Inherited thrombophilia (factor V Leiden)
Board exam relevance: in 3 of 105 exam reports · rank 111- Synonyms
- FVL, APC resistance, clotting disorder, hypercoagulability, prothrombin mutation, blood clotting tendency
- Specialty
- Internal medicine · Angiology
- Last updated
- 10/2026 · Dr. Pascal Bafteh
Contents
Definition
Inherited thrombophilia is a congenital tendency to venous thrombosis due to genetic changes in proteins that promote or limit coagulation. The classic inherited thrombophilias are:
- factor V Leiden mutation (the most common form)
- prothrombin G20210A mutation
- antithrombin deficiency
- protein C deficiency
- protein S deficiency
They are distinguished from acquired thrombophilias such as antiphospholipid syndrome.
Classification
According to the increase in risk of a first venous thromboembolism (VTE), the following are distinguished (relative risk in brackets):
Severe thrombophilias (high risk):
- antithrombin deficiency (4–50)
- protein C deficiency (15)
- protein S deficiency (5–10)
- factor V Leiden mutation, homozygous (40–80)
- prothrombin G20210A mutation, homozygous (20–30)
Mild thrombophilias (low risk):
- factor V Leiden mutation, heterozygous (5–7)
- prothrombin G20210A mutation, heterozygous (3–4)
Occurrence & epidemiology
Prevalence in the general population and in patients with VTE:
- factor V Leiden, heterozygous: about 5 % of the population, about 20 % of patients with VTE
- prothrombin G20210A, heterozygous: about 2 % and 6 % respectively
- protein C deficiency: 0.2–0.4 %
- protein S deficiency: 0.03–0.1 %
- antithrombin deficiency: 0.02–0.2 %
The factor V Leiden mutation occurs mainly in people of European descent and is rare in people of Asian or African descent. Inherited thrombophilia is found considerably more often in young patients with VTE than in older ones.
Aetiopathogenesis
Factor V Leiden: activated protein C (APC), together with protein S, degrades the activated clotting factors Va and VIIIa and thus limits coagulation. Due to the mutation in the factor V gene, factor V is resistant to cleavage by APC (APC resistance); the tendency to clot increases. Homozygous mutations increase the risk more than heterozygous ones.
Prothrombin G20210A: the mutation in the prothrombin gene is associated with a tendency to thrombosis.
Antithrombin, protein C and protein S deficiency: natural coagulation-limiting proteins are lacking or functionally impaired.
The risk of thrombosis rises particularly when acquired risk factors are added, such as estrogen-containing contraceptives, pregnancy, immobilisation or the postoperative state. Estrogens increase factor VIII and von Willebrand factor and lower free protein S.
Clinical features
Most inherited disorders only raise the risk of thrombosis from young adulthood, although clots can form at any age.
Clues to thrombophilia are:
- VTE in young adults or before the age of 50
- positive family history, especially VTE in first-degree relatives without a strong trigger
- more than one venous thrombosis
- thrombosis at unusual sites, e.g. cerebral sinus or visceral veins
Typical manifestations are deep vein thrombosis, pulmonary embolism and superficial thrombophlebitis. The factor V Leiden mutation is not a risk factor for arterial thromboembolism such as myocardial infarction or stroke.
Diagnosis
- APC resistance test: screening test for factor V Leiden; activated protein C is added to diluted patient plasma. In carriers the clotting time is prolonged much less
- Genetic analysis: detection of the factor V Leiden and prothrombin G20210A mutations; under the German Genetic Diagnostics Act only after medical information and written consent
- Functional assays: antithrombin activity, protein C activity, free protein S or protein S activity. An inherited deficiency is never diagnosed on the basis of a single functional assay, because acquired deficiencies are much more common
- Interfering factors: in the acute phase of VTE and under blood-thinning drugs, several clotting tests are distorted; genetic analyses are unaffected
- Distinction from acquired thrombophilia: antiphospholipid antibodies (lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies); antiphospholipid syndrome requires antibody persistence for at least 12 weeks
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Note: Learning content for medical education – not a treatment recommendation and no substitute for diagnosis or treatment decisions in individual cases. Treatment and management are deliberately not covered on this page.