Leiden Factor V 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.

Factor V has an important role in blood clot formation. The Leiden mutation, or “A” allele, causes factor V to remain active longer, which increases the risk of thrombophilia and pregnancy loss. This test determines if the patient carries the higher risk “A” allele.

Physiology

Factor V (Leiden) mutation 1691 is a common point mutation G→A that causes a resistance of Factor V protein degradation by the activated protein C (APC).

This mutation is associated with increased risk of venous thrombosis (increased risk of developing blood clots) and accounts for many cases of reccurent pregnancy losses^1-2.

While the mutation is present in 5% of the Caucasian women population³, most people with factor V Leiden will not develop abnormal clots.

Nevertheless, this mutation is responsible for 20-25% of the inherited venous thrombosis cases⁴.

Heterozygous individuals (G/A) have 3-8 times more risk of developing thrombosis than the normal population⁵ and homozygous individuals (A/A) have 50 to 100 times greater risk for thrombosis⁶.

Women carrying the factor V Leiden mutation, who are pregnant or on estrogen therapy, have a 30 times higher risk for venous thrombosis⁷.

Published clinical data

Studies comparing Factor V genotype between fertile controls and women experiencing reccurent pregnancy losses (RPL) showed an increased incidence of the 1691 A allele in infertile patients.
The A allele frequency of Factor V Leiden was shown to be significantly higher in RPL patients (7.5%) as compared to fertile controls (1.88%)⁸.

Depending on the studies, the A allele frequency varies from 8 to 32% in RPL patients as compared to 4 to 10% in the fertile control population^9-10.

Further, the presence of the A allele was found to place a patient with RPL at a four times higher risk for another miscarriage¹¹ while a meta-analysis estimates that this risk doubles in RPL patients¹².

Hypercoagulability due to thrombophilic factors is a key event leading to a decreased placental perfusion which induces symptoms of pre-eclampsia.

A meta-analysis including thirty-one studies with 7,522 patients showed that the factor V Leiden polymorphism (1691 G→A) is associated with a 2-fold increased risk for all and severe preeclampsia¹³. Another meta-analysis comparing healthy pregnancy to pre-eclamptic pregnancy showed that factor V Leiden polymorphism (1691 G→A) is associated with a +87% increased risk for pre-eclampsia¹⁴.
Risk for pre-eclampsia has been estimated to double in carrier patients for the allele 1691 A allele¹².

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References

1. Dawood F, Mountford R, Ferquharson R, Quenby S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage an acquired APCR. Hum Reprod 2007; 22:2546-53. 7.
2.  Mierla D, Szmal C, Neagos D, Cretu R, Stoian V, Jardan D. Association of prothrombin (A20210G) and factor V Leiden (A506G) with recurrent pregnancy loss. J Clin Med 2012; 7:222-26.
3. Zöller B, García de Frutos P, Hillarp A, Dahlbäck B. Thrombophilia as a multigenic disease. Haematologica. 1999 Jan;84(1):59-70. Review.
4.  Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP . Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912–917
5. Horne MK 3rd, McCloskey DJ. Factor V Leiden as a common genetic risk factor for venous thromboembolism. J Nurs Scholarsh. 2006;38(1):19-25. Review. 
6. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004 Mar 2;140(5):330-7.
7. Calderwood CJ, Greer IA. The role of factor V Leiden in maternal health and the outcome of pregnancy. Curr Drug Targets. 2005 Aug;6(5):567-76. Review
8. Nahas R, Saliba W, Elias A, Elias M. The prevalence of thrombophilia in women with recurrent fetal loss and outcome of anticoagulation therapy for the prevention of miscarriages. Clin Appl Thromb Hemost 2018; 24:122-8. 25.
9. D’Uva M, Di Micco P, Strina I, Placido GD. Recurrent pregnancy loss and thrombophilia. Journal of Clinical Medical Research 2010; 2:18-22.
10. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and foetal loss: a meta-analysis. Lancet 2003; 361:901–8.
11. Jusić A, Balić D, Avdić A, Pođanin M, Balić A. The association of factor V G1961A (factor V Leiden), prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women. Med Glas (Zenica).  2018 Aug 1;15(2):158-163.
12. Tempfer CB, Riener EK, Hefler LA, Keck C. Genetic thrombophilia has pleiotropic effects in pregnancy. Per Med. 2004 Dec;1(1):105-114.
13. Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005 Jan;105(1):182-92.
14. Fong FM, Sahemey MK, Hamedi G, Eyitayo R, Yates D, Kuan V, Thangaratinam S, Walton RT. Maternal genotype and severe preeclampsia: a HuGE review. Am J Epidemiol. 2014 Aug 15;180(4):335-45.