Thrombophilia Testing
On this page
Direct answer
Factor V Leiden is the commonest inherited thrombophilia in European-descended populations, yet heterozygosity raises venous thrombosis risk only modestly — the tension between how often it is found and how rarely it changes management is the entire didactic point of thrombophilia testing. The inherited panel covers factor V Leiden (G1691A, causing activated protein C resistance), the prothrombin G20210A variant, and deficiency of protein C, protein S or antithrombin, the last being the strongest inherited risk and the one associated with heparin resistance. The acquired counterpart is the antiphospholipid syndrome, defined by a clinical event plus persistent lupus anticoagulant, anticardiolipin or anti-beta-2 glycoprotein I antibodies at least twelve weeks apart. Timing governs validity: acute thrombus, warfarin, heparin and the direct oral anticoagulants all distort functional assays, so phenotypic testing waits until the patient is off anticoagulation and remote from the event, while genetic tests can be run any time.
What you must remember
- Inherited hierarchy: antithrombin deficiency carries the highest relative risk, then protein C and protein S deficiencies; factor V Leiden heterozygosity is commonest but weakest — homozygosity approaches the risk of the deficiencies.
- Activated protein C resistance: factor V Leiden resists cleavage, the basis of the functional assay; genotyping (G1691A) confirms.
- Warfarin confounding: proteins C and S are vitamin-K-dependent, so warfarin lowers their levels and mimics deficiency; antithrombin falls on heparin therapy; the direct oral anticoagulants interfere broadly with clot-based assays.
- Lupus anticoagulant logic: a prolonged APTT that fails to correct on mixing study, confirmed by correction with excess phospholipid (Russell viper venom time), plus one persistent antibody twelve or more weeks apart, per the Sydney criteria.
- Who deserves testing: strong family history, unprovoked or recurrent venous thromboembolism at a young age, thrombosis at unusual sites, recurrent pregnancy loss, or neonatal purpura fulminans workups — not every first unprovoked clot.
- Actionable outcomes: antithrombin deficiency alters heparin dosing (resistance demands higher doses or alternative anticoagulants), and antiphospholipid syndrome mandates warfarin over direct oral anticoagulants after venous events.
- Protein S free-antigen caveat: the free (not total) protein S antigen is the assay, because acute phase and pregnancy changes distort the bound fraction.
Timing a panel around a first clot
A 27-year-old athlete develops an unprovoked femoral-popliteal deep vein thrombosis and is started on apixaban; her aunt died of pulmonary embolism in her thirties. The correct plan is to defer phenotypic testing: the acute thrombus consumes antithrombin and protein C, and the direct factor Xa inhibitor distorts clot-based assays. Genetic testing for factor V Leiden and prothrombin G20210A can proceed immediately if wanted, but protein C, protein S and antithrombin levels are scheduled for when anticoagulation has concluded and at least some weeks have elapsed, interpreted against a repeat sample because levels near threshold demand confirmation. Meanwhile she is screened clinically for antiphospholipid syndrome with lupus anticoagulant, anticardiolipin and anti-beta-2 glycoprotein I at diagnosis and again at twelve weeks — persistent positivity, not a single titre, defines the syndrome. Every result is then judged by one question: will it change duration or choice of therapy? If the answer is no, testing adds anxiety without advantage, which is why guidelines restrict it.
Where candidates slip
The mixing-study step is skipped: lupus anticoagulant is remembered as "prolonged APTT" without the failure-to-correct logic that separates an inhibitor from a factor deficiency. Protein C and S levels are ordered on warfarin and reported as deficient — an everyday laboratory error and a beloved exam scenario. Antithrombin deficiency is forgotten at the bedside, where it announces itself as heparin resistance (failure to achieve therapeutic activated partial thromboplastin time despite escalating doses, with antithrombin levels drawn before any further dosing decisions). And the twelve-week persistence requirement for antiphospholipid antibodies is ignored, converting transient post-infectious positivity into a lifelong label.
Frequently asked questions
Which is the commonest inherited thrombophilia and which the strongest?
Factor V Leiden heterozygosity is commonest but weak; antithrombin deficiency carries the strongest relative risk among the classical inherited deficiencies.
Why can protein C and S not be measured during warfarin therapy?
Both are vitamin-K-dependent, so warfarin therapeutically lowers their levels, producing a biochemical picture indistinguishable from inherited deficiency.
How is a lupus anticoagulant detected?
A prolonged APTT that fails to correct with normal plasma on mixing study, then corrects with excess phospholipid (confirmed by assays such as the dilute Russell viper venom time).
What defines antiphospholipid syndrome serologically?
Lupus anticoagulant, anticardiolipin or anti-beta-2 glycoprotein I positivity persisting on testing at least twelve weeks apart, paired with a qualifying clinical event.
How does antithrombin deficiency declare itself on heparin?
As heparin resistance — subtherapeutic APTT despite escalating doses — because antithrombin is heparin's essential cofactor.
Who should be offered a thrombophilia screen?
Patients with young-age unprovoked or recurrent venous thrombosis, unusual-site thrombosis, strong family history or recurrent pregnancy loss — guided testing, not blanket screening.