefit-to-risk ratio of adopting routinary thromboprophylactic measures following the first trimester of pregnancy in these women are strongly indicated.     

Markers of activated coagulation in patients with factor V Leiden and/or G20210A prothrombin gene mutation

The activated protein C (APC) resistance phenotype associated with an abnormal factor V Leiden (FVL), and the G20210A prothrombin gene mutation are the most common findings in patients with venous thromboembolism (VTE). In a group of 210 patients, we compared the levels of markers of coagulation activation in carriers of FVL (71 heterozygous, 30 homozygous), G20210A prothrombin mutation (88 heterozygous) or both mutations combined (21 heterozygous), in order to assess whether these markers allow identification of a group of patients with a higher risk of thrombosis; they were also compared to normal values. A total of 143 patients had a personal history of VTE and 67 were asymptomatic. None of them had other hereditary causes of thrombophilia or an antiphospholipid syndrome. None were currently treated with either anticoagulant or hormonal treatment. Pregnant women were excluded.No significant difference between the four groups of patients could be found in the levels of F1+2, TAT and DDI. Levels were all significantly higher than the control values (p<0.05).The levels of F1+2 and TAT were similar in patients with or without a history of VTE, regardless of the type of mutation. DDI levels were significantly higher in patients with a history of VTE than in asymptomatic subjects (443+/-248 vs. 333+/-222 ng/ml, p=0.02) but with only 57% sensitivity and specificity. In conclusion, our study confirms the hypercoagulable state found in mutation carriers and points out the inability of F1+2 and TAT assays to identify a group of subjects at higher risk of thrombosis, within carriers of genetic risk factors. Although the sensitivity and specificity of DDI assay are low, high DDI concentrations tend to be associated with the risk of VTE.     

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).     

Factor V Leiden mutation is associated with enhanced arterial thrombotic tendency in lean but not in obese mice

The homozygous factor V Leiden mutation is associated with enhanced venous thrombotic risk. Obesity is a major risk factor for development of thrombotic cardiovascular disease. It was the objective of this study to investigate whether obesity affects the thrombotic risk associated with the mutation. Male mice with homozygous factor V Leiden mutation (Arg 504 to Gln) (FVQ/Q) and corresponding wild-type (WT) mice were kept on a standard fat diet (SFD) or high fat diet (HFD) for 14 weeks, and femoral artery thrombosis was induced by FeCl3 treatment. As compared to SFD, HFD feeding for 14 weeks resulted in significantly higher body weight and fat mass associated with adipocyte hypertrophy, which were, however, similar for both genotypes. In the FeCl3-induced arterial thrombosis model, FVQ/Q mice kept on SFD had a 40% shorter occlusion time (p = 0.015) and 40% lower blood flow (p = 0.03), as compared to WT mice. However, on HFD the occlusion time and blood flow were not significantly different for both genotypes. This finding could not be explained by differential changes of coagulation factors in either genotype fed on SFD or HFD. In conclusion, on SFD, but not on HFD, the factor V Leiden mutation is associated with enhanced thrombotic tendency after FeCl3 injury of the femoral artery, suggesting that in this model obesity rescues the increased thrombotic risk associated with the factor V Leiden mutation.