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ORIGINAL RESEARCH |
From the Cholesterol Center, Alliance Hospitals, Cincinnati, Ohio; Molecular Diagnostics Laboratories, Cincinnati, Ohio; Division of Hematology/Oncology, Weill Medical College of Cornell University, Ithaca, New York; Department of Obstetrics and Gynecology, Lis Maternity Hospital; and the Department of Hematology, Tel-Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Address reprint requests to: Charles J. Glueck, MD Cholesterol Center ABC Building 3200 Burnet Avenue Cincinnati, OH 45229 E-mail: glueckch{at}healthall.com
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Abstract |
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Methods: We compared 94 women from a previous report who had obstetric complications to 95 controls with normal pregnancies matched for ethnic background and age. We collected blood and extracted DNA after delivery. All subjects had been tested for thrombophilic mutations factor V Leiden, C677T mutation in the methylenetetrahydrofolate reductase gene, and the G20210A mutation in the prothrombin gene. In the present study we tested for the hypofibrinolytic 4G/4G mutation in the PAI-1 gene.
Results: Women who had obstetric complications were more likely than controls to be 4G/4G homozygotes, 32% (30 of 94) women versus 19% (18 of 95) controls, odds ratio (OR) and 95% confidence intervals (CI) 2.0 (1.02, 3.9). Mutations in the PAI-1 gene were independently associated with obstetric complications (OR 1.56, 95% CI 1.005, 2.43). Heterozygosity for the factor V Leiden mutation was more common in the 30 women who had PAI-1 4G/4G than in the 18 4G/4G controls (33% versus 0%, Fisher P = .008). Seventy-six percent of women had some form of thrombophilia or hypofibrinolysis compared with 37% of controls (Fisher P < .001).
Conclusions: Women with severe preeclampsia, abruptio placentae, fetal growth restriction, and stillbirth had increased incidence of the hypofibrinolytic 4G/4G mutation of the PAI-1 gene that is frequently associated with the thrombophilic factor V Leiden mutation, further predisposing them to thrombosis.
Severe preeclampsia, abruptio placentae, fetal growth restriction (FGR), and stillbirth are associated with inherited or acquired thrombophilia and appear to be mediated by inadequate placental perfusion.1,2 Of 110 Israeli women who had those severe obstetric complications, 64% had some form of inherited or acquired thrombophilia, compared with 18% of 110 women who had normal pregnancies.1 Inherited hypofibrinolytic mutations are also associated with miscarriage,3 preterm birth, stillbirth, FGR, eclampsia, and abruptio placentae.4 Genetic abnormalities in fibrinolysis have been described in the plasminogen activator inhibitor (PAI-1) gene, which functions as a fast-acting inhibitor of tissue plasminogen activator activity and is the major circulating inhibitor of fibrinolysis.3–5 The PAI-1 gene contains several polymorphic loci, including a 4G/5G insertion or deletion of 4 or 5 guanosines in the promoter region located 675 base pairs from the transcription start site that influences circulating levels of PAI-1.6 The 4G allele binds transcription-regulating factors not bound by the 5G allele, which causes the PAI gene to transcribe more PAI-1 protein than the 5G allele.6 PAI-1 levels in 4G/4G subjects are approximately 25% higher than in 5G/5G subjects. The 4G/4G mutation is associated with increased risk of thrombosis.3,5,6
Current models of familial thrombophilia often depict a multigene disorder with a critical hit threshold in which familial and acquired risk factors function additively to cause thrombosis.1,7,8 In the current study, we hypothesized that with or without thrombophilic mutations,1,2 the hypofibrinolytic 4G/4G mutation of the PAI-1 gene4–6 could be an important risk factor for severe preeclampsia, abruptio placentae, FGR, and stillbirth, related to inadequate maternal-fetal circulation. We evaluated PAI-1 gene mutations in 94 women with at least one of the four obstetric complications and 95 controls who had one or more normal pregnancies.
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Material and Methods |
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Each subject was matched with a control for age (± 2 years) and for geographic origin of each parent (Table 1
).1 All women were of Jewish origin and classified as Ashkenazi, non-Ashkenazi, or mixed, according to family origin (Table 1).1 Blood was drawn for DNA analysis at enrollment.1
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Women with at least one pregnancy complication were assigned to one of the four groups in descending order of importance: severe preeclampsia, abruptio placentae, FGR, and stillbirth.1 Placental pathology results were not assessed in the 110 cases.1
Women with deep venous thrombosis, pulmonary embolism, and arterial thrombosis were excluded1 because of concern that their inclusion in a study focused solely on obstetric comlications would bias the results toward higher rates of heritable thrombophilia.7 Any regular daily cigarette smoking by history (Table 1
) was enough to warrant the diagnosis.1 Urinary continine was not measured. Previously reported methods were used for molecular diagnoses of the hypofibrinolytic 4G/4G mutations of the PAI-1 gene6 and the thrombophilic mutations1 (Factor V Leiden, prothrombin gene promoter G20210A, and methylenetetrahydrofolate reductase).
Prevalence of 4G/4G homozygosity in a normal population is 20%,9 and we assumed that the rate would be doubled in our subjects. With 80% power and alpha of 0.05, 82 cases and 82 controls were needed. We had 94 case and 95 control samples from the original 110 cases and 110 controls, so our sample was adequate to detect a difference between cases and controls.
Differences in subject characteristics were assessed by t, 
2, and Fisher exact tests (Table 1). Odds ratios (ORs) and 95% confidence intervals (CIs) for having gene mutations in subjects compared with controls were calculated from contingency tables (Table 2). The number of coagulation abnormalities per subject in cases and controls was compared by Fisher exact test (Table 3). Thrombophilic gene mutations in 4G/4G women compared with 4G/4G controls were compared by Fisher exact test (Figure 1). Spearman correlations were calculated between genotypes and pregnancy outcomes. Stepwise logistic regression was done with the dependent variable being presence or absence of complications of pregnancy and explanatory variables being PAI-1, factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase genotypes and their interactions. No other predictors (potential confounders) were included in the model. Statistical analyses were done with SAS (SAS Institute Inc., Cary, NC).
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Results |
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). Among 94 cases and 95 controls, 84% had perfect matching by age and origin of each parent. Gestational ages at delivery and birth weights of infants were lower in subjects (Table 1). Among the 94 cases, there were 39 with FGR, 31 with severe preeclampsia, 15 with abruptio placentae, and nine with stillbirth. Twenty-two of 94 women (23%) had multiple complications. Among 31 women with severe preeclampsia, nine had eclampsia and five had hemolysis, elevated liver enzymes low platelets (HELLP) syndrome.
The 94 subjects were more likely to be homozygous for the 4G/4G mutation than controls (Table 2). Ten of 94 subjects had 4G/4G homozygosity and factor V Leiden heterozygosity compared with none of the controls (Table 2). Subjects were more likely to be homozygous for methylenetetrahydrofolate reductase mutation and heterozygous for factor V Leiden and prothrombin gene mutations than controls (Table 2). Altogether, 76% of subjects had some form of thrombophilia or hypofibrinolysis compared with 37% of controls (Table 3). Among 94 subjects, 21 (22%) had two coagulation abnormalities compared with four of 95 (4%) controls (Table 3).
Heterozygosity for the factor V Leiden mutation was more common in the 30 4G/4G subjects than the 18 4G/4G controls (33% versus 0%, Figure 1). Heterozygosity for the prothrombin gene mutation among the 30 4G/4G subjects did not differ from that in the 18 4G/4G controls (10% versus 6%), nor did homozygosity for the methylenetetrahydrofolate reductase C677T mutation (27% versus 11%, Figure 1).
Gene mutations in subjects were positively associated with major complications of pregnancy for the PAI-1 4G alleles (r = 0.17, P = .018), the prothrombin gene mutation (r = 0.15, P = .03), the methylenetetrahydrofolate reductase mutation (r = 0.20, P = .006), and the factor V Leiden mutation (r = 0.21, P = .005).
By stepwise logistic regression, hypofibrinolytic mutations in the PAI-1 gene (4G/4G versus 4G/5G, versus 5G/5G) were significantly independently associated with obstetric complications, (OR 1.56, 95% CI 1.005, 2.43). Mutations in the thrombophilic genes were also independently associated with obstetric complications. Odds ratios (95% CIs) for the prothrombin gene mutation were 4.4 (1.3, 14.8), 3.8 (1.54, 9.3) for the factor V Leiden mutation, and 3.2 (1.35, 7.6) for the methylenetetrahydrofolate reductase mutation.
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Discussion |
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The association of familial hypofibrinolysis with severe preeclampsia, abruptio placentae, FGR, and stillbirth in the present study was consistent with previous findings.3,4 However, heritable thrombophilias were more closely associated with obstetric complications. The pathogenic importance of the hypofibrinolytic 4G/4G mutation of the PAI-1 gene was emphasized in our recent study of 133 women in Cincinnati, Ohio with at least one pregnancy, who were first genotyped then had their reproductive histories examined retrospectively.4 The 4G/4G mutation was positively, independently associated with adverse pregnancy outcomes, including preterm birth, miscarriage, stillbirth, FGR, eclampsia, and abruptio placentae.4 We postulated that heritable hypofibrinolysis mediated by 4G/4G homozygosity for the PAI-1 gene represents a potentially reversible risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency.4
The 4G/4G homozygosity of the PAI-1 gene is often3,5,6,8 but not always10–12 associated with venous or arterial thrombosis. High levels of PAI activity, the PAI-1 gene product, can contribute to initiation of placental damage and thrombotic complications in preeclampsia.13–16 High levels of PAI activity also contribute to miscarriage in early pregnancy.3,17,18 Gris et al17,18 reported high PAI activity in 616 women with recurrent unexplained early miscarriages. They17,18 speculated that impaired plasmin-dependent proteolysis in women might favor miscarriage by inhibiting early placental circulation, by limiting trophoblast development, or both.
In the present study, women who were hypofibrinolytic by 4G/4G homozygosity also were likely to be thrombophilic by factor V Leiden mutation. Prothrombotic interactions between the PAI-1 4G/4G mutation and the factor V Leiden gene were reported.11,12 Factor V Leiden–induced thrombosis in the placental bed with subsequent hypoxia might enhance expression of PAI-1 as an important mechanism suppressing fibrinolysis under conditions of low oxygen tension.19
Heritable hypofibrinolysis and thrombophilia have therapeutic implications and might lead to novel therapies. Thromboprophylaxis with low-molecular-weight heparin provides an approach to prevent major complications of pregnancy mediated by thrombophilia or hypofibrinolysis, or a combined hemostatic abnormality.20–22
In the present study, 76% of women who had at least one serious pregnancy complication had some form of thrombophilia or hypofibrinolysis compared with 37% of women with normal pregnancies (P < .001). Some form of thrombophilia or hypofibrinolysis in 37% of controls was not surprising, given the prevalence in normal subjects9 of the factor V Leiden mutation (3%), the prothrombin gene mutation (4%), homozygosity for the methylenetetrahydrofolate reductase mutation (11%), and homozygosity for the 4G/4G mutations of the PAI-1 gene (20%).
Abnormal hemostasis appears to be a risk factor for placental insufficiency, with resultant first-trimester miscarriage and serious complications of late pregnancy.1–4,13–22 Thrombotic features of placental vascular lesions and the increased risk of thrombosis associated with thrombophilia or hypofibrinolysis, augmented by the hyperestrogenemia-stimulated thrombophilia of pregnancy,7,23,24 suggest a cause-and-effect relation between inherited hypofibrinolysis or thrombophilia and serious obstetric complications. We speculate that thrombophilia, hypofibrinolysis, or both reduce ureteroplacental blood flow through placental thrombosis and hypoxia, making miscarriage, preeclampsia, FGR, abruptio placentae, and stillbirth more likely than they would be otherwise, or making them more severe if they occur, or both. In FGR, thrombosis-induced reductions in placental perfusion can contribute directly to impairment of fetal growth. In abruptio placentae, thrombosis might injure maternal vessels, making them more prone to rupture. Stillbirth might be from thrombophilic-hypofibrinolytic induction of chronic placental thrombosis and reduced perfusion.
Polymerase chain reaction diagnosis of heritable thrombophilias and hypofibrinolysis is not affected by pregnancy, so results of our retrospective case-control study should not differ from those of prospective serologic studies, which would be optimal for detecting increased thrombin generation associated with a pregnancy-augmented, acquired thrombophilia, such as activated protein C resistance.25
Our findings suggest that women with pregnancy complications1–4,22 should be tested for markers of hypofibrinolysis and thrombophilia even without histories of overt thromboembolism.
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Footnotes |
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Received June 1, 2000. Received in revised form July 31, 2000. Accepted September 21, 2000.
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2. Blumenfeld Z, Brenner B. Thrombophilia-associated pregnancy wastage. Fertil Steril 1999;72:765–74.[Medline]
3. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Tracy T, Moore SK. Plasminogen activator inhibitor activity: An independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. Metabolism 1999;48:1589–95.[Medline]
4. Glueck CJ, Phillips H, Cameron D, Wang P, Fontaine RN, Moore SK, et al. The 4G/4G polymorphism of the hypofibrinolytic PAI-1 gene: An independent risk factor for serious pregnancy complications. Metabolism 2000;49:845–52.[Medline]
5. Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogenactivator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995;92:1851–5.
6. Glueck CJ, Fontaine RN, Gruppo R, Stroop D, Sieve-Smith L, Tracy T, et al. The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. Clin Orthop 1999;366:133–46.
7. Rosendaal FR. Venous thrombosis: A multicausal disease. Lancet 1999;353:1167–73.[Medline]
8. Glueck CJ, Bell H, Vadlamani L, Gupta A, Fontaine RN, Wang P, et al. Heritable thrombophilia and hypofibrinolysis. Possible causes of retinal vein occlusion. Arch Ophthalmol 1999;117:43–9.
9. Balasa VV, Gruppo RA, Glueck CJ, Stroop D, Becker A, Pillow A, et al. The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 levels in children and adults. Thromb Haemost 1999; 81:739–44.[Medline]
10. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Miletich JP. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation 1999;95:59–62.
11. Morange PE, Henry D, Tregouet B, Granel B, Aillaud MF, Alessi MC, et al. The A-844G polymorphism of the PAI-1 gene is associated with a higher risk of venous thrombosis in Factor V Leiden carriers. Arterioscler Thromb Vasc Biol 2000;20:1387–91.
12. Akar N, Yilmaz E, Akar E, Avcu F, Yalcin A, Cin S. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thrombotic patients with and without FV1691 G-A. Thromb Res 2000;97:227–30.[Medline]
13. Estelles A, Grancha S, Gilabert J, Thinnes T, Chirivella M, Espana F, et al. Abnormal expression of plasminogen activator inhibitors in patients with gestational trophoblastic disease. Am J Pathol 1996;149:1229–39.[Abstract]
14. Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic, and endothelial variables in normal pregnancies and preeclampsia. Br J Obstet Gynaecol 1994;101:488–92.[Medline]
15. Estelles A, Gilabert J, Keeton M, Eguchi Y, Aznar J, Grancha S, et al. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation. Blood 1994;84:143–50.
16. Estelles A, Gilabert J, Aznar J, Loskutoff DJ, Schleef RR. Changes in plasma levels of type 1 and 2 plasminogen activator inhibitors in normal pregnancy and in patients with severe preeclampsia. J Obstet Gynaecol Res 1996;22:9–16.[Medline]
17. Gris JC, Ripart-Neveu S, Maugard C, Tailland ML, Brun S, Courtieu C, et al. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) study. Thromb Haemost 1997;77:1096–103.[Medline]
18. Gris JC, Neuveu S, Mares P, Biron C, Hedon B, Schved JF. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med 1993;122:606–15.[Medline]
19. Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, et al. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 1998;102:919–28.[Medline]
20. Ensom MH, Stephenson MD. Low-molecular weight heparins in pregnancy. Pharmacotherapy 1999;19:1013–25.[Medline]
21. Riyazi N, Leeda M, deVries JI, Huijgens PC, van Geijn HP, Dekker GA. Low-molecular weight heparin combined with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: A preliminary study. Eur J Obstet Gynecol Reprod Biol 1998;80:49–54.[Medline]
22. Kupferminc MJ, Fait G, Many A, Lessing JB, Yair D, Bar-Am A, et al. Low molecular weight heparin for the prevention of obstetric complications in women with thrombophilias. Hypertens Pregnancy. In press.
23. Kjellberg U, Andersson NE, Rosen S, Tengborn L, Hellgren M. APC resistance and other haemostatic variables during pregnancy and puerperium. Thromb Haemost 1999;81:527–31.[Medline]
24. Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999;82:6–9.[Medline]
25. Clark P, Walker ID, Green I. Acquired activated protein-C resistance in pregnancy and associated with increased thrombin generation and fetal weight. Lancet 1999;353:292–3.
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