Inherited thrombophilia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Inherited thrombophilia comprises genetic changes that increase venous thromboembolism probability. Factor V Leiden and prothrombin G20210A are relatively common and usually modest in heterozygotes. Antithrombin, protein C and protein S deficiencies are rarer and often stronger, but their penetrance varies. Homozygous or combined defects carry greater risk. These disorders chiefly cause venous rather than atherosclerotic arterial thrombosis; routine testing after myocardial infarction or ordinary ischaemic stroke is usually unhelpful.

Testing is a decision tool, not a ritual after every clot. A surgery-provoked DVT still has a low recurrence risk after the provoking factor resolves, regardless of a common variant. An unprovoked proximal VTE already supports considering extended anticoagulation, so a panel adds no value if treatment will continue. NICE suggests hereditary testing when an unprovoked event, a first-degree family history and a genuine plan to stop coincide. APS testing is distinct because it can change agent choice.

Timing determines validity. DNA tests are not altered by anticoagulation, but functional assays are. Warfarin lowers protein C and protein S; heparin and acute thrombosis can lower antithrombin; pregnancy and oestrogen reduce free protein S; liver disease and DIC lower several proteins; DOACs interfere with many clot-based assays. A low result requires repeat confirmation when stable and appropriate family or genetic correlation before a lifelong label is given.

Management follows the clinical event. Acute DVT or PE receives evidence-based anticoagulation. At review, duration is driven by whether the event was provoked, proximal or unusual, recurrent, cancer-associated or accompanied by persistent risk, balanced against bleeding and preference. Relatives are not screened indiscriminately, but selective testing for a known high-penetrance family deficiency may guide pregnancy, oestrogen or high-risk surgery planning. Negative testing never removes ordinary VTE prevention needs.

Key points

Do not order hereditary thrombophilia testing after a clearly provoked VTE or while a patient will continue anticoagulation regardless of the result; test only when a defined result can change care.
NICE advises considering hereditary testing after unprovoked VTE when a first-degree relative has DVT or PE and stopping anticoagulation is being considered; consider APS testing separately.
Core inherited defects are factor V Leiden, prothrombin G20210A and antithrombin, protein C and protein S deficiency; MTHFR variants and homocysteine panels are not routine thrombophilia tests.
Factor V Leiden and prothrombin genotype are stable, but acute thrombosis, heparin, warfarin, DOACs, liver disease, nephrotic syndrome, pregnancy and oestrogen distort functional assays.
Confirm a low antithrombin, protein C or protein S result on a later well-state sample and exclude acquired causes before diagnosing an inherited deficiency or testing relatives.
Treat acute VTE by ordinary site-specific guidance. A thrombophilia result rarely changes the initial drug or intensity and must never delay therapeutic anticoagulation.
At three months, base continuation on provoked versus unprovoked status, recurrence, bleeding risk, sex, site, persistent factors and preference; a common heterozygous variant alone does not mandate lifelong treatment.
Pregnancy prophylaxis is risk-combination based: previous VTE, antithrombin deficiency, homozygous or combined traits, family history, weight and obstetric factors require haematology-obstetric planning.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Common gain-of-function variants

Factor V Leiden causes activated protein C resistance and prothrombin G20210A increases prothrombin; heterozygous variants mainly increase venous thrombosis risk.

Natural anticoagulant deficiency

Pathogenic SERPINC1, PROC or PROS1 variants reduce antithrombin, protein C or free protein S activity and often confer stronger familial VTE risk.

Combined inherited and acquired risk

Genotype usually requires age, surgery, immobility, pregnancy, oestrogen, obesity, inflammation or cancer as additional drivers; penetrance varies within the same family.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Activated protein C resistance
Factor V Leiden removes a key activated-protein-C cleavage site, allowing factor Va to persist and sustain thrombin generation after a vascular trigger.
2
Excess prothrombin substrate
The prothrombin 20210A variant raises circulating prothrombin, increasing the substrate available for thrombin generation and fibrin formation.
3
Lost serine-protease restraint
Antithrombin neutralises thrombin and factor Xa, while protein C with protein S inactivates factors Va and VIIIa; deficiency removes these physiological brakes.
4
Risk is probabilistic
Most heterozygotes never thrombose, while recurrence is strongly shaped by whether the index event was provoked, persistent risks, site, age and sex.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Young unprovoked VTE

A proximal clot without transient trigger at a young age raises suspicion, especially when several first-degree relatives have objectively confirmed VTE.

Recurrent phenotype

Separate objectively confirmed episodes, thrombosis at unusual sites or recurrence after stopping anticoagulation may justify specialist evaluation for persistent and inherited risks.

Strong pedigree

Multiple relatives with VTE before age 50, pregnancy-associated thrombosis or a known antithrombin, protein C or protein S defect is more informative than vague family history.

Severe deficiency

Neonatal purpura fulminans or childhood thrombosis suggests biallelic protein C or protein S deficiency rather than a common heterozygous variant.

Warfarin skin necrosisRed flag

Painful retiform skin necrosis shortly after VKA initiation can reflect rapid protein C decline and needs urgent treatment review.

Red flags requiring action

Shock, syncope, severe hypoxaemia, chest pain or cardiac arrest with suspected PE requires immediate resuscitation and reperfusion assessment rather than hereditary testing.
Widespread neonatal skin necrosis or purpura fulminans suggests homozygous severe protein C or protein S deficiency and needs urgent protein replacement and specialist anticoagulation.
Warfarin-associated skin necrosis soon after initiation can reflect rapid protein C depletion, especially in an underlying deficiency, and requires immediate anticoagulation and haematology review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line: define the testing decisionFirst stepFirst line
Why
Establish whether a result will alter anticoagulant duration, pregnancy, oestrogen or relative counselling.
Interpretation and limitations
Document event site, provoking factors, recurrence, family history and proposed action. If management is unchanged, do not test.
02
Genetic factor V Leiden and prothrombin testing
Why
Detect stable common variants when they are included in an indicated panel.
Interpretation and limitations
Results are not altered by acute thrombosis or anticoagulation, but heterozygosity confers probability rather than a requirement for lifelong treatment.
03
Antithrombin, protein C and free protein S
Why
Identify rarer natural-anticoagulant deficiencies in a strongly selected phenotype or known family.
Interpretation and limitations
Use activity and antigen methods selected by the laboratory. Repeat a low result after excluding acute thrombosis, pregnancy, liver or renal disease and drug interference.
04
Antiphospholipid antibody panel
Why
Find an acquired thrombophilia that may change oral anticoagulant selection when stopping or switching is considered.
Interpretation and limitations
Test lupus anticoagulant, anticardiolipin and anti-beta2-glycoprotein I with anticoagulant-aware methods and repeat a positive result at least 12 weeks later.
05
Phenotype-led acquired-cause assessment
Why
Identify more likely or treatable drivers before attributing thrombosis to inheritance.
Interpretation and limitations
Use age-appropriate cancer evaluation, FBC and MPN or PNH testing for unusual sites, renal and liver tests, urinalysis and anatomical imaging when indicated.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Antiphospholipid syndrome

An acquired persistent antibody disorder causes venous, arterial and obstetric events and changes anticoagulant choice, particularly in triple-positive disease.

Cancer and inflammatory thrombosis

Malignancy, myeloproliferative neoplasm, nephrotic syndrome, IBD and inflammatory disease may be more important than inherited traits and require targeted assessment.

Anatomical or local causes

May-Thurner compression, venous catheters, thoracic outlet disease and cirrhosis or abdominal inflammation can explain site-specific recurrent thrombosis.

Acquired low protein levels

Liver disease, DIC, nephrotic loss, pregnancy, acute thrombosis and anticoagulants reduce natural-anticoagulant assays and can mimic hereditary deficiency.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Acute VTETreat first and preserve only useful samplesFirst stepDVT, PE or unusual venous thrombosis is suspected or confirmed.

1Start the site-specific diagnostic and therapeutic anticoagulation pathway; do not postpone treatment for thrombophilia blood sampling.
2Document provoking factors, family history, pregnancy, oestrogen, cancer and prior events and obtain routine organ and bleeding baseline.
3Ask which result could alter later care and defer functional testing until interference has resolved and a stopping decision is genuine.

02Testing decisionApply NICE selectionThe minimum treatment course is approaching completion after a first VTE.

1Classify the event as provoked or unprovoked and assess recurrence and bleeding risk and the patient's preference about extended treatment.
2If anticoagulation will continue, do not order hereditary testing merely for completeness; if stopping is considered, assess first-degree VTE history.
3Consider hereditary testing only for the selected unprovoked familial scenario and test APS separately because agent choice may change.

03Low natural anticoagulantConfirm before labelling inheritanceAntithrombin, protein C or protein S activity is below range.

1Review acute clot timing, heparin, warfarin, DOAC, pregnancy, oestrogen, liver disease, DIC and nephrotic protein loss.
2Repeat with the specialist laboratory in a stable valid window and add antigen or genetic analysis when it distinguishes type and heritability.
3Only then offer targeted relative testing with counselling and a predefined prevention decision attached to the result.

04Pregnancy or oestrogenUse the combined risk profileA patient with a known familial defect or previous VTE is considering pregnancy, contraception or hormone therapy.

1Review the exact defect, previous event and trigger, family history, weight, age and additional obstetric or surgical risks.
2Avoid inappropriate oestrogen exposure and create an antenatal and postpartum LMWH plan for high-risk combinations through haematology and obstetrics.
3Record neuraxial and delivery timing, postpartum duration and the transition back to any long-term oral anticoagulant.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Treats acute DVT or PE and provides extended prevention in suitable patients; common inherited thrombophilia does not by itself require a different loading regimen.

Apixaban for suitable acute VTE

Give 10 mg orally twice daily for 7 days, then 5 mg twice daily for at least the remainder of the first 3 months; if extended prevention is chosen after 6 months, use 2.5 mg twice daily when clinically appropriate.

Review renal and hepatic function, active bleeding, pregnancy, APS, extremes of weight and strong CYP3A4 or P-gp interactions. Do not apply atrial-fibrillation dose-reduction criteria to acute VTE.

Provides long-term anticoagulation when a DOAC is unsuitable, including selected severe renal disease, APS or patient-specific interaction and access circumstances.

Warfarin

Initiate with therapeutic LMWH or UFH and overlap for at least 5 days and until INR is at least 2.0 on the locally defined confirmation schedule; maintain a usual VTE INR target of 2.0–3.0.

Protein C falls early, making parenteral overlap essential and skin necrosis a concern in severe deficiency. It is teratogenic, highly interactive and requires consistent INR monitoring and a procedure plan.

Prevents or treats pregnancy-associated VTE because LMWH does not cross the placenta and can be timed around delivery.

Enoxaparin in pregnancy

For therapeutic anticoagulation use 1 mg/kg subcutaneously every 12 hours; prophylactic regimens are weight- and risk-based, with 40 mg once daily commonly used at 50–90 kg under the obstetric protocol.

Use actual booking or current weight according to protocol, adjust in severe renal impairment, review platelets and bleeding, and document last dose before neuraxial anaesthesia or planned birth.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Recurrent venous thromboembolism

DVT and pulmonary embolism recur most when the index event was unprovoked or persistent risks remain; genotype modifies but rarely determines duration alone.

Unusual-site thrombosis

Cerebral, splanchnic, portal and hepatic venous thrombosis may occur, but local disease, MPN, PNH and APS usually need parallel evaluation.

Pregnancy-associated VTE

Pregnancy and puerperium amplify thrombin generation; previous VTE, antithrombin deficiency and combined defects particularly influence prophylaxis decisions.

Testing and treatment harm

False low assays, anxiety, insurance concerns and unnecessary lifelong anticoagulation can follow indiscriminate panels that do not change a clinical decision.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

For any anticoagulant, review bleeding, recurrent VTE symptoms, adherence, kidney and liver function, interactions, procedures and pregnancy plans at defined intervals.
Do not serially repeat stable DNA variants; repeat functional natural-anticoagulant results only to confirm a questionable diagnosis or when physiology and treatment have changed.
At the three-month VTE review, document provoking status, recurrence and bleeding risk and a clear stop or extend decision rather than allowing anticoagulation to continue by default.
For a confirmed high-risk family deficiency, update relatives only through consented targeted counselling and record specific pregnancy, oestrogen and perioperative implications.
During pregnancy, reassess weight, renal function, bleeding, platelet count and delivery timing, and ensure postpartum prophylaxis or lifelong-treatment resumption is not omitted.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Test only for a decision

The useful question is not whether a variant exists, but whether its result will change stopping, pregnancy or family management.

Common variants are not destiny

Most factor V Leiden and prothrombin heterozygotes never clot, and a provoked event may still require only finite treatment.

Protein assays remember physiology

Pregnancy, liver disease, nephrotic loss, acute thrombosis and anticoagulants can all create a convincing but acquired low result.

Negative does not mean low risk

Obesity, cancer, immobility, age and prior unprovoked VTE can confer substantial recurrence despite a normal inherited panel.

APS is a different branch

Unlike many inherited results, triple-positive APS changes oral anticoagulant selection and requires repeat antibody confirmation.

11Common pitfallsFrequent interpretation and management errors.

01
Sending a thrombophilia panel before treating acute PE.
02
Testing after a clearly surgery-provoked VTE without a decision consequence.
03
Diagnosing protein S deficiency during pregnancy or warfarin therapy.
04
Using MTHFR genotyping as routine thrombophilia assessment.
05
Prescribing lifelong anticoagulation for heterozygous factor V Leiden alone.
06
Assuming a negative panel removes ordinary VTE recurrence risk.