Thrombophilia and pregnancy

The presence of Factor V Leiden is the most common of the known inherited pathologies affecting blood clotting and is detected in about a quarter of all patients with thrombosis. 

It is a point mutation in the Coagulation Factor V gene (a G>A change at position 1691) that transforms amino acid 506 from arginine to glutamine and causes an alteration in the structure of the protein that prevents its inactivation by active protein C and leads to the formation of venous thrombi.

In the general European population, 0.5% to 5% are heterozygous carriers and 0.05% to 0.5% are homozygous carriers. Heterozygosity for factor V Leiden is associated with a 5 to 10-fold increased risk of venous thrombosis. For homozygous trait carriers, the individual risk of thrombosis increases by 50 to 100 times.

For pregnant women, the presence of this mutation can lead to an increased risk of thrombosis of up to 1:10 (being 1:500 in healthy pregnant women).

Inheritance is autosomal dominant with incomplete penetrance.

The second most frequent genetic defect in the coagulation system is the prothrombin (Factor II) gene mutation (present in 6-7% of thrombotic patients). Point mutation in the 3′ non-coding region of the prothrombin gene (G>A change at position 20210) is associated with elevated plasma prothrombin levels and thrombophilia. This prothrombin variant is associated with a 3-5-fold increased risk of thrombosis, as well as an increased risk of adverse pregnancy outcomes including early and recurrent miscarriage.

In pregnant women, the presence of this mutation can lead to an increased risk of thrombosis of up to 1:10 (1:500 in healthy pregnant women).

Inheritance is autosomal recessive.

Methylenetetrahydrofolate reductase (MTHFR) is another gene that plays an essential role in the arterial and venous vascular system.

The two variants rs1801133 and rs 1801131 have been associated with decreased enzyme activity and increased plasma homocysteine levels.

• The rs1801133 variant involves a C>T change at position 677 that transforms amino acid 222 from alanine to valine. Individuals with the homozygous 677TT variant have no more than 30% of normal enzyme activity, and heterozygotes of the CT genotype have 65% of normal enzyme activity and increased thermolability.
• The rs1801131 variant involves an A>C change at position 1298 that transforms amino acid 429 from glutamine to alanine. Heterozygous (AC) and homozygous (CC) carriers have a reduction in enzyme activity of 15% and 30%, respectively.

These mutations in MTHFR may increase the risk of:

• Cardiovascular disease
• Kidney failure
• Chromosomal abnormalities
• Spontaneous miscarriage
• Other diseases

Inheritance of both variants is autosomal recessive.

This variant involves a G>T change at position 103 that transforms amino acid 34 from valine to leucine. The less frequent allele (T) is considered protective against thromboembolism.