Coagulation - Activated protein C resistance

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Coagulation

Hereditary thrombophilia / hypercoagulopathies

Activated protein C resistance

Reviewer: Jeremy Parsons, M.D. (see Reviewers page)
Revised: 16 June 2012, last major update June 2012
Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.

General
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● 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

Diagrams
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Protein C pathway

Additional references
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● J Am Board Fam Pract 2000;13:111, Semin Vasc Med 2003;3:33, Kolde, Hans-Jurgen (2004). Haemostasis. Basel, Switzerland: Pentapharm Ltd

Factor V Leiden mutations

General
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● 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, are Factor V Cambridge (Arg306Thr), Factor V Hong Kong (Arg306Gly), HR2 haplotype with mutation 4070A to G (His199Arg) in exon 13 of Factor V gene (associated with other polymorphisms)

Testing recommended if venous thromboemboli occur with these features
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● 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
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● 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

Treatment
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● Treat venous thromboemboli similarly regardless of the presence of factor V Leiden

Case reports
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● 51 year old woman with heterozygous factor V Leiden and dural sinus thrombosis (Arch Pathol Lab Med 2003;127:1359)

Additional references
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● Arch Pathol Lab Med 2002;126:577, Goodnight Jr, Scott & Hathaway, William (Eds) (2001) Disorders of hemostasis & thrombosis: A clinical guide: McGraw-Hill.

End of Coagulation > Hereditary thrombophilia / hypercoagulopathies > Activated protein C resistance

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