Factor V Leiden. Polymorphism factor V Leiden, a substitution of glutamine for arginine at amino acid 506 of factor V, exemplifies the role of DNA polymorphisms in clotting abnormalities. The Leiden polymorphism renders factor V resistant to interaction with protein C. Even with adequate qualitative and quantitative function of protein S, protein C, and ATIII, the antithrombotic regulatory complex is rendered ineffective by factor V resistance to protein C binding.
The relative risk of thrombosis in the presence of factor V Leiden follows a doseresponse curve. In some families, heterozygotic carriers of factor V Leiden with 1 copy of the polymorphism have a 10-fold increased risk of venous throbosis. Homozygotes with 2 aberrant copies face a 91-fold increase.
Prothrombin 20210A. Recognition of polymorphisms at other sites along the clotting cascade is emerging. The clotting-cascade step of conversion of prothrombin to thrombin is central to thrombus formation. A change of G to A at position 20210 in prothrombin (prothrombin 20210A) elevates baseline prothrombin levels and thrombin formation.
Heterozygotic carriers of prothrombin 20210A are 3 times more prevalent among individuals with venous thrombosis and 9 times more prevalent in individuals with familial thrombosis.
Hyperhomocysteinemia. A frequent condition in the general population, hyperhomocysteinemia is also an important contributor to the overall risk of thrombotic disease.3 Although the exact mechanism for this is unclear, mild to moderate increases in homocysteine levels are associated with an increased relative risk of thrombosis (2.5). Dietary restriction of folate and vitamin B12 remains the most common cause.
However, in at least a quarter of cases, DNA polymorphisms of the homocysteinemethionine pathway are associated with hyperhomocysteinemia and a mild to moderate increase in thrombosis. The most common inherited cause, a C to T change at position 677 of MTHFR, produces a thermolabile enzyme with reduced catalytic capacity and lowered conversion of homocysteine. The diminished conversion of homocysteine to methionine is further slowed by folate deficiency.4 Other MTHFR polymorphisms also may contribute to diminished catalytic capacity of this pathway, with resultant increased levels of homocysteine.5
Polymorphisms identified in obstetric complications
Fetal loss and habitual miscarriage. Among women who experience habitual miscarriage, factor V Leiden contributes primarily to the subgroup of losses that occur during the second trimester. The association between factor V Leiden and early first-trimester fetal loss is not as robust (FIGURE).6
In the first prospective analysis of obstetric outcomes in carriers of factor V Leiden, infertility or miscarriage was 1.5 times greater than controls (95% confidence interval [CI], 1.2–2.7). In carriers who had experienced 2 or more fetal losses, factor V Leiden was 2.5 times greater than expected (95% CI, 1.2–5.13).7 Conversely, however, among families with multiple individuals with thrombotic disease, habitual early losses are not more common.8
Limited evaluations of the prothrombin gene polymorphism likewise both support and refute an association with early or late fetal loss.9 Given the relatively low incidence of late fetal loss with either polymorphism, the majority of women with factor V Leiden or a prothrombin polymorphism will have successful pregnancies.10
A variety of studies support a link between mild to moderate hyperhomocysteinemia and preeclamptic toxemia.
With respect to the methionine-homocysteine pathway, both folate deficiency and a MTHFR polymorphism play a role—alone or in combination.6 In fact, 1 study reported that hyperhomocysteinemia alone did not display a significant association with early fetal loss, suggesting that folate deficiency and MTHFR polymorphisms may operate through additional, unidentified variables. However, in a meta-analysis, hyperhomocysteinemia alone had a pooled risk of habitual pregnancy loss of 2.7 (95% CI, 1.4–5.2) and 4.2 (95% CI, 2.0–8.8) for fasting and postmethionine levels, respectively.11 The relatively weak association with hyperhomocysteinemia, the diversity in definition of habitual pregnancy loss, and the variability inherent in homocysteine testing likely contribute to these conflicting findings.
Preeclampsia. Several studies have confirmed an association between APC resistance and preeclamptic toxemia. In fact, the American College of Obstetricians and Gynecologists reports a 2.4-fold increase in factor V Leiden, a major determinant of APC resistance, among women with severe preeclamptic toxemia.12 However, analyses in non-Caucasian populations typically do not identify factor V Leiden as a risk factor.13,14
An association between the prothrombin 20210A polymorphism and severe preeclampsia is variable and not confirmed in all populations. The lower background frequency of this polymorphism may limit a sufficient sample size for detection of a significant association.
With regard to homocysteine, a variety of studies support a link between mild to moderate elevations and preeclamptic toxemia. Homocysteine is mildly elevated during pregnancies complicated by preeclamptic toxemia, and this elevation persists postpartum.15,16 Homocysteine elevations are also present in the second trimester before blood pressure increases occur.16 Even at 15 weeks’ gestation, an elevated homocysteine level indicates an almost 3-fold increased risk of severe preeclampsia.17 Based on a meta-analysis of 5 studies, mild to moderate increases in homocysteine alone are significantly associated with a risk for severe preeclampsia, while folate deficiency alone is not (TABLE 1). The hyperhomocysteinemia is explained only in part by the increased rate of MTHFR polymorphism, with other contributors unidentified.18