📋 Key Information Summary
- Thrombophilia encompasses inherited and acquired hypercoagulable states predisposing to venous thromboembolism (VTE), with the majority presenting as deep vein thrombosis (DVT) or pulmonary embolism (PE).
- Factor V Leiden (FVL) is the most common inherited thrombophilia in Australian populations, with a heterozygous prevalence of approximately 5–8% in people of European descent.
- Prothrombin G20210A mutation is the second most common inherited thrombophilia, with a heterozygous prevalence of approximately 2–3% in Europeans.
- Protein C, Protein S, and antithrombin (AT) deficiency are rarer but confer significantly higher thrombotic risk (especially homozygous compound states).
- Routine thrombophilia screening after a first unprovoked VTE is generally not recommended — test only when results will change management (e.g., anticoagulation duration, family screening in first-degree relatives).
- Testing should be deferred for at least 2–4 weeks after completing anticoagulation to avoid false-negative results from consumption or warfarin interference.
- Anticoagulation duration is determined by the balance of provoked vs unprovoked VTE, recurrence risk (VTE-DASH or Vienna Prediction Model score), and bleeding risk — not by thrombophilia genotype alone.
- Heterozygous FVL or PT G20210A alone is not an indication for extended anticoagulation after provoked VTE.
- Antithrombin deficiency, combined thrombophilias, or homozygous/mixed states generally warrant extended or indefinite anticoagulation after VTE.
- Direct oral anticoagulants (DOACs) are first-line for most patients; warfarin remains preferred for antithrombin deficiency and antiphospholipid syndrome (APS).
- Pre-procedural and peri-partum bridging with low-molecular-weight heparin (LMWH) is essential in high-risk thrombophilias (AT deficiency, Protein C/S deficiency, combined defects).
- Aboriginal and Torres Strait Islander peoples may have under-diagnosed thrombophilia; access to specialist haematology and thrombophilia clinics is limited in remote Australia, increasing the need for GP-initiated testing frameworks.
Introduction & Australian Epidemiology
Thrombophilia refers to an inherited or acquired predisposition to venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). The concept encompasses genetic mutations affecting coagulation factor function, natural anticoagulant deficiency, and acquired hypercoagulable states such as antiphospholipid syndrome (APS) and malignancy.
VTE affects approximately 1–2 per 1,000 Australian adults annually, with incidence rising sharply with age (≥6 per 1,000 in those >70 years). Thrombophilias modify recurrence risk rather than being the primary driver of first VTE events, which remain most commonly provoked by surgery, immobilisation, oestrogen-containing medications, pregnancy, and malignancy.
The overall prevalence of inherited thrombophilias in the Australian population is as follows:
| Thrombophilia | Heterozygous Prevalence | Homozygous Prevalence | Relative Risk (first VTE) |
|---|---|---|---|
| Factor V Leiden | 5–8% (European) | ~1 in 5,000 | ×3–8 (het) / ×50–80 (hom) |
| Prothrombin G20210A | 2–3% (European) | ~1 in 10,000 | ×2–5 (het) / ×20+ (hom) |
| Antithrombin deficiency | 0.02–0.2% | Rare (often lethal) | ×5–50 |
| Protein C deficiency | 0.2–0.5% | ~1 in 500,000–1,000,000 | ×7–10 (het) |
| Protein S deficiency | 0.1–1% | Very rare | ×5–10 (het) |
Key principle: A positive thrombophilia result does not automatically change management. Clinicians must evaluate the clinical context — provoked vs unprovoked VTE, recurrence risk, bleeding risk — before altering anticoagulation duration.
In Australia, inherited thrombophilias are predominantly identified in people of European descent. Factor V Leiden and prothrombin G20210A are exceedingly rare in East Asian, African, and First Nations populations, while Protein C/S and antithrombin deficiency occur across all ancestries. Thrombophilia testing patterns vary widely across Australian states and territories, with significant practice variation between metropolitan and rural/remote settings.
Inherited Thrombophilias — Factor V Leiden & Prothrombin G20210A
Factor V Leiden (FVL)
Factor V Leiden results from a point mutation (G1691A) in the F5 gene causing an arginine-to-glutamine substitution at position 506 (R506Q). This renders activated Factor V resistant to cleavage by activated Protein C (APC resistance), thereby sustaining the prothrombotic state.
Factor V Leiden — Clinical Features
F5 gene · R506Q · APC resistance
Inheritance
Autosomal dominant
VTE risk (het)
×3–8 baseline; ×30+ with OCP
VTE risk (hom)
×50–80 baseline
Recurrence (5-yr, unprovoked)
~15–20% (het); ~40%+ (hom)
Australian prevalence
5–8% European descent; <1% ATSI/Asian
Prothrombin Gene Mutation (PT G20210A)
The prothrombin G20210A mutation is a gain-of-function variant in the 3′ untranslated region of the F2 gene, leading to increased prothrombin (Factor II) plasma levels (approximately 30% elevation). Elevated prothrombin enhances thrombin generation and promotes a prothrombotic phenotype.
Prothrombin G20210A — Clinical Features
F2 gene · Gain-of-function · ↑ prothrombin
Inheritance
Autosomal dominant
VTE risk (het)
×2–5 baseline
VTE risk (hom)
×20+ baseline
Recurrence (5-yr, unprovoked)
~10–15% (het)
Synergy
Combined FVL + PT G20210A → ×20+ risk
Compound heterozygosity: Patients who carry both FVL and PT G20210A (compound heterozygotes) have a substantially elevated VTE risk (~×20) and should be managed similarly to homozygous states.
Protein C, Protein S & Antithrombin Deficiency
These natural anticoagulant deficiencies are less common than FVL or PT G20210A but confer significantly higher thrombotic risk and are more likely to influence anticoagulation decisions. All three follow autosomal dominant inheritance with variable penetrance.
Antithrombin (AT) Deficiency
Antithrombin is the primary physiological inhibitor of thrombin (Factor IIa) and Factor Xa. Deficiency may be quantitative (Type I — reduced synthesis) or qualitative (Type II — functional defect in the reactive site, heparin-binding site, or pleiotropic). AT deficiency confers the highest thrombotic risk of all inherited thrombophilias.
Type II — Heparin Binding Site
Moderate Risk
AT antigen preserved but heparin affinity reduced. Lower thrombotic risk than other Type II variants. May be missed on heparin cofactor assays.
Consider extended anticoagulation after unprovoked VTE
Type I (Quantitative)
High Risk
~50% of normal AT activity and antigen. Lifetime VTE risk of 50–80%. Often presents in young adulthood. Heparin resistance may occur.
Extended/indefinite anticoagulation after VTE; LMWH bridging peri-procedurally
Homozygous / Compound
Very High Risk
Usually lethal in utero (Type I homozygous). Type II homozygotes (pleiotropic) may survive with neonatal purpura fulminans. Requires lifelong AT concentrate and anticoagulation.
Tertiary centre management; AT concentrate (Thrombate III®); lifelong warfarin
Heparin resistance: Patients with antithrombin deficiency may exhibit heparin resistance (failure to achieve therapeutic aPTT despite escalating heparin doses) because heparin requires AT as a cofactor. Management: IV AT concentrate (if available) or switch to direct thrombin inhibitors in refractory cases.
Protein C Deficiency
Protein C is a vitamin K-dependent zymogen that, when activated by the thrombin-thrombomodulin complex, proteolytically inactivates Factors Va and VIIIa. Heterozygous deficiency confers a ×7–10 increased VTE risk. Critically, warfarin initiation can precipitate warfarin-induced skin necrosis (WISN) due to the more rapid fall in Protein C relative to procoagulant factors.
Warfarin-induced skin necrosis: In Protein C (or S) deficiency, never start warfarin without adequate heparin/LMWH bridging for ≥5 days AND until INR ≥2.0 for ≥24 hours. Consider low-dose initiation (2–3 mg) for the first 3–5 days. If skin necrosis develops, withhold warfarin, administer vitamin K, and provide fresh frozen plasma or Protein C concentrate.
Protein S Deficiency
Protein S is a cofactor for activated Protein C and also has independent anticoagulant activity via direct inhibition of prothrombinase. Three types are recognised:
| Type | Free PS | Total PS | PS Activity |
|---|---|---|---|
| Type I | ↓ | ↓ | ↓ |
| Type II | Normal | Normal | ↓ |
| Type III | ↓ | Normal | ↓ |
Measurement pitfalls: Protein S is an acute-phase reactant and levels fall during acute thrombosis, pregnancy, and oestrogen use — leading to false-positive diagnoses. Always repeat testing when the patient is well, off anticoagulation, and not pregnant. Free PS (antigen) is the most reliable assay.
Testing Indications & Interpretation
When to Test
Do not test routinely: Thrombophilia testing after a first provoked VTE, or when results will not change management, is not recommended by the RACGP, BSH, or ISTH. Testing is most useful when results will influence anticoagulation duration, family counselling, or pre-procedural planning.
Appropriate indications for thrombophilia testing in Australia:
- Unprovoked VTE in a patient <50 years, especially if considering stopping anticoagulation
- Recurrent VTE (≥2 episodes)
- VTE in unusual sites (cerebral venous sinus, hepatic, mesenteric, portal veins)
- First-degree relative with high-risk thrombophilia (AT deficiency, homozygous FVL, combined defects)
- Neonatal purpura fulminans or warfarin-induced skin necrosis (test for Protein C/S deficiency)
- Recurrent pregnancy loss (≥3 first-trimester or ≥1 second-trimester losses) — after exclusion of APS
- Heparin resistance (suggestive of AT deficiency)
When NOT to Test
- First provoked VTE with a strong transient risk factor (surgery, plaster cast, >3 days immobility)
- During acute VTE (consumption lowers Protein C/S/AT levels)
- While on anticoagulation (warfarin lowers Protein C/S; DOACs interfere with clot-based assays)
- During pregnancy or oestrogen use (falsely low Protein S)
- Routine screening in the general population or pre-employment
Interpretation Framework
| Test | Method | Timing Requirements | Interference |
|---|---|---|---|
| Factor V Leiden | DNA-based (PCR); APTT-based APC-R screening | Any time (genetic test — constant) | APC-R assay unreliable if on warfarin or lupus anticoagulant present |
| Prothrombin G20210A | DNA-based (PCR); prothrombin level screening | Any time (genetic test — constant) | Prothrombin levels unreliable on warfarin |
| Antithrombin | Chromogenic activity assay ± antigen | ≥2 weeks off anticoagulation; not during acute thrombosis | Heparin (in vitro); acute thrombosis (consumption); DIC |
| Protein C | Chromogenic or clot-based activity ± antigen | ≥2–4 weeks off warfarin (Vit K-dependent); can test on heparin | Warfarin (falsely ↓); acute thrombosis; liver disease; DIC |
| Protein S | Free PS antigen (immunological) + activity | ≥2–4 weeks off warfarin; not during pregnancy or OCP | Warfarin, pregnancy, OCP, acute thrombosis, liver disease — all falsely ↓ |
Australian Laboratory Considerations
MBS Available
Factor V Leiden (DNA)
MBS Item 73302. Available at major pathology laboratories (Sullivan Nicolaides, Douglass Hanly Moir, Melbourne Pathology). Turnaround: 5–10 business days. Bulk-billed in most settings.
MBS Available
Prothrombin G20210A (DNA)
MBS Item 73302 (often co-tested with FVL). Same turnaround and availability as FVL.
MBS Available
Protein C activity, Protein S (free Ag), Antithrombin activity
MBS Items 71108, 71110, 71106. Available at major metropolitan and regional labs. Not all remote/regional centres offer these; refer blood to tertiary lab if local turnaround is prolonged.
Referral Recommended
Specialist Haematology / Thrombophilia Clinic
Complex cases (AT deficiency, combined defects, recurrent VTE despite anticoagulation) should be referred to a hospital-based thrombophilia or haemostasis clinic. Available at most tertiary centres (Royal Melbourne, Westmead, Royal Adelaide, Princess Alexandra, Royal Perth).
Management — Anticoagulation Duration
Anticoagulation decisions in thrombophilia should be based on the clinical context of the VTE (provoked vs unprovoked), validated recurrence risk scores, bleeding risk, and patient preference — not the thrombophilia genotype alone.
Anticoagulation Duration Decision Framework
1
Classify the VTE
Provoked (major transient risk: surgery, trauma, ≥3 days immobility) vs unprovoked vs weakly provoked (OCP, long-haul travel, minor illness).
2
Assess Recurrence Risk
Use VTE-DASH score, Vienna Prediction Model, or HERDOO2. Unprovoked VTE: 5-year recurrence ~30% without anticoagulation.
3
Evaluate Thrombophilia
High-risk (AT def, combined, homozygous) → strongly favour extended anticoagulation. Low-risk (het FVL/PT) → manage by clinical context.
4
Assess Bleeding Risk
HAS-BLED score. Age ≥65, renal impairment, prior bleeding, antiplatelet therapy increase risk.
5
Shared Decision-Making
Discuss recurrence vs bleeding risk. Annual VTE recurrence on treatment ~2% vs off treatment ~5–10% (unprovoked). Patient preference is crucial.
Recommended Duration by Thrombophilia Type
| Thrombophilia | Provoked VTE | Unprovoked VTE |
|---|---|---|
| No thrombophilia | 3 months | ≥3 months; reassess for extended |
| Heterozygous FVL or PT G20210A | 3 months | ≥3 months; reassess — genotype alone does not mandate extended |
| Homozygous FVL or PT G20210A | 3–6 months; reassess | Extended/indefinite |
| Compound heterozygous (FVL + PT) | 3–6 months; reassess | Extended/indefinite |
| Protein C deficiency (het) | 3–6 months | Extended/indefinite |
| Protein S deficiency (het) | 3–6 months | Extended/indefinite |
| Antithrombin deficiency (het) | Extended/indefinite | Extended/indefinite |
| Combined thrombophilias | Extended/indefinite | Extended/indefinite |
Pharmacological Agents — Australian PBS
Apixaban
Eliquis® · Factor Xa inhibitor · DOAC
Adult dose — acute
10 mg PO BD × 7 days, then 5 mg PO BD × 6 months
Extended prophylaxis
2.5 mg PO BD (PBS-listed for extended VTE prevention)
Paediatric dose
Weight-based (≥12 months); see product PI
Renal adjustment
CrCl <25 mL/min: avoid. No dose change CrCl 25–50
Hepatic adjustment
Avoid in severe hepatic impairment (Child-Pugh C)
PBS status
✔ PBS General Benefit
Rivaroxaban
Xarelto® · Factor Xa inhibitor · DOAC
Adult dose — acute
15 mg PO BD × 21 days, then 20 mg PO OD with food
Extended prophylaxis
10 mg PO OD (PBS-listed for extended VTE prevention)
Renal adjustment
CrCl <15 mL/min: avoid. CrCl 15–49: use 15 mg for treatment (not 10 mg prophylaxis)
PBS status
✔ PBS General Benefit
Warfarin
Marevan® · Coumarin · Vitamin K antagonist
Adult dose
Individualised; target INR 2.0–3.0. Start 2–5 mg PO daily
Preferred when
Antithrombin deficiency, APS, mechanical heart valve
Renal adjustment
No specific dose change; monitor INR closely
Key interaction
Numerous drug-food interactions; INR monitoring essential
PBS status
✔ PBS General Benefit
Enoxaparin
Clexane® · LMWH · Antithrombin-dependent
Adult dose — treatment
1 mg/kg SC BD (or 1.5 mg/kg SC OD)
Adult dose — prophylaxis
40 mg SC OD (or 20 mg SC OD if CrCl <30)
Paediatric dose
0.75 mg/kg SC BD (<2 months); 0.5 mg/kg SC BD (≥2 months)
Key role
Bridging anticoagulation; pregnancy; peri-procedural in high-risk thrombophilias
PBS status
✔ PBS General Benefit
DOACs vs Warfarin — choice in thrombophilia: DOACs (apixaban, rivaroxaban) are first-line for most thrombophilia patients with VTE. However, warfarin is preferred in: (1) antithrombin deficiency (DOACs are AT-independent and may be less effective), (2) antiphospholipid syndrome (warfarin superior to rivaroxaban per TRAPS trial), and (3) mechanical heart valves.
Monitoring
Week 1–2
Initial VTE treatment phase. Ensure therapeutic anticoagulation achieved. If on warfarin: commence bridging with LMWH, monitor INR daily until stable.
Month 3
First reassessment point. For provoked VTE with low-risk thrombophilia: consider stopping anticoagulation. For unprovoked VTE or high-risk thrombophilia: reassess for extended therapy.
Month 6
Second reassessment if on extended anticoagulation. Check renal function (affects DOAC dosing). Review bleeding risk (HAS-BLED). Reconfirm patient preference.
Annually
Annual review of extended anticoagulation. FBC, renal function, LFTs. Reassess bleeding risk. Discuss de-escalation if recurrence risk has declined. Document shared decision.
Warfarin Monitoring
- Target INR: 2.0–3.0 for most VTE. Target INR 2.5–3.5 for APS with recurrent thrombosis.
- INR monitoring every 1–2 weeks initially, then every 4–6 weeks when stable.
- Time in therapeutic range (TTR) should be >65% — if lower, consider DOAC switch if appropriate.
- CYP2C9 and VKORC1 genotyping (MBS Item 73302) may guide initial dosing in complex cases.
DOAC Monitoring
- DOACs do not require routine coagulation monitoring.
- Check renal function (eGFR) every 6–12 months — essential for dose adjustment.
- Anti-Xa levels (calibrated for specific DOAC) can be measured in clinical emergencies (major bleeding, urgent surgery, suspected treatment failure) — available at tertiary centres.
Special Populations
Pregnancy
DOACs (apixaban, rivaroxaban, edoxaban, dabigatran)
Contraindicated in pregnancy (teratogenic risk, especially first trimester). Discontinue and switch to LMWH before conception or immediately upon pregnancy diagnosis.
Enoxaparin (Clexane®)
First-line anticoagulation in pregnancy. Dose: treatment 1 mg/kg SC BD; prophylactic 40 mg SC OD. Adjust for weight. Safe in all trimesters. Does not cross placenta.
Warfarin
Teratogenic (warfarin embryopathy) weeks 6–12. Avoid in first trimester. May use weeks 13–36 in exceptional cases (e.g., mechanical valve). Switch to LMWH before delivery.
AT concentrate (Thrombate III®)
For AT-deficient pregnant women: AT replacement peri-partum to maintain activity >80%. Coordinate with obstetric haematology. Not PBS-listed — hospital supply.
Paediatrics
VTE in children
Childhood VTE is rare (~0.07–0.14 per 10,000 children/year). Most are provoked (central venous catheters, malignancy). Inherited thrombophilia testing should be guided by paediatric haematology.
Neonatal purpura fulminans
Homozygous Protein C or S deficiency. Emergent: fresh frozen plasma 10–20 mL/kg, Protein C concentrate (Ceprotin®), transition to warfarin with careful LMWH bridging.
Elderly (≥65 years)
Anticoagulation considerations
Higher bleeding risk (HAS-BLED ≥3). Renal decline affects DOAC dosing. Annual risk-benefit reassessment is essential. DOACs preferred over warfarin (fewer monitoring visits, lower ICH risk).
Renal Impairment
CrCl 30–50 mL/min
Rivaroxaban: use 15 mg for treatment. Apixaban: no dose change. Monitor renal function every 3–6 months.
CrCl 15–29 mL/min
Apixaban may be used with caution (limited data). Rivaroxaban: 15 mg treatment dose. Avoid dabigatran. Consider warfarin as alternative.
CrCl <15 mL/min / Dialysis
Warfarin is preferred. DOACs not recommended. LMWH: dose-reduce and monitor anti-Xa levels.
Hepatic Impairment
Child-Pugh A–B
DOACs may be used with caution in mild-moderate hepatic impairment. Monitor LFTs. Synthetic liver function affects Protein C/S levels — interpret with caution.
Child-Pugh C
Avoid DOACs. Warfarin with careful INR monitoring. Coagulopathy may mimic or mask thrombophilia.
Immunocompromised
Cancer-associated VTE
LMWH (enoxaparin 1 mg/kg SC BD) was traditional standard; DOACs (rivaroxaban, apixaban) now PBS-listed alternatives in cancer. GI/GU malignancies: higher bleeding risk with DOACs — assess carefully.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
📚 References
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