Vitamin K

History

  • Warfarin/coumadin has historically been used in rodenticides -> induces lethal hemorrhage
    • Some of the newer rodenticides contain such long-acting vitamin K antagonists that they not only kill the rodent, but they can also kill dogs/cats that may eat them

Sources of Vitamin K

  • Bacterial Synthesis of Vitamin K in Colon: represents the major source of vitamin K
  • Dietary Vitamin K: decreased dietary vitamin K has a minimal impact on vitamin K stores (since most vitamin K is obtained from colonic bacterial sources)
    • Average daily vitamin K intake (in USA): 100 ug/day
    • Ileum is the major site of vitamin K absorption: hepatically-synthesized bile acids are secreted into the small intestine, where they are required for fat absorption (vitamin K is a fat soluble vitamin)
    • Food Sources
      • Cauliflower
      • Green, Leafy Vegetables: kale, spinach
      • Liver
      • Margarine
      • Vegetable Oils: olive, canola, soybean

Physiology

  • Forms of Vitamin K: phylloquinone can be converted to menaquinone in some organs
    • Phylloquinone (Vitamin K1): natural form found in animal and vegetable sources
    • Menaquinone (Vitamin K2): natural form synthesized by intestinal bacterial flora, found in hepatic tissues
    • Menadione (Vitamin K3): synthetic, water-soluble form
  • Function: vitamin K is required for the post-translational carboxylation of glutamic acid (via vitamin K epoxide reductase) in the vitamin K-dependent clotting factors (factor II/prothombin, factor VII, factor IX, and factor X), the vitamin K-dependent anticoagulant factors (protein C, protein S, and protein Z), select bone proteins (osteocalcin, matrix-Gla protein), and some ribosomal proteins
    • Gamma carboxyglutamic acid is necessary to allow the protein to bind to membranes: gamma carboxyglutamic acid chelates positively-charged calcium, allowing binding to the negatively-charged phosphate head groups of membrane phospholipids)
    • Gamma carboxyglutamic acid assists in forming the necessary structure of such proteins by forming calcium-mediated intrachain interactions that link two gamma-carboxyglutamic acids to a calcium ion

Etiology of Vitamin K Deficiency

  • Inadequate Dietary Vitamin K Intake
    • Alcoholism (see Ethanol)
    • Long-Term Total Parenteral Nutrition (TPN)
    • Malnutrition
  • Intestinal Vitamin K Malabsorption
    • Ascaris (see Ascariasis)
    • Bacterial Overgrowth
    • Biliary Disease: due to impaired bile acid secretion into small intestine
      • Cholestasis
      • Common Bile Duct Obstruction (Cholangiocarcinoma, Biliary Stone, Biliary Stricture, etc)
      • Primary Biliary Cirrhosis
      • T-Tube Drainage
    • Celiac Disease (see Celiac Disease)
    • Cholestyramine (see Cholestyramine): binds to bile acids
    • Chronic Pancreatitis (see Chronic Pancreatitis)
    • Crohn’s Disease (see Crohn’s Disease)
    • Short Gut Syndrome: from multiple prior bowel resections
    • Tropical Sprue
    • Ulcerative Colitis (see Ulcerative Colitis)
  • Loss of Vitamin K Storage Sites
  • Drugs: mechanism of vitamin K deficiency from these agents is unknown
  • Other

Etiology of Vitamin K Antagonism

  • Coumadin (see Coumadin): inhibits the hepatic gamma carboxylation of glutamic acid
  • Coumadin-Containing Herbs
    • Chamomile (Matricaria recutita, Chamaemelum mobile) (see Chamomile)
    • Fenugreek (Trigonella foenum-graecum) (see Fenugreek)
    • Horse Chestnut (Aesculus hippocastanum)
    • Motherworth (Leonurus cardiaca)
    • Red Clover (Trifolium pratense)
  • High-Dose Vitamin E (see Vitamin E)

Diagnosis/Clinical

  • Prolonged INR: vitamin K-dependent clotting factor activity is more reflected in the PT/INR than in the PTT
  • Factor II/VII/IX/X Levels: decreased
    • If factor V is also low, as well, this suggests a defect in hepatic synthetic function and cannot be attributed to vitamin K deficiency alone
  • Increased Risk of Fractures/Osteoporosis: due to role of vitamin K in the synthesis of bone proteins, such as osteocalcin
  • Hemorrhagic Disease of the Newborn
    • Early Onset: intracranial and retroperitoneal bleeding (occurring at 1-7 days postpartum)
    • Late Onset (occuring as late as 3 months postpartum)
    • To prevent this in newborns (who have minimal hepatic stores of vitamin K at birth), vitamin K is given prophylactically soon after birth

Treatment

  • Oral Vitamin Vitamin K1 (Phytonadione): 5-10 mg /day
    • Excellent absorption
    • Expected improvement in INR within 1 day
  • Subcutaneous Vitamin K
    • Absorption is erratic
  • Intravenous Vitamin K1 (Phytonadione): 1 mg/day
    • Faster normalization of INR than PO dosing
    • Side Effects: anaphylaxis

References

  • Vitamin K and energy transduction: a base strength amplification mechanism. Science 269:1684, 1995
  • Lancet 345:229, 1995