Inherited Thrombophilia
On this page
Direct answer
Inherited thrombophilia is a genetic predisposition to venous thromboembolism, and the commonest are factor V Leiden and the prothrombin G20210A variant, each raising risk several-fold when heterozygous. Deficiencies of antithrombin, protein C and protein S are rarer but carry a higher thrombotic risk. Factor V Leiden makes factor V resistant to activated protein C, while antithrombin, protein C and protein S deficiencies reduce natural anticoagulant activity. Testing must be timed carefully, because acute thrombosis, pregnancy, warfarin and heparin all alter protein C, protein S and antithrombin levels.
What you must remember
- Factor V Leiden: arginine 506 to glutamine substitution (R506Q) that resists inactivation by activated protein C; genetic testing gives a definitive result at any time.
- Prothrombin G20210A: a 3-prime untranslated region variant raising prothrombin levels; heterozygous carriers have a moderate increase in risk.
- Antithrombin deficiency: heparin resistance and a high risk in pregnancy and surgery; levels fall with heparin, nephrotic syndrome and liver disease.
- Protein C and S: vitamin K dependent natural anticoagulants; warfarin lowers protein C early, so skin necrosis can follow warfarin started without heparin cover in deficiency.
- Testing timing: functional protein C, protein S and antithrombin assays are unreliable during acute thrombosis, pregnancy, oral contraceptive use or on warfarin and heparin.
- Indications: unprovoked venous thrombosis in young adults, a strong family history, recurrence and thrombosis at unusual sites such as cerebral or mesenteric veins.
- Antiphospholipid syndrome: an acquired thrombophilia tested alongside, not part of inherited testing.
A worked case: a clot on the contraceptive pill
A 28-year-old woman develops a deep vein thrombosis while taking an oral contraceptive, and her mother had a clot in her thirties.
- Classify the event: The pill is a transient provoking factor, but the family history makes the case worth testing.
- Anticoagulate and change contraception: Anticoagulation starts, and the contraceptive is stopped and replaced with a non-oestrogen method.
- Send genetic tests: Factor V Leiden and prothrombin G20210A give a result regardless of anticoagulation.
- Defer functional assays: Protein C, protein S and antithrombin are measured only after the patient is off acute therapy and off oral contraceptives, since these conditions distort the results.
Contrast a 35-year-old man with recurrent deep venous thrombosis, whose antithrombin activity is low during heparin treatment. That result cannot be interpreted until heparin is stopped and the level is repeated, since an unexpectedly low value may reflect the drug rather than inherited deficiency.
Where the examiner sets the trap
Four traps recur on this topic.
- Trap: testing protein C or protein S during acute thrombosis or on warfarin. Correct: these conditions produce falsely low results, which leads to a wrong diagnosis.
- Trap: treating a positive factor V Leiden result in a provoked thrombosis as a reason for lifelong anticoagulation. Correct: duration depends on provocation, site and bleeding risk, and the evidence does not support it on its own.
- Trap: starting warfarin without heparin cover in protein C deficiency. Correct: skin necrosis can follow, and heparin cover at warfarin initiation prevents it.
- Trap: choosing a functional assay as the safe test in pregnancy. Correct: genetic tests are unaffected by pregnancy or anticoagulation.
Frequently asked questions
Which mutation causes factor V Leiden thrombophilia?
Factor V Leiden is a point mutation in the factor V gene that makes factor V resistant to inactivation by activated protein C, increasing the risk of venous thrombosis. Heterozygous carriers have a moderately raised risk, and genetic testing confirms the diagnosis at any time.
When should protein C and protein S levels be tested?
Functional protein C and protein S levels should be measured when the patient is not acutely thrombosed, not pregnant, not on oral contraceptives and ideally off warfarin, because these conditions lower them. Genetic testing can be used when timing is uncertain or the patient cannot stop anticoagulation.
Why does warfarin cause skin necrosis in protein C deficiency?
Protein C is a vitamin K dependent anticoagulant, so warfarin lowers it faster than the procoagulant factors, producing a transient hypercoagulable state. Heparin cover at warfarin initiation prevents this skin necrosis.
Does a positive factor V Leiden result mean lifelong anticoagulation?
Not on its own. The decision on duration depends on whether the thrombosis was provoked, its site, the risk of recurrence and bleeding risk, so a heterozygous result alone seldom justifies indefinite therapy.