Vitamin K cycle and gamma-carboxylation
Trigger · II, VII, IX, X Protein C and S VKORC1
Reduced vitamin K is the cofactor for gamma-glutamyl carboxylase, which adds a second carboxyl group to glutamate residues in the Gla domains of factors II, VII, IX and X and of proteins C, S and Z. Only carboxylated factors can chelate calcium and dock onto anionic phospholipid membranes. Vitamin K epoxide reductase (VKORC1) regenerates the reduced vitamin, and is the target of warfarin.
Detail
- Carboxylates
- Factors II, VII, IX and X plus proteins C, S and Z (mnemonic 1972: ten, nine, seven, two)
- Enzymes
- Gamma-glutamyl carboxylase, using reduced vitamin K, oxygen and CO2; VKORC1 regenerates vitamin K from the 2,3-epoxide
- Sources
- Phylloquinone (K1) from green leafy vegetables and menaquinone (K2) from gut flora; fat-soluble, so absorption needs bile salts and pancreatic lipase
- Half-lives
- Factor VII about 4-6 h (shortest, so the PT moves first), protein C about 8 h, factor IX about 24 h, factor X about 40-50 h, prothrombin about 60-72 h
- Reversal
- Vitamin K (intravenous effect over 6-12 h), prothrombin complex concentrate for immediate replacement, or fresh frozen plasma if PCC is unavailable
When it goes wrong
Vitamin K deficiency from fat malabsorption — obstructive jaundice, coeliac disease, cystic fibrosis, chronic cholestasis — or prolonged broad-spectrum antibiotics
PT/INR prolongs first because factor VII has the shortest half-life, then the APTT. It corrects with parenteral vitamin K, unlike the prolonged PT of hepatocellular failure, which does not
No prophylactic vitamin K at birth (poor placental transfer, low breast-milk content, sterile gut)
Vitamin K deficiency bleeding of the newborn, classically day 2-7 with umbilical, gastrointestinal or intracranial haemorrhage; prevented by 1 mg intramuscular vitamin K at delivery
Warfarin loaded without heparin cover in a patient with protein C deficiency
Warfarin-induced skin necrosis at day 3-5: protein C (half-life about 8 h) falls long before prothrombin (60-72 h), leaving a transient prothrombotic window with dermal microvascular thrombosis over breast, buttock and thigh
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