Hereditary thrombophilia / hypercoagulopathies

Activated protein C resistance / Factor V Leiden

Last author update: 1 June 2012
Last staff update: 10 September 2020

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PubMed Search: Activated protein C resistance / Factor V Leiden

Jeremy C. Parsons, M.D.
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Cite this page: Parsons JC. Activated protein C resistance / Factor V Leiden. website. Accessed February 23rd, 2024.
Definition / general
  • Most common hereditary predisposition to venous thrombosis (20% of first episodes of thrombosis, 50% of familial thrombosis)
  • Normally, activated protein C degrades activated factors V and VIII by cleaving specific arginine residues
  • Almost all patients with activated protein C resistance have Factor V Leiden mutation that causes resistance to degradation by activated protein C
  • Approximately 64% of people with venous thrombosis have activated protein C deficiency
  • Does not appear to reduce life expectancy
  • Acquired forms of activated protein C deficiency can lead to elevated factor VIII levels
  • Factor V Leiden mutations:
    • 95% with activated protein C resistance have point mutation at an arginine cleavage site (Arg506Gln, 1691 G to A) called R506Q or Factor V Leiden
    • Mutation causes delayed inactivation by activated protein C, prolonging its life span and procoagulant activity
    • 3 - 5% frequency in heterozygous form in general white population
    • Rare in African blacks and Asians
    • Heterozygotes have 5 - 10x increased risk for venous thrombosis
    • Homozygotes have 80x increased risk for venous thrombosis; risk occurs later in life
    • Homozygosity or heterozygosity without symptoms may not require treatment
    • Presence of second risk factor (genetic or acquired) is often necessary to produce thrombosis
    • Acquired risk factors are smoking, malignancy, trauma, surgery, oral contraceptive use, estrogen replacement therapy, antiphospholipid antibody, heterozygosity for prothrombin G20210A, elevated serum homocysteine

  • Other low frequency factor V mutations, which have unclear association with venous thrombosis:
    • Factor V Hong Kong (Arg306Gly)
    • HR2 haplotype with mutation 4070A to G (His199Arg) in exon 13 of Factor V gene (associated with other polymorphisms)
Diagrams / tables

Images hosted on other servers:

Protein C pathway

  • Testing recommended if venous thromboemboli occur with these features:
    • Recurrent
    • Before age 50 years
    • Unprovoked at any age
    • At unusual anatomic sites (cerebral, mesenteric, portal or hepatic veins)
    • In patient with first degree relative with venous thromboemboli before age 50 years
    • Related to pregnancy or estrogen use or unexplained pregnancy loss in second or third trimesters
    • May be recommended in family members (with family history), female family members who are pregnant or considering oral contraceptives

  • Testing NOT recommended:
    • General population screen
    • Routine test during pregnancy
    • Routine test before or during oral contraceptive use or hormone replacement therapy in patients without a family history of thrombosis
    • As newborn initial test
    • As initial test in patients with arterial thrombotic events

Case reports
  • Treat venous thromboemboli similarly regardless of the presence of factor V Leiden
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