Prothrombin Factor II and Pregnancy: Research Review

While pregnant, a person’s risk for blood clots in their veins (venous thromboembolism) increases 5- to 6-fold. If they have hereditary thrombophilia, that risk can increase more than 30-fold. Additionally, thrombophilia increases the chance of blood clots in the placenta, which can increase the likelihood of pregnancy loss.

Prothrombin (blood coagulation factor II) has an important role in blood clot formation. The “A” allele of prothrombin increases a person’s prothrombin levels, which then increases the risk of thrombophilia and pregnancy complications. A prothrombin factor II test uses DNA analysis to determine if a patient carries any copies of the higher risk “A” allele.

Physiology

The prothrombin factor II 20210 G→A mutation has been identified as the second most common independent risk factor for venous thrombosis¹ and is associated with many disorders including thrombophilia, pregnancy complications or cardiovascular diseases.

The mutation is associated with increased plasma levels of prothrombin and is present in 1-3 % of the Caucasian women population².

The 20210 A allele of the prothrombin gene is associated with an approximately 3-fold increased risk of venous thrombosis^3-7.

Published clinical data

Many studies have found that carrier for the prothrombin factor II 20210 G→A mutation are at significantly higher risk for early recurrent pregnancy loss and sporadic later loss (risk doubles)^8-9. Pregnancy-associated thrombosis has been estimated to occur in 1 in 17 heterozygous carrier and in 1 in 6 homozygous carrier for the prothrombin factor II 20210 G→A^10-11.

A meta-analysis of 11 studies including a total of 856 women with pre-eclampsia and 1244 controls (healthy pregnancies) showed that carrier of the prothrombin factor II 20210 G→A are at increased risk for pre-eclampsia (+80%)¹².

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References

1. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated regions of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:3698-703.
2. Zöller B, García de Frutos P, Hillarp A, Dahlbäck B. Thrombophilia as a multigenic disease. Haematologica. 1999 Jan;84(1):59-70. Review.
3. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemostas 1998; 79:706-8.
4. Arruda VR, Annichino Bizzacchi JM, Goncalves MS, Costa FF. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemostas 1997; 78:1430-3.
5.  Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3’-untranslated region of the prothrombin gene. Br J Haematol 1997; 98:907-9.
6.  Ferraresi P, Marchetti G, Legnani C, et al. The heterozygous 20210 G/A prothrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease. Arterioscler Thromb Vasc Biol 1997; 17:2418-22.
7.  Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemostas 1997; 78:990-2.
8. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003 Mar 15;361(9361):901-8.
9. Gao H, Tao FB: Prothrombin G20210A mutation is associated with recur­rent pregnancy loss: A systematic review and meta-analysis update. Thromb Res, 2015; 135: 339–46
10. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000 Feb 10;342(6):374-80.
11. Samama MM, Rached RA, Horellou MH, Aquilanti S, Mathieux VG, Plu-Bureau G, Elalamy I, Conard J. Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone. Br J Haematol. 2003 Oct;123(2):327-34.
12. Tempfer CB, Riener EK, Hefler LA, Keck C. Genetic thrombophilia has pleiotropic effects in pregnancy. Per Med. 2004 Dec;1(1):105-114.