Phys · haematological
Thrombophilia and Venous Thromboembolism
Also known as venous thromboembolism · VTE · deep vein thrombosis · DVT · pulmonary embolism · thrombophilia · Factor V Leiden · antiphospholipid syndrome · APS · heparin-induced thrombocytopenia · HIT · prothrombin G20210A · protein C deficiency · protein S deficiency · antithrombin deficiency · lupus anticoagulant
Consultant-physician-depth guide to inherited and acquired thrombophilia and venous thromboembolism (VTE) for FRACP DWE and DCE — Factor V Leiden and prothrombin G20210A, protein C/S and antithrombin deficiency, antiphospholipid syndrome (lupus anticoagulant, anticardiolipin, beta-2 glycoprotein I), when to test and when not to test, DVT diagnosis (Wells score, D-dimer, compression ultrasound), DOACs first-line, warfarin for APS, LMWH for pregnancy and cancer, HIT (4T score, PF4 antibody), cerebral and splanchnic vein thrombosis, and the TRAPS, EINSTEIN-CHOICE, SELECT-D, Hokusai-CANVAS and Caravaggio trials.
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Target exams
Red flags
- Massive PE with hypotension — consider thrombolysis; do not delay for imaging if critically unstable
- Antiphospholipid syndrome with multi-organ thrombosis and thrombocytopenia — catastrophic APS, a medical emergency treated with combination anticoagulation, corticosteroids, plasma exchange and IVIG
- Platelet fall over 50 per cent 5 to 14 days after heparin exposure with new thrombosis — heparin-induced thrombocytopenia; stop all heparin and switch to argatroban or danaparoid
- Cerebral venous sinus thrombosis with headache, seizures and focal deficits — anticoagulate even with haemorrhagic infarction on imaging
- Unprovoked VTE at a young age with a family history — screen for inherited thrombophilia, but only after the acute event has settled and anticoagulation has been paused
Thrombophilia and Venous Thromboembolism
The answer first
Venous thromboembolism (VTE) — deep vein thrombosis (DVT) and pulmonary embolism (PE) — arises when Virchow's triad (venous stasis, endothelial injury, hypercoagulability) converges. Most clots are provoked by a transient risk factor (surgery, immobility, cancer, pregnancy, oestrogen). A minority occur unprovoked, and it is in this group that a thrombophilia — inherited or acquired — may be lurking. The diagnosis of DVT rests on the Wells pretest probability combined with D-dimer and compression ultrasound [4].
Two bedside rules that change outcome: [1]
- First-line anticoagulation is a DOAC (apixaban, rivaroxaban, dabigatran or edoxaban), not warfarin, for most patients with VTE — UNLESS there is antiphospholipid syndrome, pregnancy, a mechanical heart valve, or severe renal failure. In triple-positive APS, warfarin is preferred because the TRAPS trial showed excess thrombosis with rivaroxaban [6].
- Duration follows the trigger. Provoked VTE gets 3 to 6 months. Unprovoked VTE gets at least 6 months, with consideration of indefinite therapy if bleeding risk is acceptable. Cancer-associated VTE is indefinite while the cancer is active.
Thrombophilia testing is not a blanket investigation. It is reserved for selected patients — unprovoked VTE at a young age, recurrent events, unusual sites (cerebral, splanchnic), and a strong family history — and it must be timed correctly: not during the acute clot or while on anticoagulation, because both distort the assays. Test 4 to 6 weeks after stopping anticoagulation if practical [3].
References10ShowHide
- [1]Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C Nature, 1994.PMID 8164741
- [2]Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis Blood, 1996.PMID 8916933
- [3]Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS) J Thromb Haemost, 2006.PMID 16420554
- [4]Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management Lancet, 1997.PMID 9428249
- [5]Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism N Engl J Med, 2017.PMID 28316279
- [6]Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome Blood, 2018.PMID 30002145
- [7]Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D) J Clin Oncol, 2018.PMID 29746227
- [8]Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism N Engl J Med, 2018.PMID 29231094
- [9]Agnelli G, Becattini C, Meyer G, et al. Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer N Engl J Med, 2020.PMID 32223112
- [10]Ferro JM, Canhão P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) Stroke, 2004.PMID 14976332