Risk of Pregnancy-related Venous Thrombosis in Carriers of Severe Inherited Thrombophilia

2001 ◽  
Vol 86 (09) ◽  
pp. 800-803 ◽  
Author(s):  
Cristina Legnani ◽  
Paolo Bucciarelli ◽  
Elvira Grandone ◽  
Valerio De Stefano ◽  
Pier Mannuccio Mannucci ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Gene Mutations ◽  
Factor V Leiden ◽  
Study Cohort ◽  
Factor V ◽  
Thrombotic Risk ◽  
Increased Risk ◽  
Prothrombin Gene ◽  
Heterozygous Carriers ◽  
Anticoagulant Prophylaxis

SummaryHomozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes, 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.

Polymorphisms in the protein C gene as risk factor for venous thrombosis

2009 ◽  
Vol 101 (01) ◽  
pp. 62-67 ◽  
Author(s):  
Carine Doggen ◽  
Hans Vos ◽  
Pieter Reitsma ◽  
Frits Rosendaal ◽  
Elisabeth Pomp
Keyword(s):  
Oral Contraceptive ◽  
Venous Thrombosis ◽  
Protein C ◽  
Contraceptive Use ◽  
Factor V Leiden ◽  
Factor V ◽  
Thrombotic Risk ◽  
Control Subjects ◽  
Oral Contraceptive Use ◽  
Increased Risk

SummaryProtein C is an important inhibitor of blood coagulation. We investigated the effect of two polymorphisms within the promoter region of the protein C gene (C/T at position 2405 and A/G at position 2418) on risk of venous thrombosis and on plasma protein C levels. In addition the combined effect of the two polymorphisms with factor V Leiden and oral contraceptive use was investigated. Previous studies on these polymorphisms were small and were not able to investigate synergistic effects. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), protein C levels were determined in 2,043 patients with venous thrombosis and 2,857 control subjects, and the two polymorphisms in 4,285 patients and 4,863 control subjects. The CC/GG genotype was associated with the lowest protein C levels. Compared to carriers of the TT/AA genotype – a genotype associated with higher protein C levels – the risk of venous thrombosis in CC/GG carriers was 1.3-fold increased (95% confidence interval 1.09–1.48). The combination of factor V Leiden with the CC/GG genotype led to a 4.7-fold increased risk, compared to non-carriers with the TT/AA genotype. Oral contraceptive use together with the CC/ GG genotype resulted in a 5.2-fold increased risk. In conclusion, the CC/GG genotype is associated with lower levels of protein C and an elevated risk of venous thrombosis compared to the TT/AA genotype. There is no clear synergistic effect of the CC/ GG genotype with factor V Leiden or oral contraceptive use on thrombotic risk.

Detection of Factor V Leiden and Prothrombin Gene Mutations in Patients Who Died With Thrombotic Events

2002 ◽  
Vol 126 (10) ◽  
pp. 1193-1196
Author(s):  
Rostislav D. Ranguelov ◽  
Nancy Rosenthal ◽  
Christine Bromley ◽  
Mohammad A. Vasef
Keyword(s):  
At Risk ◽  
Gene Mutation ◽  
Gene Mutations ◽  
Factor V Leiden ◽  
Factor V ◽  
Wild Type ◽  
Increased Risk ◽  
Factor V Gene ◽  
Prothrombin Gene ◽  
V Gene

Abstract Context.—Individuals with factor V or prothrombin gene mutations are at increased risk for thrombotic events. Furthermore, the risk of recurrent deep venous thrombosis in heterozygous carriers of both factor V Leiden and prothrombin gene mutations is high enough that some investigators suggest lifelong warfarin prophylaxis for these individuals, even with a single spontaneous thrombotic event. Objectives.—To assess the incidence of factor V Leiden and prothrombin gene mutations in an autopsy population and to determine if these tests can prove useful in identification of at-risk family members. Design.—We analyzed factor V Leiden and prothrombin gene mutations in 45 patients who died with or of thrombotic events, using archival tissue and multiplex allele-specific polymerase chain reaction amplification. The wild-type factor V gene was amplified in all 45 patients, whereas the wild-type prothrombin gene was amplified in 29 patients. Results.—Two patients (4.4%) who died with thrombotic events at the ages of 35 and 92 years were heterozygous for factor V gene mutation. Two additional patients (6.7%), who died with thrombotic events at the ages of 26 and 39 years, were heterozygous for prothrombin gene mutation. Patients homozygous for either factor V or prothrombin gene or simultaneously heterozygous for both genes were not detected in our study. Conclusions.—Our findings suggest that screening the relatives of elderly patients who die with thrombotic events would not be cost-effective because of the low incidence of these mutations in the autopsy population. However, because the incidence of these mutations appeared significantly more frequently among individuals who died at 39 years or younger, testing the relatives of this subset of patients may prove useful for detection of at-risk individuals who would benefit from preventive anticoagulation therapy.

scholarly journals FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control Study

2011 ◽  
Vol 30 (1) ◽  
pp. 51-54
Author(s):  
Iva Salatić ◽  
Katarina Kiralj ◽  
Gorana Mitić ◽  
Igor Veselinović ◽  
Dušan Vapa
Keyword(s):  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Case Control Study ◽  
Factor V Leiden ◽  
Case Control ◽  
Factor V ◽  
Increased Risk ◽  
Fv Leiden ◽  
Heterozygous Carriers ◽  
Control Study

FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control StudyBetween September 2007 and February 2010, the occurrence of symptomatic deep venous thrombosis (DVT) was investigated in a cohort of 79 consecutive patients. A case-control study inclu ded 71 healthy controls matched with cases for sex and age. The prevalence of factor V G1691A mutation genotype was analyzed. Eighteen cases (22.79%; 95% confidence interval (CI) 13.53% to 32.03%) and four controls (5.63%; 95% CI 0.27% to 10.99%) were heterozygous carriers of FV Leiden (p= 0.025). The odds ratio for DVT was 4.94 (95% CI 1.58 to 15.42) and the relative risk 4.04 (95% CI 1.44-11.38) compared with FV 1691G carriers. Four cases were homozygous carriers of FV Leiden, giving a prevalence of 5.06% (95% CI 0.23 to 9.89%) and no controls, therefore OR and RR calculation was based on the prevalence of homozygotes in the general Caucasian population. The OR for DVT was 47.28 (95% CI 0.04 - 52167.3) and the RR 45.57 (95% CI 0.04 to 49540.77; p=0.025) compared with FV 1691 G carriers. Our study confirms that factor V Leiden carriers in Vojvodina, as in similar studies previously carried out in other populations, have an increased risk of developing DVT. The evaluated risk of DVT in heterozygous carriers of the mutation is four- to five-fold higher, whereas for homozygous carriers it is 45- to 48-fold higher than in non-carriers. These results confirm that patients with DVT and their relatives should undergo screening for FV Leiden mutation.

Survey of Factor V Leiden and Prothrombin Gene Mutations in Systemic Lupus Erythematosus

2001 ◽  
Vol 20 (4) ◽  
pp. 259-261 ◽  
Author(s):  
R. Topaloglu ◽  
C. Akıerli ◽  
A. Bakkaloglu ◽  
O. Aydıntug ◽  
S. Ozen ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Gene Mutations ◽  
Factor V Leiden ◽  
Factor V ◽  
Systemic Lupus ◽  
Prothrombin Gene

Factor V Leiden (G1691A) and Prothrombin Gene G20210A Mutations as Potential Risk Factors for Venous Thromboembolism after Total Hip or Total Knee Replacement Surgery

2002 ◽  
Vol 87 (04) ◽  
pp. 580-585 ◽  
Author(s):  
G. Larson ◽  
T. L. Lindahl ◽  
C. Andersson ◽  
L. Frison ◽  
D. Gustafsson ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Factor V Leiden ◽  
Composite Endpoint ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
G20210a Mutation ◽  
Symptomatic Pulmonary Embolism ◽  
Increased Risk ◽  
Prothrombin Gene

SummaryPatients (n = 1600) from 12 European countries, scheduled for elective orthopaedic hip or knee surgery, were screened for Factor V Leiden and prothrombin gene G20210A mutations, found in 5.5% and 2.9% of the populations, respectively. All patients underwent prophylactic treatment with one of four doses of melagatran and ximelagatran or dalteparin, starting pre-operatively. Bilateral ascending venography was performed on study day 8-11. The patients were subsequently treated according to local routines and followed for 4-6 weeks postoperatively. The composite endpoint of screened deep vein thrombosis (DVT) and symptomatic pulmonary embolism (PE) during prophylaxis did not differ significantly between patients with or without these mutations. Symptomatic venous thromboembolism (VTE) during prophylaxis and follow-up (1.9%) was significantly over-represented among patients with the prothrombin gene G20210A mutation (p = 0.0002). A tendency towards increased risk of VTE was found with the Factor V Leiden mutation (p = 0.09). PE were few, but significantly over-represented in both the Factor V Leiden and prothrombin gene G20210A mutated patients (p = 0.03 and p = 0.05, respectively). However, since 90% of the patients with these genetic risk factors will not suffer a VTE event, a general pre-operative genotyping is, in our opinion, of questionable value.

scholarly journals High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (6) ◽  
pp. 1504-1508 ◽  
Author(s):  
FR Rosendaal ◽  
T Koster ◽  
JP Vandenbroucke ◽  
PH Reitsma
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Absolute Risk ◽  
Thrombotic Event ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Increased Risk ◽  
The Absolute

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.

scholarly journals The HR2 Haplotype of Factor V Is not Associated with the Risk of Myocardial Infarction

2000 ◽  
Vol 84 (11) ◽  
pp. 815-818 ◽  
Author(s):  
Carine Doggen ◽  
Marieke de Visser ◽  
Hans Vos ◽  
Rogier Bertina ◽  
Volkert Cats ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Factor V Leiden ◽  
Myocardial Infarctions ◽  
Control Group ◽  
Factor V ◽  
Increased Risk ◽  
Factor V Gene ◽  
Heterozygous Carriers ◽  
First Myocardial Infarction ◽  
Control Study

SummaryThe HR2 haplotype of the factor V gene, which contains the histidine to arginine substitution at position 1299, has been reported to be associated with reduced factor V levels. Because high factor V levels have been found to be associated with an increased risk of myocardial infarction, we examined how the presence of the R2 allele affected the risk of myocardial infarction in the case-control “Study of Myocardial Infarctions Leiden”.Among 560 men with a first myocardial infarction before the age of 70 years, 9.5% were heterozygous carriers of the R2 allele. The control group consisted of 646 men, in which 9.9% were heterozygous and 0.2% homozygous carriers of the R2 allele. The risk of myocardial infarction in the presence of the R2 allele was not increased (odds ratio, 0.9; 95% confidence interval 0.6 to 1.4). Exclusion of factor V Leiden carriers did not change this result. The risk was 4.4-fold increased for smokers who carried the R2 allele compared to non-smoking noncarriers. No synergy was found between metabolic risk factors and the presence of the R2 allele.We conclude that the risk of myocardial infarction for men in the presence of the R2 allele of the His1299Arg polymorphism is neither increased nor decreased.

New Interactive Effects Involving Factor XIII Gene Polymorphisms in Venous Thrombotic Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2590-2590
Author(s):  
Maria C. Pintao ◽  
Dayse M. Lourenço ◽  
Francisco H.A. Maffei ◽  
Vania M. Morelli ◽  
Amelia G. Araujo ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Specific Activity ◽  
Interactive Effect ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Interactive Effects ◽  
Coagulation Cascade ◽  
Factor V ◽  
Thrombotic Risk ◽  
Increased Risk

Abstract Venous thrombosis (VT) is considered to be a multifactorial disorder in which several genetic and acquired risk factors interact dynamically. Coagulation factor XIII (FXIII) is an enzyme that participates in the final steps of the coagulation cascade. A number of gene variations have been described in both FXIII A and B subunits. FXIIIA Val34Leu, Tyr204Phe and Pro564Leu polymorphisms have been associated to increased specific activity of FXIII, and FXIIIA Val34Leu has been claimed to be protective against VT in several studies. In the FXIII B subunit, two common polymorphisms (His95Arg and G30899A) have been also reported, but its association with VT is uncertain. In addition, possible interactive effects between these polymorphisms and between these polymorphisms and the two most prevalent mutations associated with VT, factor V Leiden (FVL) and factor II (FII) G20210A mutations, have not been explored. In the present study, we determined the prevalence of the five above-mentioned FXIII polymorphisms in 418 consecutive patients with an objective diagnosis of VT and in 418 age-, gender- and race-matched controls in the BRATROS (Brazilian Thrombosis Study) case-control investigation. Genotyping for Val34Leu, Pro564Leu, His95Arg and G30899A was performed by PCR amplification followed by MseI, BstUI, NsiI and BspHI restriction digestion analysis, respectively. Genotyping for Tyr204Phe was performed by single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing of samples showing mobility shifts. Odds ratios (OR) as a measure of relative risks of VT, and 95% confidence intervals (CI95), were calculated. Stratified analyses were performed to search for interactions between the FXIII polymorphisms and between the FXIII polymorphisms, FVL and FII G20210A. Overall OR for VT linked to Val34Leu was 0,78 (CI95: 0,59–1,03); OR for heterozygotes (HT) was 0,85 (CI95: 0,64–1,13) and for homozygotes (HM) the OR was 0,33 (CI95: 0,15–0,71). Overall OR linked to G30899A was 1,06 (CI95: 0,81–1,39); OR for HT was 0,96 (CI95: 0,72–1,28) and for HM the OR was 1,58 (IC95: 1,00–2,49). No impacts over the risk of VT were observed, related to the other three polymorphisms investigated. When stratified analyses were performed to search for interactions, a trend towards increased risk of VT was detected when the Val34 allele was co-inherited with the Arg95 allele (OR 1,45; CI95: 0,97–2,18), and a trend towards decreased thrombotic risk was verified when the Leu34 and Leu564 alleles were co-inherited (OR 0,63; CI95: 0,40–1,00). Furthermore, increased risk for VT was observed when the mutant A30899 allele was co-inherited with FII G20210A, pointing to a notable interaction effect (OR 18,29; CI95: 2,41–138,87). The data confirm that homozygosity for FXIII Val34Leu is protective against the occurrence of VT in our population. In addition, the findings point to a previously unknown increased risk of VT related to homozygosity for FXIIIB G30899A of the order of 58%. Lastly, an impressive interactive effect (18-fold increased risk of VT) between FXIIIB G30899A and FII G20210A is reported for the first time. Taken together, the findings from the present investigation strengthen the clinical significance of FXIII in vascular thrombosis and reinforce the concept of VT as a multigenic disease.

The Risk for Venous Thrombosis in Patients with Increased Body Mass Index and Interactions with Other Genetic and Acquired Risk Factors: The MEGA Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1234-1234
Author(s):  
Daniel D. Ribeiro ◽  
Willem M. Lijfering ◽  
Frits R. Rosendaal ◽  
Suzanne C. Cannegieter
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Blood Group ◽  
Reference Group ◽  
Factor V Leiden ◽  
Factor V ◽  
Odds Ratios ◽  
Thrombosis Risk ◽  
Increased Risk ◽  
High Bmi

Abstract Abstract 1234 Background: Obesity (prevalence of 20–25% in Western populations), blood group non-O (present in 50% of Western populations) and factor V Leiden (present in 5% of Caucasian populations) are frequent prothrombotic risk factors and may therefore have a considerable impact on the overall incidence of venous thrombosis. We previously reported that the increased risk of venous thrombosis in individuals with a high BMI is mediated by factor VIII induced APC-resistance, and that the combination of blood group non-O with a high BMI or factor V Leiden leads to higher venous thrombosis risks than expected when these prothrombotic factors are analyzed separately (ASH Annual Meeting Abstracts. 2009;114:453). However, small numbers did not enable us to sufficiently study the risk of venous thrombosis for the combination of a high BMI with factor V Leiden and blood group non-O, or to study these effects in subgroups. Objectives: To investigate whether the presence of factor V Leiden with blood group non-O can modify the risk for venous thrombosis in individuals with different body mass index strata in a larger population based study than previously reported. To evaluate the presence of gene-environment interactions in specific subgroups. Methods: MEGA study: 4956 consecutive patients aged 18–70 years with a first episode of venous thrombosis, and 6297 age- and sex-matched controls were included. Information about BMI, blood group and factor V Leiden was available in 4062 patients and 4659 controls. Odds ratios for venous thrombosis and their 95% confidence intervals (95% CIs) were calculated for BMI tertiles with logistic regression and adjusted for age and sex (matching factors). An interaction analysis among the BMI tertiles, factor V Leiden and blood group non-O was performed. Subgroup analyses involved stratification by venous thrombosis place (i.e. deep vein thrombosis or pulmonary embolism), sex, and presence or absence of acquired venous thrombosis risk factors. Results: A progressive increase in BMI was associated with an increased risk for venous thrombosis, odds ratios 1.1 (95% CI, 0.9–1.3) for those with a BMI in the median tertile, and 1.9- (95% CI, 1.6–2.3) for those in the upper tertile, as compared to individuals in the first BMI tertile, blood group O, and no factor V Leiden (i.e. the reference group). The addition of factor V Leiden and blood group non O in the model increased the risk in all BMI tertiles; odds ratios for venous thrombosis were 3.8 (95% CI, 3.2–4.6) in the third BMI tertile of individuals with blood group non-O, and 5.4 (95% CI, 3.5–8.5) in the third BMI tertile of individuals with factor V Leiden, respectively. When both factor V Leiden and blood group non-O were present, odds ratios for venous thrombosis were 9.1 (95% CI, 5.9–14.0) in the first BMI tertile, 9.4 (95% CI, 6.6–13.5) in the second BMI tertile, and 12.5 (95% CI, 8.9–17.6) in the BMI third BMI tertile as compared to the reference group. Subgroup analyses revealed similar joint interactions of BMI with blood group non-O and factor V Leiden on venous thrombosis risk. Disclosures: No relevant conflicts of interest to declare.

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