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Inherited and acquired thrombophilia

Breakdown · Factor V Leiden Antiphospholipid

Losing the natural anticoagulant brakes — antithrombin, protein C, protein S — or becoming resistant to them tips the balance towards thrombosis. Factor V Leiden and the prothrombin G20210A variant are common and weak; antithrombin, protein C and protein S deficiencies are rare and strong. Antiphospholipid syndrome is the acquired cause that changes management.

Traced from the start

  1. Tissue factor and the extrinsic triggerVitamin K cycle and gamma-carboxylation
  2. Contact activation system (factor XII, prekallikrein, high-molecular-weight kininogen)
  3. Subendothelial collagen and von Willebrand factor
  4. Tissue factor-factor VIIa complex (extrinsic tenase)Factor IXaFactor VIIIa and its von Willebrand factor carrierActivated platelet phospholipid surface
  5. Factor XaFactor VaProthrombin (factor II)
  6. Thrombin (factor IIa)
  7. Protein C, protein S and thrombomodulinAntithrombin
  8. Inherited and acquired thrombophilia

Detail

Commonest
Factor V Leiden (about 5% of Europeans heterozygous) and prothrombin G20210A (about 2%)
Most thrombogenic
Antithrombin deficiency, then protein C and protein S deficiency; homozygous or compound defects are worse again
Acquired causes
Antiphospholipid syndrome, malignancy, nephrotic syndrome, myeloproliferative neoplasms with JAK2 V617F, paroxysmal nocturnal haemoglobinuria, pregnancy and the combined oral contraceptive pill
Testing pitfalls
Do not test during acute thrombosis, on warfarin (which lowers protein C and S) or on heparin (which lowers antithrombin); a lupus anticoagulant cannot be interpreted while a patient is on a DOAC

When it goes wrong

Antiphospholipid syndrome — a lupus anticoagulant, anticardiolipin or anti-beta-2-glycoprotein I antibody persisting on repeat testing at least 12 weeks apart

Arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia, with a paradoxically prolonged APTT that fails to correct on mixing; anticoagulate with warfarin rather than a DOAC, and use aspirin plus LMWH in pregnancy

Unprovoked venous thrombosis at an unusual site — cerebral, splanchnic, portal or hepatic vein

Look for a myeloproliferative neoplasm (JAK2 V617F) or paroxysmal nocturnal haemoglobinuria as well as inherited thrombophilia

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