The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A

Background : The risk of venous thromboembolism (VTE) during pregnancy in double heterozygous carriers of factor (F) V Leiden and prothrombin G20210A is not established. Hence, whether or not these women deserve antithrombotic prophylaxis when pregnant is unknown. Patients and methods : In the frame of a multicenter family study, 52 double heterozygous carriers of FV Leiden and prothrombin G20210A who had remained pregnant at least once before knowledge of thrombophilia, were retrospectively investigated with respect to the occurrence of first VTE during pregnancy and puerperium. They were compared with 104 heterozygous carriers of FV Leiden, 104 of prothrombin G20210A and 104 women without thrombophilia. Results : Double heterozygotes were similar to single heterozygous carriers and non-carriers for the age at first pregnancy, age at testing and rate of full-term pregnancies. No VTE during pregnancy was observed in the four groups of women, whereas in the puerperium it occurred in two double carriers (1.8% of pregnancies, 95% CI: 0.5–6.3), three single FV Leiden carriers (1.5%, 0.5–4.3), two single prothrombin G20210A carriers (1%, 0.2–3.6) and one non-carrier (0.4%, 0–2.5). Conclusions : The risk of first VTE during pregnancy and puerperium in double heterozygous carriers of FV Leiden and prothrombin G20210A is low and similar to that of single carriers. As for single heterozygotes, antithrombotic prophylaxis in asymptomatic double heterozygous carriers appears to be justified only in puerperium.     

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations

BACKGROUND: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. OBJECTIVE: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. METHODS: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. RESULTS: Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy [25 vs. 12%, relative risk (RR) 2.0, 95% CI 1.4-3.0]. The live birth rate of the second pregnancy after an early first loss ( 12 weeks), the live birth rates were 68% (95% CI 46-85) and 80% (95% CI 49-94) for carriers and non-carriers, respectively (RR 0.9, 95% CI 0.5-1.3). CONCLUSIONS: Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.     

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms

Background: Pregnancy is associated with a 10‐fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy‐related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. Materials and Methods: The study comprised 377 155 women with 613 232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. Results: The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1–8.3] and 9.4 (95% CI 2.1–42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy‐related VT occurred in 1.1/1000 non‐carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. Conclusions: Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy‐related VT was low.     

Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia

BACKGROUND: Patients with factor (F) V Leiden or the prothrombin G20210A polymorphism are at increased risk of developing deep vein thrombosis (DVT). On the other hand, the risk of developing pulmonary embolism (PE) appears to be low in carriers of FV Leiden, perhaps because of a lower tendency to develop iliofemoral DVT than non-carriers. For prothrombin G20210A, data are scanty and controversial. METHODS: The clinical manifestations (isolated DVT, DVT and PE, and isolated PE), the extension of DVT, and the presence of transient risk factors were retrospectively investigated in 115 patients with heterozygous FV Leiden, 87 with prothrombin G20210A and 200 with no thrombophilia marker. RESULTS: Isolated symptomatic PE was less prevalent in patients with FV Leiden (6%) than in those with prothrombin G20210A (21%) and no thrombophilia (23%) (P > 0.0001). The rate of distal DVT was higher in patients with no thrombophilia (16% vs. 7% for FV Leiden and 6% for prothrombin G20210A) (P = 0.02). No difference in the incidence of PE from distal and proximal DVT, the extension of proximal DVT and the type of transient risk factors for venous thromboembolism (VTE) was found in the three groups. Patients with prothrombin G20210A had a younger age at their first VTE (24 years, P < 0.0001) and a higher rate of DVT accompanying PE (P = 0.04) than those with FV Leiden or no thrombophilia. CONCLUSIONS: Carriers of prothrombin G20210A, unlike those of FV Leiden, have an increased risk of developing isolated PE. This difference was not explained by a different rate of distal DVT, extension of proximal DVT, or distribution of transient risk factors in the two groups. Patients with prothrombin G20210A have more severe clinical manifestations than those with FV Leiden or no thrombophilia.     

Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study

Summary.  The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.     

Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A

Summary.  Background : Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives : To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods : In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results : The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions : Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients.     

The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case–control study

BACKGROUND: The FIIG20210A polymorphism has been associated with arterial wall thickness and atherothrombotic diseases in selected subgroups. The FVArg506Gln polymorphism does not seem to be associated with arterial diseases. Few data are available on these polymorphisms and the risk of peripheral arterial disease (PAD). OBJECTIVES: To study the association between the FIIG20210A and FVArg506Gln polymorphisms and PAD and its clinical severity. To examine the potential interactions with traditional vascular risk factors. PATIENTS AND METHODS: We studied 184 consecutive male patients under 70 years of age with symptomatic PAD and 330 age-matched male controls free of symptomatic PAD and with no cardiovascular history. We evaluated the FIIG20210A and FVArg506Gln polymorphisms in all subjects. RESULTS: Mean age was 57.1 +/- 7.2 years (cases) and 56.7 +/- 7.6 years (controls). The FII20210A allele was more frequent in PAD patients with odds ratios (OR) of 3.77 (1.39-10.2) in univariate analysis and 4.30 (1.3-14.7) after adjustment for diabetes, smoking, hypertension and hypercholesterolemia. In smokers or past smokers the magnitude of the association was markedly increased but there was no evidence of an interaction between tobacco exposure and FIIG20210A. In case subjects, the FII20210A allele was also associated with critical ischemia [OR = 4.1 (1.1-15.7), P = 0.039 in multivariate analysis]. FVArg506Gln was not associated with PAD [OR = 0.65 (0.27-1.54) and 0.77 (0.28-2.1) in univariate and multivariate analyses, respectively]. CONCLUSIONS: The FIIG20210A gene polymorphism may be a risk factor for PAD and its severity. In contrast, the FVArg506Gln polymorphism is not associated with PAD.     

Influence of the factor II G20210A variant or the factor V G1691A mutation on symptomatic recurrent venous thromboembolism in children: an international multicenter cohort study

Summary.  Objective:  To determine the relative importance of the factor (F) II G20210A or FV G1691A mutations as risk factors or predictors for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. Methods:  In the present cohort, the rate of VTE recurrence and the time to recurrence in relation to FII, FV, age, and sex was determined in consecutively enrolled patients with VTE aged newborn to ≤18 years carrying the FII ( n  = 64) or FV ( n  = 194) mutation. 158 children with VTE without thrombophilia served as controls. Patients were followed for a median of 58 months. Data were pooled across participating sites to increase power and to enhance the generalizability of the data. Incidence rates were given as events per 1000 person-years. Results:  Of the 416 children enrolled, 44 had recurrent VTE at a median of 12 months following VTE onset. The overall incidence rate of recurrence was 19.8, 57.9 in patients with the FII variant, 17.9 for FV carriers, and 11.8 in the control cohort. When comparing FII patients, FV children and the control cohort multivariate analysis (Cox regression) adjusted for age and sex showed that the FII variant (hazard ratio 2.6; 95% confidence interval 1.1–5.9) influenced the hazard for recurrent VTE. Conclusions:  Based on multivariate analysis, the presence of the FII variant was associated with an increased risk of VTE recurrence.     

Inherited thrombophilias and unexplained pregnancy loss: an incident case-control study

Summary.  Background:  Despite an initial impressive impact, a critical appraisal of the link between pregnancy loss and inherited thrombophilias is currently growing. Furthermore, little is known about the paternal thrombophilic phenotype and pregnancy loss. Objective:  We sought an association between unexplained pregnancy loss and parental factor V Leiden (FVL) and Prothrombin G20210A (PTG) mutations. Methods:   Design – Incident case–control study. Setting – University Hospital of Brest (France). Patients – Women and their partners from the West Brittany area, consecutively referred for unexplained pregnancy losses (two or more consecutive losses at or before 21 weeks of gestation, or at least one later loss). Controls – Women and their partners with no history of pregnancy loss and at least one normal pregnancy, from the same geographic area, recruited using electoral lists. Statistical analysis – Comparison of FVL and PTG allele frequency between cases and controls using the chi-square test. Separate analyses were performed according to the type of pregnancy loss (early recurrent or later loss). Results:  311 women (mean age: 32.8) and 284 of their partners were enrolled as cases while 599 women (mean age: 34.3) and 297 of their partners were recruited as controls. The prevalence of female, male or couple thrombophilic mutations was not statistically different between cases and controls whatever the definition of pregnancy loss retained. Conclusions:  Presently, there is no clinical indication to routinely test for FVL and likely PTG mutations in women with early recurrent pregnancy loss. Moreover, our results did not reveal that paternal thrombophilic polymorphism should be further explored.     

The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study

BACKGROUND: The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied. OBJECTIVE: In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE). METHODS: Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers. RESULTS: One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7-1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8-6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status. CONCLUSIONS: Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.     

Factor V Leiden is associated with pre‐eclampsia but not with fetal growth restriction: a genetic association study and meta‐analysis

Summary. Background: Adverse pregnancy outcomes have been related to environmental and/or genetic factors. Of interest are genes associated with the clotting system as any perturbation in the balance of thrombotic and thrombolytic cascades could affect the placental circulation and hence the viability of the developing fetus. Several previous reports using relatively small numbers of cases and controls have suggested that there is a relationship between poor pregnancy outcomes and two polymorphisms, one in the factor V gene, the 1691G to A change (rs6025) located on chromosome 1q23 (factor V Leiden, FVL), and the other in the prothrombin gene, 20210G to A change (rs1799963) on chromosome 11p11‐q12 (PT). These results, however, are conflicting. Methods: We genotyped 6755 mother/infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether maternal or fetal FVL or PT, either alone or in combination, are associated with fetal growth restriction (FGR) or pre‐eclampsia (PE). We also added the present results to previous cohort studies using meta‐analysis. Results: Smoking, primiparity and lower body mass index (BMI) were all associated with FGR, but neither maternal nor fetal FVL or PT, singly or in combination, were associated with FGR in the ALSPAC cohort. Meta‐analysis confirmed the lack of association between maternal FVL and FGR with a pooled odds ratio (OR) of 1.15 [95% confidence interval (CI) 0.95–1.39]. High BMI, primiparity, diabetes and chronic hypertension were all associated with pre‐eclampsia. Combining ALSPAC results with previous studies in a meta‐analysis indicated that maternal FVL is significantly associated with pre‐eclampsia, with a pooled OR of 1.49 (95% CI 1.13–1.96). Conclusion: Neither maternal nor fetal FVL or PT, singly or in combination, are associated with FGR; this contradicts previous case–control studies and meta‐analyses based on these studies. In a meta‐analysis of all published cohort studies to date, maternal FVL appears to increase the risk of pre‐eclampsia by almost 50%. This result is robust, homogeneous and does not appear to be affected by publication bias.     

Factor V Leiden as a risk factor for preterm birth – a population‐based nested case–control study

Summary. Background: Preterm birth is a major cause of neonatal morbidity and mortality, occurring in 5–13% of deliveries in developed countries. Genetic thrombophilia can theoretically contribute to the induction of preterm delivery, but the role of thrombophilia as risk factor is unclear. Objectives: To assess factor V Leiden, FII G20210A and other selected inherited and acquired variables as risk factors for preterm birth. Patients/Methods: We performed a population‐based nested case–control study of 100 000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers. Clinical data were obtained from medical records and standardized questionnaires. We studied 324 cases with preterm delivery at or after 22 and before 37 completed weeks of gestation, and 752 controls. Results: FV Leiden was associated with a 2.4‐fold risk (95% confidence interval [CI] 1.3–4.6) of preterm birth in all pregnancies, and a 2.6‐fold risk (95% CI 1.4–5.1) in singleton pregnancies. FV Leiden was especially associated with late preterm birth at or after 32 weeks of pregnancy, with an odds ratio (OR) of 2.9 (95% CI 1.5–5.6) in all pregnancies and an OR of 3.1 (95% CI 1.6–6.2) in singleton pregnancies. FII G20210A was not associated with preterm birth. Twin pregnancy (OR 12.0, 95% CI 6.0–24.1) and a history of venous thrombosis (OR 3.8, 95% CI 1.4–9.8) were associated with increased risk. High educational level and modest overweight (body mass index 25–29.9 kg m^?2) had protective effects. Conclusions: Maternal carriage of FV Leiden was associated with increased risk of late but not early preterm birth. FII G20120A was not associated with preterm birth.     

The association of prothrombin A19911G polymorphism with plasma prothrombin activity and venous thrombosis: results of the MEGA study, a large population-based case–control study

BACKGROUND: Prothrombin (FII) G20210A mutation and elevated plasma prothrombin activity are known risk factors for venous thrombosis. The risk of venous thrombosis among 19911G carriers of the prothrombin A19911G polymorphism has not been extensively investigated. OBJECTIVES AND METHODS: We assessed prothrombin activity, FIIG20210A, and FIIA19911G polymorphisms in a large population-based case-control study, the Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis. Four thousand three hundred and sixty-five consecutive patients with a first episode of deep vein thrombosis of the leg or pulmonary embolism were included. The control group (n = 4779) consisted of partners of patients or persons gathered using a random-digit dialing method. We studied the effect of FIIA19911G polymorphism on prothrombin activity and thrombosis risk, also in combination with factor V Leiden. RESULTS: Among FII20210-GG control subjects, FII19911-GG carriers had 7.1% [95% confidence interval (CI): 5.7-8.5] higher mean prothrombin activity than FII19911-AA carriers and the risk for GG carriers was 1.43-fold increased compared to AA carriers [odds ratio (OR) 1.43; 95% CI: 1.27-1.61]. Among FII20210-GA control carriers, the mean prothrombin activity in both FII19911-AA and -AG carriers was nearly equivalent [131.7% and 133.4%; mean difference (95% CI) = 1.7% (-7.2-10.7)]. Because of genetic linkage, FII19911-GG carriers were very rare on a FII20210-GA background, as only one FII20210A carrier had FII19911-GG. In FII20210-GA carriers, the OR increased from 3.05 (95% CI: 2.17-4.27) in subjects with FII19911-AA to 3.33 (2.28-4.85) in subjects with FII19911-AG, compared to those with FII20210-GG and FII19911-AA. CONCLUSIONS: The FIIA19911G polymorphism is associated with mildly elevated prothrombin activity and is a risk factor for venous thrombosis.     

Comparative study between the Light Cycler and the PCR-restriction fragment length polymorphism in detecting factor V Leiden and factor II 20210G>A mutations

OBJECTIVES: To test reproducibility, speed and cost of testing for factor V Leiden and FII 20210G>A in our practice. DESIGN AND METHODS: We compared conformity, reproducibility, speed and cost using the Light Cycler (LC) and PCR-RFLP. RESULTS: There was 100% conformity and reproducibility. LC was faster but 23% more expensive per sample. When equipment depreciation and patient expenses are added, LC testing becomes cheaper. CONCLUSION: In our practice, LC provides fast, reproducible and cost-effective results.     

Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case–control study

Dysfunction of the protein C anticoagulant system is associated with venous thromboembolism (VTE) and thrombomodulin (TM) is a critical cofactor within the protein C system. The aim of this study was to test the hypotheses that polymorphisms or haplotypes within the TM gene are common risk factors for VTE. We screened the TM putative promoter, exon and 3'-untranslated region for sequence variations in a random sample (n = 266) of consecutive idiopathic, objectively confirmed non-Olmsted County VTE patients referred to the Mayo Clinic. We then genotyped a sample of Olmsted County, MN residents with a first lifetime, objectively confirmed VTE in the 25-year period, 1966-90 (n = 223), and a sample of Olmsted County residents without VTE (n = 237) for polymorphisms either discovered in the screening population or previously published, and tested for an association of VTE with TM genotype or haplotypes using unconditional logistic regression and generalized linear models, respectively. We also genotyped these Olmsted County cases and controls at 20 'null' genetic maker loci and tested for population admixture. Nine novel and three previously described mutations were identified in the screening population. Mutations within the TM promoter, EGF(1-5), serine/threonine-rich, transmembrane, and cytoplasm regions were absent or uncommon. TM845G-->A (Ala25Thr; lectin region), TM2136T-->C (Ala455Val; EGF(6) region), TM2470C deletion (3'-untranslated region), and 4363A-->G (3'-flanking region) were more common, but were not associated with VTE by genotype or haplotype. Null genetic marker allele frequencies did not differ significantly among cases and controls. We conclude that polymorphisms or haplotypes within the TM gene are not common risk factors for incident VTE.