hereditary thrombophilia
Contents
Inherited defects (gain of clotting factor or loss of natural anticoagulant) shifting haemostatic balance toward thrombosis. Results almost never alter acute management; value lies in counselling on duration of anticoagulation, family screening, and prophylaxis in pregnancy or hormone exposure. Do not screen unselected patients with VTE.
defects
| Class | Defect | Mechanism | Relative VTE risk |
|---|---|---|---|
| Gain of function | Factor V Leiden (F5 G1691A) | Resistance to activated protein C | Hetero 3–5×, homo ~80× |
| Gain of function | Prothrombin Gene Mutation (G20210A) | ↑ plasma prothrombin | 2–3× |
| Loss of function | Antithrombin Deficiency | ↓ inhibition of thrombin & Xa | 20–50× (highest) |
| Loss of function | Protein C Deficiency | ↓ inactivation of Va/VIIIa | 10–15× |
| Loss of function | Protein S Deficiency | Cofactor for protein C | 10–15× |
Factor V Leiden is the most common (~5% of Caucasians). Antithrombin deficiency carries the highest per-person risk and the strongest case for prophylaxis.
when to test
Do not order a thrombophilia screen in unselected patients with VTE. Recurrence risk after a first unprovoked VTE is similar regardless of genetic result, so management is unchanged.
| Scenario | Test? |
|---|---|
| Cerebral sinus or splanchnic vein thrombosis | Yes — also screen for Myeloproliferative Neoplasms (JAK2) and Paroxysmal Nocturnal Haemoglobinuria |
| Warfarin-induced skin necrosis | Yes — protein C deficiency |
| Heparin resistance | Yes — antithrombin deficiency |
| Asymptomatic relative of proband with high-risk defect, considering pregnancy or oestrogen | Yes — may change prophylaxis |
| First unprovoked VTE < 50 yrs | No — does not change duration |
| Strong family history alone | No — may inform counselling but rarely changes patient management |
| Arterial thrombosis (stroke/MI) | No — FVL/PGM are not arterial risk factors; screen for Antiphospholipid Syndrome in young stroke |
| Recurrent pregnancy loss | No — screen only for Antiphospholipid Syndrome. ALIFE2 (2023) showed no benefit of LMWH on live birth in inherited thrombophilia |
diagnostic timing & assay interference
Test 2–4 weeks after stopping anticoagulation. Never during acute thrombosis or active inflammation.
| Test | Acute thrombosis / inflammation | Heparin | Warfarin | Anti-Xa DOAC | Pregnancy |
|---|---|---|---|---|---|
| FVL / PGM (PCR) | Unaffected | Unaffected | Unaffected | Unaffected | Unaffected |
| Antithrombin activity | ↓ (consumption) | ↓ (false positive) | No effect | Falsely normal/high | ↓ |
| Protein C activity | ↓ (consumption) | No effect | ↓ (false positive) | Falsely normal/high | No effect |
| Protein S (free antigen) | ↓ (false positive — see below) | No effect | ↓ (false positive) | Variable | ↓↓ (physiological) |
| Lupus anticoagulant | CRP interferes | Interferes | Interferes | Interferes (false positive) | Difficult |
C4b-binding protein is an acute phase reactant that binds free protein S. Any inflammatory state (including the acute thrombus itself) lowers free protein S and mimics deficiency. Do not diagnose protein S deficiency if CRP is elevated.
Apixaban and Rivaroxaban inhibit the reagent factor Xa used in chromogenic antithrombin and protein C assays, producing falsely normal or high activity levels. You cannot exclude antithrombin or protein C deficiency on an anti-Xa DOAC.
management
acute VTE
- Standard anticoagulation per Deep Vein Thrombosis / PE protocols
- Antithrombin deficiency + heparin resistance → switch to argatroban or supplement with antithrombin concentrate
duration of anticoagulation
- Provoked VTE + hereditary defect → standard 3–6 months
- Unprovoked VTE → indefinite therapy decided by recurrence risk factors (male sex, residual D-dimer, residual thrombus), not thrombophilia status alone
- High-risk defects (antithrombin deficiency, homozygous FVL, compound heterozygotes) strengthen the case for indefinite anticoagulation
prophylaxis
- Hormones: avoid oestrogen-containing contraception and HRT in all carriers. Progestin-only methods are acceptable.
- Pregnancy in asymptomatic carriers (no personal VTE history):
| Defect | Antepartum | Postpartum (6 weeks) |
|---|---|---|
| Heterozygous FVL or PGM | None | None (consider if other risk factors) |
| Homozygous FVL or PGM, compound heterozygote | Prophylactic LMWH | Prophylactic LMWH |
| Antithrombin deficiency | Prophylactic to intermediate-dose LMWH | Prophylactic LMWH |
| Protein C / S deficiency | Individualise — consult haematology | Prophylactic LMWH |
- Pregnancy with prior VTE: therapeutic or prophylactic LMWH antepartum + 6 weeks postpartum regardless of thrombophilia status
what NOT to do
- Do not screen for hereditary thrombophilia in arterial events
- Do not screen for hereditary thrombophilia in recurrent pregnancy loss
- Do not test during acute thrombosis or while on anticoagulation (PCR for FVL/PGM excepted)
- Do not diagnose protein S deficiency on a single low value or in the setting of inflammation/pregnancy/oestrogen exposure
- Do not start Warfarin without bridging in known protein C deficiency — risk of skin necrosis
- Do not use DOACs to interpret anti-Xa-based antithrombin or protein C assays