- Because polymorphisms affecting thrombotic potential are frequent (2% to 20% of the general population), even a slightly increased risk of thrombosis affects a far greater number of pregnancies than complete deficiencies of clotting factor proteins S and C or antithrombin III.
- Observational studies suggest a role for heparin or folate supplementation in women with thrombophilia polymorphisms and prior adverse pregnancy outcomes.
- Hyperhomocysteinemia, which sometimes develops from the influences of a polymorphism, has been linked to preeclampsia and may contribute to placental abruption and infarct.
- The Leiden polymorphism of the factor V, with its greater propensity for thrombosis, occurs at increased frequency in women who experience habitual miscarriages.
When obstetric histories of habitual or late fetal loss, preeclampsia, intrauterine growth retardation, and placental abruption or infarct suggest placental compromise, a search for thrombophilia is warranted. This article examines:
- evidence implicating inherited thrombophilia polymorphisms in these adverse outcomes
- promising findings of 2 interventional studies of pregnancy outcomes in thrombophilia carriers: enoxaparin treatment for women experiencing habitual late fetal loss, and folic acid treatment for severe preeclampsia.
Polymorphisms linked to thrombotic risk
The adverse pregnancy outcomes described above represent a spectrum of disease with considerable overlap in etiology. The risk of each is increased in the presence of even 1 of the other complications.
A similar placental pathology is common to these outcomes, suggesting aberrant maternal/fetal perfusion as a unifying feature. The causes of such perfusion abnormalities are diverse, although placental infarct and microthrombi suggest an underlying perturbation of the clotting cascade.
Although clotting factor deficiencies including protein S, protein C, and antithrombin III have long been known to increase thrombotic disease risk, these hereditary deficiencies occur in less than 1% of the general population, and thus contribute minimally to placental compromise and adverse outcomes.1
Of greater clinical significance are changes in DNA sequences collectively known as gene polymorphisms. These gene sequence changes occur with variable population frequency and impact on protein function.
Now recognized are several polymorphic genes which modulate the balance between the opposing prothrombotic and antithrombotic actions of the clotting cascade. Polymorphisms of clotting-cascade proteins occur in 1% to 4% of the population, with variable impact on thrombotic risk.
Polymorphisms linked to endothelial damage
Gene polymorphisms outside the clotting cascade also can increase the risk of thrombosis. Inflammation of the endothelial lining due to elevated homocysteine is associated with an increased risk of both venous and arterial thrombosis. In the conversion of homocysteine to methionine, highly polymorphic gene sequences of the methylene tetrahydrofolate reductase enzyme (MTHFR) can slow the pathway, resulting in hyperhomocysteinemia. Polymorphisms influencing homocysteine metabolism occur in up to 20% of individuals in some populations.
The power of polymorphisms
Genetic polymorphisms do not necessarily imply a disease state. These DNA changes are preserved in populations, and their effects on the proteins they code are variable, even of benefit in some populations. (That may explain the continued presence of polymorphisms despite their negative clinical impact in other populations.) The effect of a genetic polymorphism on the quantitative or qualitative function of a protein is variable, and often occurs in combination with other genetic, physiologic, or environmental changes.
The frequency of a specific polymorphism varies from population to population, reflecting ancient adaptation to specific environments. Given the complex interactions required for modulation of the opposing thrombotic and antithrombotic processes of the clotting cascade, genetic polymorphisms affecting key receptors, enzymes, and cofactors all contribute to functional control of clotting.
Without this precise control, 1 mL of blood can convert the total body volume of fibrinogen to fibrin—and clot formation—in 10 to 15 seconds.2 The process leading to the fibrin plugs of pathologic thrombi differs little from the appropriate hemostasis of a laceration, leading to the description of thrombosis as “fibrin plugs in the wrong place or at the wrong time.”2
The major inhibitors of thrombosis are antithrombin III (ATIII), protein C, and protein S, which form a complex to prevent excessive clotting. Typically, this complex binds with factors V and VIII, rendering them inactive and thus limiting the progression of clot formation. Loss of interaction between this antithrombotic complex (ATIII-protein S-protein C) and the clotting-cascade factors leads to unregulated progression of the clotting cascade and excessive thrombosis formation.
Polymorphisms identified in clotting abnormalities
Resistance to activated protein C. Occurring in 2% to 5% of the general population, resistance to activated protein C (APC) results in loss of clot inhibition and increased thrombotic potential of the clotting cascade, as reflected in the striking 20% to 60% incidence of APC resistance among individuals with thrombotic disease. While APC resistance can be acquired, such as through antiphospholipid antibody syndrome, in the majority of cases an inherited polymorphism of factor V is responsible.