Factor V Leiden: the venous thrombotic risk in thrombophilic families

Factor V Leiden (FVL) leads to a sevenfold increased risk of venous thrombosis and is present in 50% of individuals from families referred because of unexplained familial thrombophilia. We assessed the association of FVL with venous thromboembolism (VTE) in 12 thrombophilic families of symptomatic probands with FVL in a retrospective follow-up study. We screened 182 first- and second-degree relatives of the 12 unrelated propositi for the FVL mutation and the occurrence of VTE. The incidence rate of VTE in carriers of FVL (0.56%/year) was about six times the incidence for the Dutch population (0.1%/year). The incidence rate in non-carriers also appeared to be higher (0.15% per year). At the age of 50 years, the probability of not being affected by VTE was reduced to 75% for carriers and to 93% for non-carriers (P = 0.009). Identification of carriers of FV Leiden may be worthwhile in young symptomatic individuals and their relatives with a strong positive family history of venous thromboembolism or a history of recurrent venous thrombosis who may be at risk (e.g. pregnancy, use of oral contraceptives). After adjustment for prothrombin G20210A (present in two families), even higher thrombotic incidence rates were found in carriers and non-carriers of FVL. This makes the presence of other unknown prothrombotic risk factors more probable in these families.     

Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis.

Factor V Leiden is the most common genetic defect associated with venous thromboembolism. Its clinical expression is limited and shows a wide intrafamilial and interfamilial variation, which might be explained by the influence of other genetic risk factors. We retrospectively studied 226 patients with factor V Leiden and documented venous thromboembolism (probands) and 400 first-degree carrier relatives to assess the contribution of concomitant genetic risk factors to the occurrence of venous thromboembolism. The prothrombin G20210A mutation was found in 8.3%, homozygosity of factor V Leiden in 7.2%, and inherited deficiencies of antithrombin, protein C or protein S in 4.7% of symptomatic carriers (probands and relatives), as compared with 6.0, 3.4 and 0.9% of asymptomatic carriers, respectively. The total follow-up time in relatives was 11 049 years. Prevalences of venous thromboembolism were 10.8% in single heterozygous factor V Leiden carrier relatives, 16.0% in double-heterozygotes for factor V Leiden and the prothrombin mutation, 36.8% in homozygotes for factor V Leiden, and 40.0% in double-heterozygotes for factor V Leiden and an inherited deficiency of protein C or protein S. Annual incidences in these groups were 0.39, 0.57, 1.41, and 4.76%, respectively. Multivariate analysis showed a small, non-significant additional effect of the prothrombin mutation on the risk of venous thromboembolism in heterozygotes for factor V Leiden [adjusted hazard ratio, 1.3; 95% confidence interval (CI), 0.5-3.8]. This effect was more pronounced for homozygosity of factor V Leiden (adjusted hazard ratio, 3.9; 95% CI, 1.7-9.0) and inherited protein C or protein S deficiencies (adjusted hazard ratio, 17.5; 95% CI, 3.8-81.2). Our data provide evidence of clustering of the evaluated genetic thrombophilic defects in symptomatic factor V Leiden carriers and support the assumption that the clinical expression of factor V Leiden depends on clustering in a part of carriers.     

Factor XIII Val34Leu and the risk of venous thromboembolism in factor V Leiden carriers

A mutation in factor XIII (Val34Leu) was reported to protect against venous thromboembolism. We evaluated the effect of Val34Leu on thrombotic risk in 352 factor V Leiden carriers who were first-degree relatives of 132 thrombotic propositi carrying factor V Leiden. The total observation period was 2,594 years in 92 Val34Leu carriers and 7,444 years in 260 non-carriers. The annual incidence of a first episode of venous thromboembolism was 0.31% in Val34Leu carriers and 0.44% in non-carriers [relative risk (RR) for venous thromboembolism: 0.7, 95% CI 0.3-1.5]. Age-specific RR for venous thromboembolism were (for Val34Leu carriers and non-carriers respectively): 1.0 (95% CI 0.3-3.2) in the age group of 15-30 years, 0.4 (95%, CI 0.05-3.0) in the age group of 30-45 years, 0.6 (95% CI 0.1-2.9) in the group aged 45-60 years and 0.5 (95% CI 0.06-4.5) in relatives older than 60 years. In conclusion, the impact of FXIII Val34Leu on the venous thromboembolic risk is modest, suggesting that screening for this mutation in factor V Leiden carriers is not justified.     

Cerebral venous sinus thrombosis as a recurrent thrombotic event in a patient with heterozygous prothrombin G20210A genotype after discontinuation of oral anticoagulation therapy: How long should we treat these patients with warfarin?

Background

Cerebral venous sinus thrombosis is an uncommon condition with many clinical manifestations, and hereditary prothrombotic conditions such as factor Leiden V, deficiency of protein S, protein C and antithrombin III, as well as prothrombin gene mutation, may account for 10–15% of cases. To date, conflicting results have been reported for recurrent venous thrombosis in the patients with factor V Leiden and prothrombin G20210A mutation, since some studies have shown a higher risk for recurrent venous thrombosis in carriers of these two mutations than in non-carriers, and the last study showed higher risk only for carriers of double defect (homozygous or double heterozygous for this mutations).

Methods

Case report is presented.

Results

We report a case of cerebral sinus thrombosis as a recurrent thrombotic event in a patient with heterozygous prothrombin G20210A genotype after discontinuation of oral anticoagulation therapy.

Conclusion

Since many facts are controversial, the use of secondary prophylaxis for thrombosis in these patients is still a matter of debate without clear consensus recommendation. Data on the risk of recurrent thrombotic events in thrombophilic patient is insufficient. The main unclear question concerning these patients is: how long and whom should we treat with long-term anticoagulant therapy as secondary prophylaxis of DVT? The problem for practitioner is that we do not have guidelines and precise recommendations for secondary thromboprophylaxis in this or similar cases. This case is remarkable for its favorable and quick outcome and its rarity, because CSVT is an uncommon condition and heterozygous prothrombin G20210A genotype was only found predisposing factor for CSVT. Further studies of risk of recurrent venous thrombosis in patients with heterozygous prothrombin G20210A genotype with the larger sample size are required.

     

Outcome of Patients with Venous Thromboembolism and Factor V Leiden or Prothrombin 20210 Carrier Mutations During the Course of Anticoagulation

Background

Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored.

The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation

The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long-term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti-thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti-phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Cox's proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1.3; 95% CI, 0.7-2.3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype.     

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

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

FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population

The absolute rate of recurrence of venous thromboembolism (VTE) is approximately 5% per year. There is a lower rate of recurrence in provoked VTE, and higher in idiopathic one. So far, there is no consensus whether hereditary thrombophilia should be considered as a persistent risk factor, and whether it requires long-term anticoagulant therapy. The aim of our study was to estimate the risk of recurrent VTE in patients carrying FV Leiden mutation in Serbian population.In retrospective study (1994-2006), we have evaluated the risk of recurrent VTE in 56 patients who are carriers of FV Leiden mutation, in comparison to group consisting of 56 patients non-carriers of FV Leiden mutation. Patients with FII G20210A and MTHFR C677T mutations, antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, malignancies and diabetes were excluded from the study.Recurrent VTE occurred in 44.6% of the patients, carriers of the FV Leiden mutations, vs. 26.7% in non-carriers group (P<0.05). The incidence rate was 3.7 and 2.2% per year, respectively. The estimated relative risk of recurrence for FV Leiden carriers was 1.67 (95% CI 0.99-2.81, P=0.049). The 60% of patients with mutation and only 13% without mutation develop rethrombosis during first year after discontinuance of therapy (P<0.01).In our study patients with symptomatic VTE who are carriers of the FV Leiden gene mutations have a higher risk of recurrent VTE than non-carriers. Our data suggest the importance of the FV Leiden mutation detection and the estimation of the clinical condition for successful secondary prophylaxis of VTE.     

Prevalence of the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A prothrombin gene mutation in the Thai population

We investigated the prevalence of a genetic variation in the factor V gene (G1691A Leiden mutation) and the prothrombin gene (G20210A) using polymerase chain reaction techniques in samples from 500 normal Thai population and among 50 unselected Thai patients with an objectively confirmed history of deep venous thrombosis. The prevalence of factor V Leiden and the prothrombin G20210A gene mutation in a group of 500 healthy controls was 0.2% in both groups (allele frequency of 0.1%). Of the 50 adult patients studied, none was a carrier of factor V Leiden or the prothrombin G20210A gene mutation. Our findings confirm that the prevalence of factor V Leiden and prothrombin G20210A gene mutation is lower among Asians than Caucasians and that the distribution of factor V Leiden is similar to that of the prothrombin G20210A variant. The low prevalence of these two mutations can, at least in part, account for the lower frequency of deep venous thrombosis reported in the Thai population. Screening for factor V Leiden and prothrombin gene mutation is of limited benefit and may not be cost-effective in Thai patients with the first episode of deep venous thrombosis.     

Prediction,prevention, and treatment of venous thromboembolic disease in pregnancy

Pregnancy is recognized as an independent risk factor for venous thromboembolism leading to thromboembolic events, particularly in women with prior venous thrombosis, family history of thrombosis, or additional thrombophilic risk factors. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification on the basis of probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. For this reason, routine thrombophilia screening of all pregnant women is not recommended. However, a combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor (such as surgery or trauma) and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis also appears to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (> 10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. In many cases, the absolute magnitude of risk is unknown or estimated, and recommendations are often empiric.     

Thrombosis in a patient with combined homozygosity for the factor V Leiden mutation and a mutation in the 3'-untranslated region of the prothrombin gene.

The factor V Leiden mutation and a guanine-to-adenine mutation at nucleotide 20210 in the 3'-untranslated region of the prothrombin gene are the most prevalent genetic defects in patients with deep venous thrombosis. Heterozygosity for the factor V Leiden and the prothrombin gene mutations is found in approximately 20 and 6% of unselected patients with deep venous thrombosis, respectively, whereas the prevalences of the two mutations in the general Caucasian population are approximately 6 and 2%, respectively. We evaluated an 18-year-old man presenting with a spontaneous episode of superficial venous thrombosis for the presence of an inherited thrombotic disorder. After excluding deficiencies of antithrombin, protein C, and protein S, genomic DNA from the patient was tested for the presence of the factor V Leiden and prothrombin gene mutations. Consanguinity was not present in the family. Genotyping demonstrated that the patient was homozygous for the factor V Leiden and prothrombin gene mutations. The likelihood of identifying an individual in the general population who is homozygous for both mutations similar to our patient is estimated to be less than 1 in 10 million.     

Prevalence of genetic prothrombotic factors (factor V Leiden and II20210 prothrombin mutation) in glomerular nephropathies with or without thrombosis

The presence of genetic prothrombotic factors (factor V Leiden and the prothrombin II20210 mutation) was investigated in 38 patients with glomerulonephritis with or without a history of thrombotic events and/or nephrotic syndrome. We found an increased prevalence (36%) of heterozygous factor V Leiden in those patients with a history of thrombotic events. This is ten times the prevalence in the normal Spanish population. Carrier status for this mutation may be a determining factor in the development of thrombotic events along with the acquired disorders of coagulation to which these patients are prone. We found only one patient who was a carrier of the G-A II20210 mutation of the prothrombin gene; this patient had no history of venous thrombosis or embolism. Our findings suggest the need to measure activated protein C resistance and to look for the most frequent genotype causing it, Factor V Leiden, in patients with glomerulonephritis to identify those at risk who may benefit from prophylaxis against thrombosis.     

Genetic risk factors of thrombosis

Genetic risk factors became a frequent predisposing cause of venous thromboembolism (VTE) since the discovery of two mutations: factor V Leiden and G20210A mutation of prothrombin gene. One of these both mutations is associated with around 25% of VTE events. Interaction of genetic risk factors, such as interaction of FV Leiden or G20210A mutation of prothrombin with antithrombin, protein C or protein S deficiencies, as well as interaction with acquired risk factors, have demonstrated that venous thrombosis is a multifactorial disease. The search for thrombophilia must be done in VTE occurring before the age of 45, in case of recurrencies and in case of familial history of VTE.     

Prevalence of factor V Leiden and prothrombin 20210 A variant in Bulgarian patients with pulmonary thromboembolism and deep venous thrombosis.

Factor V Leiden mutation and prothrombin variant 20210 A are well-known risk factors for venous thrombosis (DVT). Recent papers have reported a lower prevalence of factor V Leiden in patients with pulmonary thromboembolism (PTE) than in patients with deep venous thrombosis. The aim of the present study was to compare the prevalence of factor V Leiden and the prothrombin 20210 G <-- A mutation in patients with DVT and in patients with PTE. We studied 128 consecutive patients (45 with DVT, 40 with PTE, and 43 with DVT and PTE) for factor V Leiden and prothrombin 20210 A. One hundred healthy persons matched by age and sex were used as controls. Factor V Leiden was present in five of the patients with PTE [12.5%; 95% confidence interval (CI), 1.5-23.5%; not significant], 15 of the patients with DVT (33.3%; 95% CI, 9.6-38.7%; P < 0.001), and 12 of the patients with DVT and PTE (27.9%; 95% CI, 4.8-33%; P = 0.001). Results for the prothrombin 20210 A mutation were as follows: four of 40 patients with PTE (10%; 95% CI, 0-13.3%; P = 0.46), nine of 45 (20%) of the patients with DVT (95% CI, 0.5-25.5%; P < 0.05) and eight of 43 with DVT and PTE were heterozygous (18.6%; 95% CI, 0-23.9%; P = 0.02). In conclusion, there is a significantly higher frequency of factor V Leiden among patients with DVT than in patients with PTE. However, there is no significant difference of factor V Leiden or 20210 A prothrombin mutation in patients with DVT than in patients with combined DVT/PTE, therefore patients with DVT, carriers of the mutations, do not appear to be at lower risk for pulmonary embolism.     

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in a Mediterranean area.

BACKGROUND: Thromboembolism has been reported to be associated with inflammatory bowel disease. AIM: To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events. PATIENTS AND METHODS: A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls. RESULTS: One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively. CONCLUSIONS: Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.     

G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism

OBJECTIVES: The study was done to determine whether the G20210A mutation in the prothrombin gene increases the risk of recurrent venous thromboembolism (VTE), both alone and in combination with factor V Leiden. BACKGROUND: Several inherited defects of coagulation are associated with increased risk of first VTE, including a recently identified G20210A mutation in the prothrombin gene. However, whether the presence of this mutation confers an increased risk of recurrent venous thromboembolism is controversial. METHODS: A total of 218 men with incident venous thromboembolism were genotyped for the prothrombin mutation and for factor V Leiden and were followed prospectively for recurrent VTE over a follow-up period of 7.3 years. RESULTS: A total of 29 men (13.3%) suffered recurrent VTE. Five of the 14 carriers of the prothrombin mutation developed recurrent VTE (35.7%; incidence rate = 8.70 per 100 person-years), while 24 of 204 individuals who did not carry the prothrombin mutation developed recurrent VTE (11.8%; incidence rate = 1.76 per 100 person-years). Thus, presence of the G20210A mutation was associated with an approximate fivefold increased risk for recurrent VTE (crude relative risk [RR] 4.93; 95% confidence interval [CI] 1.9-12.9; p = 0.001; age-, smoking-, and body mass index-adjusted RR 5.28; 95% CI 2.0-14.0; p = 0.001). In these data, recurrence rates were similar among those with an isolated mutation in the prothrombin gene (18.2%) as compared to those with an isolated factor V Leiden mutation (19.2%). However, all three study participants who carried both mutations (100%) suffered a recurrent event during follow-up. CONCLUSIONS: In a prospective evaluation of 218 men, the presence ofprothrombin mutation was associated with a significantly increased risk of recurrent VTE, particularly among those who co-inherited factor V Leiden.     

Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.     

Laboratory thrombophilias and venous thromboembolism

Inherited abnormalities of coagulation are increasingly recognized in patients with venous thromboembolism. Common causes of hypercoagulability, also known as thrombophilia, include factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be suspected in patients who develop idiopathic venous thromboembolism at a young age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained pregnancy loss, or if there is a family history of thrombotic disorders. The most cost-effective approach is to initially screen for factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies because these are the most common defects causing thrombophilia. Long-term anticoagulation is controversial but should be considered if unprovoked venous thromboembolism recurs.     

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in Mediterranean area

Background. Thromboembolism has been reported to be associated with inflammatory bowel disease.Aim. To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events.Patients and methods. A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls.Results. One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively.Conclusions. Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.     

Inherited thrombophilia and gestational venous thromboembolism

Thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification based on probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. Within the past 10 years, a significant improvement in risk estimation has been achieved due to the identification of new genetic risk factors of thrombosis. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low--indicating that pregnancy-associated thrombosis is multicausal, resulting from the interaction of combined defects. A combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor, for example, surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (>10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk in many cases is unknown and current recommendations remain empirical.