19 Inherited Thrombophilias
- Test only if result changes management (extended AC, prophylaxis, pregnancy)
- Don’t screen general population or determine CHC eligibility
- Risks: cost, false reassurance (negative), anxiety (positive), false results
- Tests inaccurate w/ acute VTE, heparin, DOACs, warfarin, pregnancy, liver disease, chemotherapy
- Shared decision-making: patient must be well-informed
19.1 Introduction
Thrombophilia & hypercoagulable state: hereditary/acquired thrombosis predisposition
Key concepts: - Homozygous/heterozygous/compound heterozygous: zygosity determines risk - Heterozygotes lower risk than homozygotes - Compound heterozygosity (FVL + PGM): highest risk - Penetrance: genetic mutation presence ≠ clinical thrombosis - Incomplete for all inherited thrombophilias - Most mutations don’t cause VTE events
19.2 Epidemiology of Inherited Thrombophilias
| Thrombophilia | Prevalence (%) | Risk 1st VTE | RR Recurrent VTE |
|---|---|---|---|
| AT deficiency | 0.02 | 5-10 | 1.9-2.6 |
| PC deficiency | 0.2 | 4-6.5 | 1.4-1.8 |
| PS deficiency | 0.03-0.13 | 1-10 | 1.0-1.4 |
| FVL heterozygous | 3-7 | 3-5 | 1 |
| FVL homozygous | 0.02 | 9-12 | 1.0-2.6 |
| PGM heterozygous | 0.7-4 | 2-3 | 0.7-1.4 |
| PGM homozygous | 0.014 | 4 | 1.2 |
| FVL + PGM compound | 0.01 | 7-20 | 1.0-4.3 |
19.2.1 Factor V Leiden
FVL (F5 G1691A): - Prevalence: 3-8% European origin, 1.2% African American - Pathophysiology: G→A point mutation → ↑ prothrombin (133% normal) → ↑ APC resistance - Risk: 3-5 fold ↑ if heterozygous; substantially higher homozygous - Homozygous: 1 in 500-1600 of European origin
19.2.2 Prothrombin 20210 Mutation
PGM (F2 G20210A): - Prevalence: 0.7-4% Southern Europe, 2% USA, 0.5% African American - Pathophysiology: G→A outside coding region → ↑ prothrombin synthesis (133% normal) - Risk: 2-3 fold ↑ if heterozygous; varies homozygous - Geography: most common Southern European ancestry
19.2.3 Protein C Deficiency
PC (PROC): - Prevalence: 1 in 500-600 general population - Higher in: East Asian VTE populations (7.1%) - Challenge: homozygous extremely rare; heterozygotes more common - Clinical pearl: absent in newborns → potential DIC risk
19.2.4 Protein S Deficiency
PS (PROS1): - Prevalence: 1 in 800-3000 (true prevalence unknown due to testing difficulty) - Challenge: establishing normal PS range difficult; diagnosis accuracy limited - Higher in: East Asian VTE populations (8.3%) - Biology: PS exists free (active) & bound (inactive); proportions vary
19.2.5 Antithrombin Deficiency
AT (SERPINC1): - Mechanism: serine protease inhibitor; complexes w/ thrombin, Xa, IXa - Heparin effect: dramatically potentiates AT-protease complexes - Pathology: abnormal gene → impaired reactive site/heparin binding - Clinical: VTE + heparin resistance (unactivated factors) - Prevalence: rare; highest absolute thrombosis risk
19.3 Pathophysiology
19.3.1 Factor V Leiden (F5)
- Mutation: G→A point mutation outside coding region
- Defect: abolished APC resistance → ↑ Factor Va inactivation failure
- Consequence: ↑ Factor V circulation → ↑ thrombin generation
- Mechanism: Loss of APC inhibition → unopposed factor V activity
19.3.2 Prothrombin 20210 (F2)
- Mutation: G→A outside coding region
- Defect: molecule itself unaltered; ↑ synthesis (133% normal)
- Consequence: ↑ thrombin → ↑ thrombosis risk
19.3.3 Protein C (PROC)
- Dual defect: homozygous → inactivates Factors Va & VIIIa failure
- Risk: ↑ thrombosis; severe deficiency → DIC in newborns
- Mechanism: PC loss → unopposed factor Va/VIIIa amplification
19.3.4 Protein S (PROS1)
- Dual cofactor role:
- Cofactor for activated PC (inactivates Va/VIIIa)
- Cofactor for tissue factor pathway inhibitor (inhibits Xa, VIIa)
- Circulation states: free (active) 40%, bound (inactive) 60%
- Acquired causes: ↓ free PS in acute phase, pregnancy
- Consequence: ↑ unopposed Factor Va/VIII → ↑ thrombosis
19.3.5 Antithrombin (SERPINC1)
- Normal function: inhibits Xa, IXa, XIa, XIIa via serine protease complexes
- Heparin: accelerates AT-protease complex 1000-fold
- Deficiency: ↓ natural anticoagulation → heparin resistance
- Pathology: abnormal gene → reactive site/heparin binding defects
19.4 Compounding Risk Factors
VTE rarely isolated; accumulation of factors: - Inherited thrombophilia - Family history VTE - Exogenous estrogen - Pregnancy - Surgery/trauma/immobilization - Malignancy - Prolonged immobility
19.4.1 Family History of VTE
- Risk: 1st-degree relative w/ VTE → 2-4 fold personal risk ↑
- Definition: unprovoked VTE in relative increases risk more than provoked
- Warning: negative thrombophilia test doesn’t eliminate family risk
- Counseling: still recommend estrogen avoidance, immobility minimization
19.4.2 Pregnancy & Exogenous Estrogen
- Heterozygous PGM: 3-15 fold ↑ VTE risk in pregnancy
- Heterozygous FVL: similar magnitude ↑ risk
- FVL + PGM compound: 8-18 fold ↑ risk
- Homozygous states: 47 fold ↑ risk
- All thrombophilias: ↑ risk w/ oral contraceptives & HRT
19.5 ASH Recommendations: Thromboprophylaxis in Pregnant Individuals
| Thrombophilia | +Family Hx (A/P) | -Family Hx (A/P) |
|---|---|---|
| Homozygous FVL | ✓/✓ | ✓/✓ |
| FVL + PGM compound | ✓/✓ | ✓/✓ |
| Homozygous PGM | ✓/✓ | X/X |
| AT deficiency | ✓/✓ | X/X |
| PC deficiency | X/✓ | X/X |
| PS deficiency | X/✓ | X/X |
| Heterozygous FVL | X/X | X/X |
| Heterozygous PGM | X/X | X/X |
Footnote: Recommendations based on family history = 1st-degree VTE relative; negative family history = no VTE in FVL/PGM/AT deficiency relatives
Pregnant individual counseling: - Heterozygous FVL/PGM: minimize exogenous estrogen exposure - All thrombophilias: favor progestin-only over CHCs - High-risk (homozygous/compound): antepartum + postpartum prophylaxis - ASH against antepartum prophylaxis except high-risk states (see table)
19.6 Assays for Thrombophilia
Test accuracy depends on clinical context. Abnormal results possible w/: - Acute VTE - Heparin/DOACs/warfarin - Pregnancy - Liver disease - Chemotherapy - Elevated Factor VIII - LAC or inhibitors
Always correlate w/ clinical presentation & timing.
19.6.1 Factor V Leiden & Prothrombin Mutations (F5, F2)
FVL screening: - aPC resistance assay: PTT/PT/Russell viper venom w/ normal plasma - Results: abnormally low ratio suggests resistance - Confirmatory: genotyping determines heterozygous vs homozygous - Pitfalls: false+ w/ elevated FVIII, estrogen, LAC; false- w/ anticoagulants
PGM screening: - Factor II activity assay: not sensitive - Standard: genetic testing (PCR/sequencing) - Advantages: detects heterozygous/homozygous; unaffected by medications
19.6.2 Protein C (PROC)
Activity assay (clot-based/chromogenic): - Clot-based: functional measure; affected by FVIII, PS, LAC variation - Chromogenic: synthetic substrate; detects Type I & some Type II defects - Pitfalls: false-low w/ warfarin, DOACs, elevated FVIII - Types: Type I (activity = antigen), Type II (activity < antigen)
Antigen assay: - Differentiates Type I from Type II deficiency - Repeat abnormal results; check during anticoagulation-free period
19.6.3 Protein S (PROS1)
Challenges: - Free vs bound states vary 40-60% w/ physiologic conditions - Pregnancy/acute phase: ↓ free PS (false-positive appearance) - Estrogen: ↓ free PS
Assays: - Clot-based activity: most sensitive; affected by same variables as PC - Free PS antigen: alternative; avoids activity assay confounders - Best: free PS antigen + activity if abnormal
19.6.4 Antithrombin (SERPINC1)
Activity assay (chromogenic): - Gold standard: heparin-enhanced chromogenic w/ Xa or IIa substrate - Functional measurement; most sensitive screening - Types: Type I (activity = antigen), Type II (activity < antigen), Type III (rare)
Interpretation: - Repeat abnormal results w/o heparin - Chromogenic w/o heparin differentiates Type IIa (reactive site) vs IIb (heparin binding) - LAC false-prolongs aPTT but does NOT exclude AT def; specific LAC testing needed
19.7 Reasons For & Against Testing
| For | Against |
|---|---|
| Informs AC duration | Rarely changes management |
| Identifies extended prophylaxis candidates | False positive anxiety |
| Explains thrombosis to patient | False negative reassurance |
| Suboptimal test performance | |
| Poor medical advice based on results | |
| Insurance/employment impact |
19.8 Indications for Testing
Test if result changes management: - Pregnancy in patient w/ thrombophilia - Unprovoked VTE (may indicate extended AC) - Family history VTE (pregnancy/estrogen counseling) - Recurrent VTE despite prophylaxis
Don’t test: - Provoked VTE w/ major risk factor (surgery, trauma, immobility) - Asymptomatic relatives (low yield, high anxiety) - General population screening - Acute VTE/anticoagulation period
Shared decision-making essential: - Discuss false-positive anxiety & false-negative reassurance - Review management implications pre-testing - Document discussion & rationale
19.9 Treatment Implications
19.9.1 VTE w/ Provoked Event (Surgery/Trauma/Immobility)
Standard approach: - 3 months AC typical; rarely extend based on thrombophilia - Recurrence risk ~1 per 1000/year (low) - Bleeding risk 5-15 per 1000/year (higher) - Test recommendation: NOT indicated; doesn’t change duration
19.9.2 VTE Unprovoked
Consider if: - High thrombosis risk (recurrence ~10 per 1000/year) weighs against bleeding - Thrombophilia found → possible indefinite AC - Multiple risk factors compound
Don’t test: - Won’t change acute management - Test during anticoagulation-free period if needed
19.9.3 No VTE but Family History/Thrombophilia
Consider testing if: - Family history strong (multiple relatives, young VTE) - Planning pregnancy w/ thrombophilia - Starting estrogen (CHC/HRT)
AT/PC/PS deficiency: - Favorable risk-benefit pregnancy planning - Antithrombin highest risk
FVL/PGM heterozygous: - Weak risk; recommend against testing
19.9.4 Estrogen-Based Risk Factors (CHC/HRT)
Testing: - May identify candidates for non-estrogen alternatives - Limited value: most heterozygous mutations compatible w/ CHCs - Shared decision-making about alternative contraceptives
Testing inaccurate during acute VTE, heparin, DOACs, warfarin, pregnancy, liver disease, chemotherapy. Evaluate timing before interpretation.
19.10 Bibliography
ASH VTE guidelines Bacon S, Kirtesplatz S, Middledorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv. 2023;7(12):7101-7138.
Middledorp S, Nieusstat, R, Bäumun Kreuziger L, et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: hematologic testing. Blood Adv. 2023;7(12):7101-7138.
Other society guidelines Ascherlaje DJ, Michalski DS, Chandrahasa A, et al. (2023). Thrombophilia testing: a British Society for Haematology guideline. Br J Haematol. 1980;133:450.
McConnell T, Harriings MC, Horney JS, Keeley S. Guideline committee: Venous thromboembolism in adults: clinical guidance on diagnosis, management, & thrombophilia testing. BMJ. 2020;Sep 985.
Pathophysiology of thrombophilia Makker RA. Laboratory evaluation of thrombophilia. Methods Mol Biol. 2023;2684:177-201.
Patrono D, Cormes VM, Musarella S, et al. A comprehensive review of risk factors for venous thromboembolism: first epidemiology to pathophysiology. Rev J Med Sci. 2023;326(4):369-389.
Thrombophilia assays Amnis J, Heileisen P. Thrombophilia testing—a systematic review. Clin Lab. 2023;69(6):250-715.
Hannington B, Hart C. Laboratory diagnostics in thrombophilia. Semin Hematol. 2023;60(2):97-110.
Makker R. A., et al. (2021). Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH. J Thromb Haemost. 19(1):68-74.