Thrombophilia
Inherited or acquired predisposition to venous thromboembolism, requiring selective testing in appropriate clinical contexts rather than blanket screening.
Key Facts
Thrombophilia includes inherited defects (Factor V Leiden, prothrombin gene mutation, protein C/S/AT deficiency) and acquired causes (antiphospholipid syndrome) Factor V Leiden is the most common inherited thrombophilia in Caucasians (~5% heterozygous prevalence) Thrombophilia testing should NOT be performed during acute VTE, anticoagulation, pregnancy, or acute illness BSH guidelines recommend selective testing – not routine screening after first provoked VTE Consider testing for: unprovoked VTE <50 years, recurrent VTE, family history, unusual site thrombosis, warfarin-induced skin necrosis Antiphospholipid syndrome is the most important acquired thrombophilia; requires clinical event + persistent positive antibodies Testing rarely changes acute management but may influence duration of anticoagulation and family counselling
Overview
Key Facts
Thrombophilia refers to a group of inherited and acquired conditions that increase the tendency to form blood clots, predominantly venous thromboembolism.
Epidemiology
- Inherited thrombophilias found in 30-50% of patients with unprovoked VTE
- Factor V Leiden heterozygosity: 5% of Caucasians (rare in Asian/African populations)
- Prothrombin G20210A: 2-3% of Caucasians
- Protein C deficiency: 0.2-0.4% of general population
- Protein S deficiency: 0.1-0.5%
- Antithrombin deficiency: 0.02-0.2% (highest thrombotic risk)
Aetiology
Inherited:
- Factor V Leiden (FVL) – activated protein C resistance
- Prothrombin gene mutation (G20210A) – raised prothrombin
- Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
- (Rare: dysfibrinogenaemia, elevated factor VIII)
Acquired:
- Antiphospholipid syndrome (most important)
- Malignancy
- Pregnancy/HRT/COCP
- Nephrotic syndrome
- Myeloproliferative neoplasms (JAK2)
Pathophysiology
- Each thrombophilia disrupts the balance between pro- and anti-coagulant pathways
- Factor V Leiden: point mutation renders factor Va resistant to inactivation by activated protein C → persistent thrombin generation
- Protein C/S deficiency: reduced natural anticoagulant activity → uncontrolled thrombin
- Antithrombin deficiency: reduced inhibition of thrombin and factor Xa → strongest inherited thrombophilia
- Risk is additive with multiple thrombophilias or combined with environmental risk factors (COCP, immobility, surgery)
Clinical Presentation
Venous Thromboembolism
- DVT (most common presentation) – lower limb predominance
- Pulmonary embolism
- Unusual site thrombosis: cerebral venous sinus, portal/hepatic/mesenteric vein (consider JAK2 MPN also)
- Recurrent VTE despite adequate provocation assessment
Other Presentations
- Pregnancy complications (especially antiphospholipid syndrome): recurrent miscarriage, pre-eclampsia, IUGR, placental abruption
- Warfarin-induced skin necrosis (protein C deficiency) – occurs within first few days of warfarin
- Neonatal purpura fulminans (homozygous protein C/S deficiency)
Red Flags
- VTE in patients <50 years without provocation → investigate
- Recurrent VTE → consider thrombophilia and antiphospholipid syndrome
- Arterial AND venous thrombosis → antiphospholipid syndrome
- Family history of VTE in first-degree relatives
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Antiphospholipid syndrome | Arterial/venous thrombosis, pregnancy morbidity | Lupus anticoagulant, aCL, anti-β2GP1 |
| Malignancy-associated VTE | Weight loss, new symptoms, age >40 | CT CAP, age-appropriate screening |
| Myeloproliferative neoplasm | Erythrocytosis, thrombocytosis, splenomegaly | FBC, JAK2 |
| Nephrotic syndrome | Heavy proteinuria, hypoalbuminaemia | Urine ACR, albumin |
| Paroxysmal nocturnal haemoglobinuria | Unusual site thrombosis, haemolysis, cytopenia | Flow cytometry (CD55/59) |
| HIT | Heparin exposure, platelet drop | 4T score, anti-PF4 |
Diagnosis / Investigation
When to Test (BSH Guidelines)
- Unprovoked VTE aged <50 years
- Recurrent VTE
- VTE at unusual sites (cerebral, portal, mesenteric)
- Family history of VTE and thrombophilia
- Warfarin-induced skin necrosis
- Neonatal purpura fulminans
- Recurrent pregnancy loss
When NOT to Test
- During acute VTE (false results)
- While on anticoagulation (affects protein C, S, AT, lupus anticoagulant)
- During pregnancy or oestrogen use
- Routine after first provoked VTE
Thrombophilia Screen
- Factor V Leiden: genetic test (PCR) – unaffected by anticoagulation
- Prothrombin G20210A: genetic test (PCR)
- Protein C activity: functional assay (affected by warfarin, pregnancy, acute illness)
- Protein S activity/free antigen: functional assay (affected by warfarin, pregnancy, COCP)
- Antithrombin activity: functional assay (affected by heparin, acute thrombosis)
- Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin IgG/IgM, anti-β2-glycoprotein I IgG/IgM – must be positive on two occasions ≥12 weeks apart
- Homocysteine: if hyperhomocysteinaemia suspected
Timing
- Genetic tests (FVL, prothrombin) can be done anytime
- Functional tests: ideally >2 weeks after completing anticoagulation and >8 weeks post-thrombosis
Management
Non-pharmacological
- Risk factor counselling: avoid COCP/HRT, weight management, hydration during travel, compression stockings
- Pregnancy counselling: pre-conception advice, specialist obstetric care
- Family screening: if clinically significant thrombophilia identified
Pharmacological
Acute VTE treatment:
- Standard anticoagulation as per VTE guidelines (DOAC or LMWH/warfarin)
- Thrombophilia does NOT change acute management
Duration of anticoagulation:
- First provoked VTE + thrombophilia: standard 3 months
- First unprovoked VTE + thrombophilia: consider extended/lifelong anticoagulation (individualised)
- Recurrent VTE: lifelong anticoagulation
- Antithrombin deficiency: highest risk – strong consideration for lifelong anticoagulation after first event
- Antiphospholipid syndrome with VTE: lifelong warfarin (target INR 2-3); DOACs may be inferior (TRAPS trial)
Pregnancy (with thrombophilia and history of VTE or pregnancy morbidity):
- Prophylactic LMWH (enoxaparin 40mg SC OD) throughout pregnancy + 6 weeks post-partum
- Antiphospholipid syndrome: LMWH + aspirin 75-150mg OD from conception
Referral Criteria
- All patients with identified thrombophilia → haematology for counselling
- Pregnancy planning with known thrombophilia → specialist obstetric haematology
Prognosis
- Risk of first VTE varies by thrombophilia:
- FVL heterozygous: 3-8× increased risk (absolute annual risk ~0.5%)
- FVL homozygous: 50-80× increased risk
- Antithrombin deficiency: 25-50× increased risk (highest risk)
- Protein C/S deficiency: 5-10× increased risk
- Combination of thrombophilias significantly increases risk
- Most carriers never develop VTE (requires additional trigger)
- Appropriate anticoagulation duration decisions improve outcomes
- Antiphospholipid syndrome: recurrence rate >50% without lifelong anticoagulation
Other Relevant Information
Thrombotic Risk by Thrombophilia Type
| Thrombophilia | Prevalence | VTE Risk (OR) | Annual VTE Risk |
|---|---|---|---|
| Factor V Leiden (het) | 5% | 3-8× | 0.5% |
| Factor V Leiden (hom) | 0.02% | 50-80× | 1-3% |
| Prothrombin G20210A (het) | 2-3% | 2-4× | 0.3% |
| Protein C deficiency | 0.2-0.4% | 5-10× | 0.5-1% |
| Protein S deficiency | 0.1-0.5% | 5-10× | 0.5-1% |
| Antithrombin deficiency | 0.02-0.2% | 25-50× | 1-3% |
| Antiphospholipid syndrome | 1-5% | 5-10× | Variable |
What Affects Thrombophilia Test Results
| Test | Affected By |
|---|---|
| FVL / Prothrombin gene | Nothing (genetic – always accurate) |
| Protein C | Warfarin, acute thrombosis, liver disease |
| Protein S | Warfarin, COCP, pregnancy, inflammation |
| Antithrombin | Heparin, acute thrombosis, liver disease, nephrotic syndrome |
| Lupus anticoagulant | Heparin, DOACs (some assays) |