Genetic factors associated with thrombosis in pregnancy in a United States population

doi:10.1067/mob.2000.106820

American Journal of Obstetrics and Gynecology

Volume 183, Issue 5, November 2000, Pages 1271-1277

https://doi.org/10.1067/mob.2000.106820 Get rights and content

Abstract

Objective: Polymorphisms in the genes for factor V (factor V Leiden), prothrombin, methylenetetrahydrofolate reductase, and angiotensin-converting enzyme have been associated with the occurrence of venous thrombosis. The objective of this study was to determine the relationships of these polymorphisms to thrombosis during pregnancy. Study Design: This case-control study included 41 case patients with venous thrombosis during pregnancy and 76 control subjects matched for hospital and for race (white vs black) who had a normal pregnancy. Results: Among white subjects, mutations in the genes for factor V and prothrombin were associated with increased risks of venous thrombosis during pregnancy (factor V: odds ratio, 18.3; 95% confidence interval, 2.7-432; P =.001; prothrombin: odds ratio ∞; 95% lower confidence limit, 1.7; P =.01). No black subject had either of these two mutations. For both black and white subjects the D/D genotype of the gene for angiotensin-converting enzyme entailed increased risk compared with the other genotypes (odds ratio, 2.7; 95% confidence interval, 1.2-6.3; P =.02). The polymorphism in the gene for methylenetetrahydrofolate reductase was unrelated to thrombosis during pregnancy among both blacks and whites. Conclusion: Women who had thrombotic complications during pregnancy demonstrated an increased prevalence of genetic mutations related to coagulation. The additional risk of thrombosis during pregnancy associated with such genetic mutations can be substantial. (Am J Obstet Gynecol 2000;183:1271-7.)

Section snippets

Methods

Women at 2 New Jersey hospitals and 2 Georgia hospitals who had a deep venous thrombosis or pulmonary embolism during pregnancy were eligible as case patients. These case patients were identified retrospectively by computer search for the appropriate International Classification of Diseases, Ninth Revision codes (671.30-671.54, 671.90-671.94, and 673.20-673.24) in the hospitals’ records from 1991 through 1996. A total of 158 women at the 4 hospitals were identified as potential case patients.

Results

Thirty-one of the case patients had a deep vein thrombosis in the leg, hip, or pelvic area; 6 had an ovarian vein thrombosis; 2 had a retinal thrombosis; and 2 had a pulmonary embolism. For 28 of the case patients the clot occurred during pregnancy, with an average gestational age of occurrence of 22 weeks’ gestation (range, 4-40 weeks’ gestation). In 11 women the clot occurred during the postpartum period, and in 2 women the clot occurred after a pregnancy loss. Of these 13 women with clots

Comment

In this case-control study we found a higher prevalence of mutations in the F5, F2 , and ACE genes among white women who had thrombosis during pregnancy than among those who did not have thrombosis. Among black women with thrombosis during pregnancy a higher prevalence of the mutation in the ACE gene was observed than among those who did not have thrombosis. Mutations in the F5 and F2 genes were not present in any of the black study subjects. Because the population prevalences of these

References (25)

CJ Berg et al.
Pregnancy related mortality in the United States, 1987-1990
Obstet Gynecol
(1996)
JS Greengard et al.
Activated protein C resistance caused by Arg506Gln mutation in factor Va [letter]
Lancet
(1994)
T Koster et al.
Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study
Lancet
(1993)
DS Dizon-Townson et al.
The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis
Am J Obstet Gynecol
(1997)
E Grandone et al.
Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations
Am J Obstet Gynecol
(1998)
JM Benson et al.
Oligonucleotide ligation assay for detection of the factor V mutation (Arg506→Gln) causing protein C resistance
Thromb Res
(1996)
WC Hooper et al.
A racial difference in the prevalence of the Arg506→Gln mutation
Thromb Res
(1996)
H Austin et al.
The prevalence of two genetic traits related to venous thrombosis in whites and African-Americans
Thromb Res
(1997)
E Letsky et al.
Maternal hemostasis: coagulation problems of pregnancy
PM Ridker et al.
Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men
N Engl J Med
(1995)

SR Poort et al.

A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis

Blood

(1996)

I Martinelli et al.

High risk of cerebral-vein thrombosis in carriers of a prothrombin gene mutation and in users of oral contraceptives

N Engl J Med

(1998)

Cited by (58)

Thrombophilia and venous thromboembolism in pregnancy: A meta-analysis of genetic risk
2015, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Of the 32 potentially eligible articles, 18 articles were excluded (reasons presented in Chart 1) and 14 remained for final analysis. Two had overlapping data, leaving a total of 12 eligible studies [4,11–21]. No studies were added from manual search of the reference lists.
Three common polymorphic variants, namely Factor V Leiden (FVL), Prothrombin G20210A (PT G20210A) and Methylenetetrahydrofolate Reductase (MTHFR) C677T are candidate genes for venous thromboembolism (VTE) in pregnancy. We performed a literature review and meta-analysis of pertinent genetic association studies (GAS) in pregnancy, to quantify the genetic risk of VTE in pregnancy. We used the model-free approach of generalized odds ratio (OR_G) to estimate gene-to-disease association and explored the mode of inheritance using the degree of dominance h index. Twelve case–control GAS studies provided the full genotype distributions for at least one candidate gene to assess the genetic risk. FVL was associated with a significant risk of VTE in pregnancy (OR_G 7.28; 95% confidence interval 5.53–9.58) and a dominant mode of inheritance (h = 0.76), that is the effect of heterozygous carriers will lie close to the homozygous mutant genotype.
PT G20210A mutation was also associated with a significant VTE risk (OR_G 5.43; 95% CI 3.66–8.03) and had an over-dominant mode of inheritance (h = 1.5), suggesting that the effect of heterozygous carriers may exceed that of homozygous mutant. MTHFR C677T had no association with VTE risk in pregnancy (OR_G 1.24; 95% CI 0.88–1.73). Our analysis provided robust data on VTE in pregnancy, relative to FVL and PT G20210A status and suggested that the genetic effects of heterozygous over homozygous carriers do not justify stratification of heterozygous as “lower risk” over homozygous mutants. On clinical grounds this may impact decisions to preferentially exclude heterozygous from anticoagulation prophylaxis.
Thrombophilias in Pregnancy
2011, Hematology/Oncology Clinics of North America
Citation Excerpt :
In order for the criteria to be met, lupus anticoagulant must be positive, or cardiolipin or β 2 glycoprotein 1 must be of medium or high titer on 2 or more laboratory blood draws at least 12 weeks apart. Either an acquired or inherited thrombophilia can be identified in 20% to 50% of white women who have a venous thromboembolic event during pregnancy or the postpartum period.16,24 To better understand the importance of thrombophilia in pregnancy, Robertson and colleagues25 conducted a systemic review of previously published studies evaluating the importance of thrombophilia in pregnancy-associated VTE.
Venous thromboembolism in African-Americans: A literature-based commentary
2010, Thrombosis Research
Citation Excerpt :
These investigators in a more comprehensive case-control-study, Genetic Attributes of Thromboembolism (GATE), that simultaneously enrolled both black and white VTE cases with the average age of the cases being 47-years, also found FVL to be rare in black cases [32]. In a case-control study of VTE in pregnancy, Dilley et al [38] similarly found FVL to be likewise absent in black VTE cases. Similarly, Hira et al [39] found FLV to be absent in black South African women with pre-eclampsia and eclampsia and furthermore in an analysis of 231 consecutive pregnant African-American women, the prevalence FVL was also found to be rare [40].
Among the cardiovascular diseases and after ischemic heart disease and stroke, venous thromboembolism (VTE) is the third leading cause of death in the U.S. (3). Although VTE is seen across most ethnic groups in the U.S. as well as throughout the world, the rate varies. In the U.S., American Indians/Alaskan Natives as well as Asians have been reported to have a significantly lower rate of deep vein thrombosis (DVT) and pulmonary embolism (PE) as compared to blacks and whites. In sharp conrast blacks appear to have much higher rates than whites. Although these rate differences are thought in part by some to be attributable to disparities in diagnosis and care as well as genetics, it nevertheless is important to define as well as to understand the true incidence and impact so that both public health and clinical resources can be maximally utilized. The purpose of this commentary is to review the VTE burden in the U.S. with respect to ethnicity in terms of clinical demographics and genetics with particular emphasis on blacks.
Correlation of angiotensin converting enzyme activity and the genotypes of the I/D polymorphism in the ACE gene with preterm birth and birth weight
2008, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Angiotensin II is also thought to be responsible in production of inflammatory mediators cytokines such as interleukin 1 and 6 and tumor necrosis factor (TNFα) which has been consistently shown to be associated with preterm labor [21]. Women who had thrombotic complications during pregnancy showed an increased prevalence of DD genotype of the ACE gene [22]. A further mechanism by which ACE can affect the placental vasculature is by releasing a tissue factor.
Preterm birth remains one of the most challenging areas in obstetrics. The pathogenesis of preterm labor is multifactorial and research on preterm birth has focused principally on infection and inflammatory markers. Recently the focus has turned to potential genetic factors influencing preterm birth. Uteroplacental insufficiency and thrombotic vasculopathy are considered part of the pathogenesis of preterm labor. Investigating the gene expression in the maternal/fetal interface seems of importance to expand our knowledge of the pathophysiology of preterm birth. The renin–angiotensin system (RAS) appears to play an important role in fetal/placental development and uteroplacental circulation. Hence, the aim of this study was to investigate angiotensin converting enzyme (ACE) activity and I/D polymorphisms in the ACE gene in mothers and infants with appropriately grown infants in relation to preterm birth and infant birth weight.
We conducted a cross-sectional study of 113 term pregnancies (≥37 weeks) and 18 preterm pregnancies (<37 weeks). Umbilical cord bloods (venous and arterial) were obtained from the placenta immediately after delivery for serum ACE activity, ACE genotype analysis of the I/D polymorphism and the acid-base status. Maternal venous samples were obtained just after delivery for analysis of ACE activity and ACE genotype.
The distribution of the maternal ACE genotypes was similar for preterm and term births as was maternal ACE activity. Preterm infants were more likely to be of the DD genotype than term infants (7/18 (39%) vs. 11/83 (13%), p = 0.02) (adjusted p = 0.04). There was no correlation between ACE activity and birth weight (r² 0.00, p = 0.82).
These findings suggest that the ACE genotype of the infant may influence the risk of preterm birth among appropriately grown fetuses.
Prevention and Management of Venous Thromboembolism in Pregnancy
2007, American Journal of Medicine
Citation Excerpt :
Both acquired and inherited thrombophilia increase the risk for maternal thrombosis. Several studies have compared the prevalence of inherited thrombophilia in women who experienced VTE in pregnancy versus those who did not.20–24 Factor V Leiden and the prothrombin gene mutation each confer approximately a 10-fold increased risk for VTE in pregnancy.
Normal pregnancy is accompanied by an increase in clotting factors. The resulting hypercoagulable state has likely evolved to protect women from hemorrhage at the time of miscarriage and childbirth. During pregnancy, women are 4 times more likely to suffer from venous thromboembolism (VTE) compared with when they are not pregnant. Relative to pregnancy, the risk postpartum is even higher. The incidence of VTE is approximately 2 per 1,000 births, and VTE accounts for 1 death per 100,000 births, or approximately 10% of all maternal deaths. The most important risk factors during pregnancy are thrombophilia and a history of thrombosis. A history of thrombosis increases the risk for VTE to 2% to 12%. Thrombophilia increases not only the risk for maternal thrombosis but also the risk of poor pregnancy outcome. Despite the increased risk for thrombosis during pregnancy and the postpartum period, most women do not require anticoagulation. Those who do require anticoagulation include women with current VTE, women on lifelong anticoagulation, and many women with thrombophilia or a history of thrombosis. Recommended options for anticoagulation in pregnancy are limited to heparins, which do not cross the placenta. Low-molecular-weight heparin (LMWH) is preferred over unfractionated heparin because LMWH has a longer half-life and is presumed to have fewer side effects. The longer half-life is a disadvantage around the time of delivery, when unfractionated heparin, with its shorter half-life, is easier to manage. For women who develop or are at high risk for heparin-induced thrombocytopenia or severe cutaneous reactions, fondaparinux is probably the agent of choice. Women who do not require lifelong anticoagulation, but require anticoagulation during pregnancy, will still require anticoagulation for the first 6 weeks postpartum.
Thromboembolism in Pregnancy: Recurrence and Its Prevention
2007, Seminars in Perinatology
Citation Excerpt :
The risk factors for arterial thromboembolism were similar to those for venous thromboembolism, except for stroke, where hypertension OR = 6.1 (4.5, 8.1) and thrombocytopenia OR = 6.0 (1.5, 24.1) were more important risk factors and myocardial infarction, where hypertension OR = 11.7 (6.9, 21.2) and smoking OR = 6.2 (4.1, 9.5) were more important risk factors. Thrombophilia is present in 20%18 to 40%15,19 of women who experience venous thromboembolism during pregnancy and the postpartum period. Both acquired and inherited thrombophilia increase the risk, but it is not clear whether thrombophilia increases the risk of recurrent venous events during pregnancy and the postpartum period.
Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. Women with a history of thrombosis have a three- to fourfold increased risk of recurrence when they are pregnant compared with when they are not. The risks are even higher postpartum. The rate of recurrent venous thromboembolic events without anticoagulation is 2.4% to 12.2%, whereas the rate with anticoagulation is 0% to 2.4%. Because the rates of recurrent thromboembolism can be reduced with anticoagulation, women with a history of thrombosis who are not on lifelong anticoagulation will likely require anticoagulation during pregnancy, or at least during the postpartum period. Women who are already on lifelong warfarin for the prevention of recurrent venous thromboembolism should be counseled about the teratogenic effects of warfarin and offered the opportunity to be converted to heparin before conception. During pregnancy, low-molecular-weight heparin, with fewer side effects and a longer half-life, is generally preferred over unfractionated heparin. Unfractionated heparin with its shorter half-life is generally preferred around the time of delivery. Women on antiplatelet medication for prevention of arterial thromboembolism may be converted to low-dose aspirin after conception and supplemented with low-dose heparin or low-molecular-weight heparin during pregnancy. Because current recommendations rely on case series and expert opinion, additional studies including randomized trials might enhance our ability to prevent recurrent thromboembolism in pregnancy.

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^☆☆: Reprint requests: Anne Dilley, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mail Stop E-64, Atlanta, GA 30333.

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ObstetricsGenetic factors associated with thrombosis in pregnancy in a United States population☆,☆☆

Abstract

Section snippets

Methods

Results

Comment

Obstet Gynecol

Lancet

Lancet

Am J Obstet Gynecol

Am J Obstet Gynecol

Thromb Res

Thromb Res

Thromb Res

Maternal hemostasis: coagulation problems of pregnancy

Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men

N Engl J Med

A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis

Blood

High risk of cerebral-vein thrombosis in carriers of a prothrombin gene mutation and in users of oral contraceptives

N Engl J Med

Obstetrics
Genetic factors associated with thrombosis in pregnancy in a United States population☆,☆☆