Contraceptives + HRT PGx

Genes: F2, F5
Lab method: RFLP
No of
detectable
markers:		 2 (F2 20210G>A, F5 1691G>A)
TAT: 2 weeks
Specimen requirements: 2-4 ml of blood with anticoagulant EDTA

300 ng DNA in TE, AE or pure sterile water at 100-250 ng/µl
The A260/A280 ratio should be 1.8-2.0. DNA sample should be run on an agarose gel as a single band, showing no degradation, alongside with a quantitative DNA marker.
Ordering information: Go to online ordering or download sample submission form

Indications for genetic testing:

  1. A history of first and recurrent venous thromboembolism (VTE),  especially in women with a history of VTE during pregnancy or in association with use of estrogen-containing contraceptives
  2. A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
  3. Age greater than 50 years with a first unprovoked VTE
  4. A family history of recurrent thrombosis
  5. Testing at-risk female relatives
  6. Genetic counseling

Venous thromboembolism manifests most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism.  DVT is the most frequent VTE, with the legs being the most common site. Thrombosis in unusual locations may also occur, but less commonly.

Inherited genetic factors predisposing tendency to develop VTE are Factor V Leiden mutation in the F5 gene and mutation 20210G>A in the F2 (prothrombin) gene.

F5 Leiden and prothrombin thrombophilia are inherited in an autosomal dominant manner, heterozygosity for the above mentioned variants results in an increased risk for thrombosis; homozygosity for the variants confers a higher risk for thrombosis than heterozygosity.

The clinical expression of thrombophilia is influenced by family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travelling, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and older age.

F5 Leiden thrombophilia is the most common inherited form of thrombophilia. Heterozygosity for the Leiden variant occurs in 3%-8% of the general US and European populations. F2 20210G>A heterozygosity occurs in 1.7%-3% of the general US and European populations. The prevalence varies by population. The highest heterozygosity rate is found in Europe.

Women heterozygous for F5 Leiden and F2 20210G>A variants and a history of VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT). Women homozygous for these variants with or without prior VTE should avoid estrogen-containing contraception and HRT.

Asymptomatic women heterozygous for the variants should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms, those choosing use of:
• Oral contraceptives should avoid third-generation and progestins with a higher thrombotic risk.
• Short-term HRT for severe menopausal symptoms should avoid oral formulations.

References:

Barrett-Connor E et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.
Juul K et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004;140:330–7.
Kujovich JL. Factor V Leiden Thrombophilia. GeneReviews® . Seattle (WA): University of Washington, Seattle; 1993–2021. 1999 May 14 [updated 2018 Jan 4].
Kujovich JL. Prothrombin Thrombophilia. GeneReviews®  Initial Posting: July 25, 2006; Last Update: February 4, 2021.
Pabinger I et al. Factor V. Leiden mutation increases the risk for venous thromboembolism in cancer patients – results from the Vienna Cancer And Thrombosis Study (CATS). J Thromb Haemost. 2015 Jan;13(1):17–22.
Renoux C et al. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost. 2010;8:979–86.
Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost. 2009;7Suppl 1:301–4.
Sweetland S et al. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost. 2012;10:2277–86.
Van Vlijmen EF et al. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2016;14:1393–403.