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Condition report · Cardiovascular

Thrombophilia (Factor V Leiden, Prothrombin)

Whole genome sequencing evaluates ALL thrombophilia genes from a single comprehensive test, including Factor V Leiden (F5), Prothrombin G20210A (F2), protein C (PROC), protein S (PROS1), antithrombin III (SERPINC1), and additional clotting factor variants.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

Hereditary thrombophilia is an inherited genetic condition that increases your body's tendency to form abnormal blood clots in blood vessels

Hereditary thrombophilia encompasses genetic variants that increase the risk of venous thromboembolism (DVT and PE). Factor V Leiden (F5 R506Q) is the most common, affecting ~5% of Europeans (heterozygous: 3-8x VTE risk; homozygous: 50-80x risk). Prothrombin G20210A (F2) affects ~2-3% of Europeans (2-5x risk). Protein C deficiency (PROC), protein S deficiency (PROS1), and antithrombin III deficiency (SERPINC1) are rarer but higher-risk.

Compound genotypes dramatically multiply risk: FVL heterozygous + prothrombin heterozygous = ~20x VTE risk (potentially lifelong anticoagulation). FVL homozygous = 50-80x risk. Protein C or antithrombin deficiency + FVL = very high risk. Only comprehensive testing revealing ALL thrombophilia variants enables accurate risk stratification and appropriate anticoagulation duration decisions.

Clinical implications include anticoagulation duration after first VTE (3-6 months vs. lifelong based on genotype), hormonal contraception counseling (estrogen-containing contraceptives contraindicated in FVL/prothrombin carriers), pregnancy management (LMWH prophylaxis for higher-risk genotypes), and extended post-surgical prophylaxis. Every woman should ideally have thrombophilia screening before starting estrogen-containing contraception.

Estrogen-containing contraceptives are contraindicated in FVL and prothrombin carriers, but 5-8% of European women carry these variants unknowingly. Pre-prescribing thrombophilia screening prevents potentially fatal PE.

The 2 conditions we analyse

Inherited Thrombophilia

What a diagnosis changes

Anticoagulation (duration by genotype); avoid estrogen-containing contraceptives; LMWH for pregnancy prophylaxis; extended post-surgical anticoagulation; lifelong anticoagulation for compound/high-risk genotypes

Genes analysed

Also known as

hereditary hypercoagulable disorder; hereditary thrombophilia

Includes 16 related subtypes ↓
  • factor 5 excess with spontaneous thrombosis
  • heparin cofactor 2 deficiency
  • hereditary antithrombin deficiency
  • hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
  • hereditary thrombophilia due to congenital protein C deficiency
  • hereditary thrombophilia due to congenital protein S deficiency
  • thrombomodulin-related bleeding disorder
  • thrombophilia due to activated protein C resistance
  • thrombophilia due to protein C deficiency, autosomal dominant
  • thrombophilia due to protein C deficiency, autosomal recessive
  • thrombophilia due to protein S deficiency, autosomal dominant
  • thrombophilia due to protein S deficiency, autosomal recessive
  • thrombophilia due to thrombin defect
  • thrombophilia, familial, due to decreased release of tissue plasminogen activator
  • thrombophilia, X-linked, due to factor 8 defect
  • thrombophilia, X-linked, due to factor 9 defect
MONDO:0100240MedGen 391721

Protein S Deficiency

Autosomal dominant

An inherited shortage of the natural anticoagulant protein S, caused by changes in PROS1, that raises the risk of blood clots in the veins.

What a diagnosis changes

Knowing about it informs decisions about clot prevention around surgery, pregnancy and oestrogen-containing medicines.

Genes analysed

Also known as

Protein S deficiency disease

Includes 3 related subtypes ↓
  • hereditary thrombophilia due to congenital protein S deficiency
  • thrombophilia due to protein S deficiency, autosomal dominant
  • thrombophilia due to protein S deficiency, autosomal recessive
MONDO:0002304MedGen 69229

Why whole genome sequencing

Thrombophilia testing determines anticoagulation duration, contraception safety, and pregnancy management. Compound genotypes require comprehensive testing, not single-gene FVL testing alone.

Compound genotypes require ALL variants tested simultaneously, because single-gene testing misses critical risk multiplication

Testing FVL alone without prothrombin gives an incomplete picture. A patient with FVL heterozygous (3-8x risk, time-limited anticoagulation) who ALSO carries prothrombin heterozygous (compound ~20x risk, potentially lifelong anticoagulation) would be undertreated. WGS tests all thrombophilia genes simultaneously.

Pre-contraception thrombophilia screening should be universal: WGS identifies the 5-8% of women at elevated VTE risk from estrogen

If every woman had thrombophilia screening before starting estrogen-containing contraception, FVL and prothrombin carriers would receive progestin-only or non-hormonal alternatives, preventing potentially fatal pulmonary embolism. WGS provides this screening alongside comprehensive health genetics.

Limitations

  • Structural variants in the PROC, PROS1, and SERPINC1 genes are known to be relevant to this condition. These are not included in small variant analyses.

Other cardiovascular conditions

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