Vitamin K & Coagulation

1. Vitamin K & Coagulation Ahmad Shihada Silmi Msc, FIBMS IUG Medical Technology Dept

2. What is Vitamin K? • Fat soluble compound • Necessary for the synthesis of several proteins required for blood clotting • Vit K 1 (Phylloquinone)- natural form- found in plants- provides the primary source of vitamin K to humans through dietary consumption 2) Vitamin K2 compounds (Menaquinones)- made by bacteria in the human gut- provide a smaller amount of the human vitamin K requirement Vitamin K2

3. Dietary Sources Vitamin K is consumed primarily from green leafy vegetables and some fruits. It may also be found in dairy products, meats and eggs.

4. Physiological Effects of Vitamin K • Vitamin K serves as an essential cofactor for a carboxylase that catalyzes carboxylation of glutamic acid residues on vitamin K-dependent proteins. These proteins are involved in: 1) Coagulation2) Bone Mineralization3) Cell growth

6. Coagulation • The transformation of liquid blood into a solid gel • Stops blood flow in the damaged area • Involves a cascade of activation of plasma proteins • These proteins are produced in the liver • Fibrin is the final protein which produces a meshwork to trap RBC and other cells

7. Vitamin K Dependent Coagulation • Certain clotting factors/proteins require calcium to bind for activation • Calcium can only bind after gamma carboxylation of specific glutamic acid (Glu) residues in these proteins • Glu --> Gla modification needed for Ca2+ binding, clot formation • Vitamin K acts as a cofactor for this carboxylation reaction • The role of vitamin K in the carboxylation of specific proteins is a cyclic process called “Vitamin K Cycle” • These proteins are known as “Vitamin K dependent” proteins

8. Vitamin K Dependent Proteins • factor II (prothrombin) • factor VII (proconvertin) • factor IX (thromboplastin component) • factor X (Stuart factor) • protein C & protein S • Protein Z

9. Clotting Cascade

10. PIVKA • Deficiency of vitamin K is associated with a decrease of the functional activity of these factors. • These non-functional proteins are released into the circulation in normal levels & are called Protein Induced by Vitamin K Absence or Antagonism ( PIVKA).

11. PIVKA Properties • Can not bind Calcium ions. • Are not adsorbed on aluminum hydroxide & barium salts. • Can be activated in vitro with venom of certain snakes (Echis Carinatus). • This Ecarin characteristic is the basis of their laboratory measurement.

13. Vitamin K Cycle Vitamin KH2 Glutamic Acid Reductase Vitamin K Vitamin K Dependent Carboxylase Warfarin Inhibits Epoxide Reductase Gamma Carboxy Glutamic Acid Vitamin K Epoxide

19. Warfarin is a competitive antagonist of Vitamin K Scully, M. The Biochemist, 2002

20. WARFARIN: MECHANISM OF ACTION

21. Warfarin CYP2C9 Epoxide Reductase Inactivation Pharmacokinetic  -Carboxylase (GGCX) Warfarin inhibits the vitamin K cycle Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z)

23. INDICATIONS • Prophylaxis and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) • Prophylaxis and treatment of Atrial fibrillation • Valvular stenosis • Heart valve replacement • Myocardial infarction

24. WHY TO MONITOR WARFARIN THERAPY? • Narrow therapeutic range • Can increase risk of bleeding

25. MONITORING OF WARFARIN THERAPY • Prothrombin time • PT ratio • INR (International Normalized Ratio)

26. PROTHROMBIN TIME (PT) • Time required for blood to coagulate is called PT • Performed by adding a mixture of calcium and thromboplastin to citrated plasma • As a control, a normal blood sample is tested continuously • PT ratio (PTR) = Patient’s PT Control PT

27. FACTORS INFLUENCING DOSE RESPONSE • Inaccurate lab testing • Poor patient compliance • Concomitant medications • Levels of dietary vitamin K • Alcohol • Hepatic dysfunction • Fever

28. DURATION OF THERAPY • Venous thromboembolism: Minimum 3 months, usually 6 months • AMI: During initial 10-14 days of hospitalization or until patient is ambulatory • Mitral valve disease/Mechanical heart valves: Lifelong • Bioprosthetic heart valves: 3 months • Atrial fibrillation: Lifelong • Prevention of cerebral embolism: 3-6 months

29. CONTARINDICATIONS AND PRECAUTIONS • Hypersensitivity to warfarin • Condition with risk of hemorrhage • Hemorrhagic tendency • Inadequate laboratory techniques • Protein C & S deficiency • Vitamin K deficiency • Intramuscular injections

30. SIDE EFFECTS • Hemorrhage • Skin necrosis • Purple toe syndrome • Microembolization • Teratogenecity Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.

31. SWITCHOVER FROM ONE BRAND OF WARFARIN TO ANOTHER/ ACENOCOUMAROL • Check patient’s INR • Start with dose of 2 mg; increase dose slowly as required

32. Vitamin K Deficiency Results in impaired blood clotting and, potentially, bleeding. Vitamin K deficiency can result from: • a lack of vitamin k in the diet • disorders that reduce fat absorption • Taking certain drugs, including anticonvulsants and some antibiotics • Use of coumarin anticoagulants

33. Symptoms of Vitamin K Deficiency • Bruising from bleeding into the skin • Nosebleeds • Bleeding gums • Bleeding in stomach • Blood in urine • Blood in stool • Tarry black stool • Extremely heavy menstrual bleeding • In infants, may result in intracranial hemorrhage

34. Vitamin K Deficiency in Infants Newborns are prone to vitamin K deficiency because… • Vitamin K and lipids are not easily transported across the placental barrier • Prothrombin synthesis in the liver is an immature process in newborns, especially when premature. • The neonatal gut is sterile, lacking the bacteria that is necessary in menaquinone synthesis. • Breast milk is not a good source of vitamin K Results in a hemorrhagic disease called vitamin K deficiency bleeding (VKDB) This disease is associated with breastfeeding, maladsorption of lipids, or liver disorders.

35. Adequate Intake for Vitamin K As outlined by the Food and Nutrition Board (FNB) of the Institute of Medicine in the US (January 2001)

36. Prevention/Treatment • Vitamin K can be given orally • In the case of someone who improperly absorbs fat or is at high risk of bleeding, Vitamin K can be injected under the skin • If a drug is causing Vitamin K deficiency, the dose is altered or extra Vitamin K is given • In people who suffer from both severe liver disorders and Vitamin K deficiency, Vitamin K injections may be insufficient so blood transfusions may be necessary to replenish clotting factors • It is recommended that all newborns are given an injection of phylloquinone (Vitamin K1) into the muscle to prevent intracranial bleeding after delivery • Formulas for infants contain Vitamin K

37. Quiz Time! Where are two ways we get Vitamin K? Name a good source of dietary Vitamin K What type of chemical reaction does Vitamin K assist in? Which anticoagulant inhibits Vitamin K? Name a sign of Vitamin K deficiency.

38. Summary • Vitamin K is a fat soluble compound necessary for the synthesis of several proteins involved in blood clotting • It acts as a cofactor for a carboxylation reaction • A deficiency in Vitamin K results in impaired blood clotting and possibly bleeding • The anticoagulant Warfarin inhibits Vitamin K • Vitamin K can be given orally or through injection for prevention/treatment of deficiency

39. Thank you! 

40. References • Bowen, R. (1999). Vitamin K. Hypertext of Biomedical Sciences. Colorado State University. Accessed January 12, 2009 http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamink.html • Higdon, J. (2004). Vitamin K. Linus Pauling Institude, Micronutrient Information Centre. Oregon State University. Accessed January 12, 2009 http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/ • Johnson, L.E. (2007). Vitamin K. Merck Online Medical Library. Accessed January 12 2009 http://www.merck.com/mmhe/sec12/ch154/ch154l.html • Stanfield, C.L & Germann, W.J. (2007). Principles of Human Physiology 3rd Edition. p. 446-448. • Vitamin K. (2008). Medline Plus. U.S. National Library of Medicine. Accessed January 12, 2009 http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html • Vitamin K. (2005). Merck Online Medical Library. Accessed January 12 2009 http://www.merck.com/mmpe/sec01/ch004/ch004n.html Images taken from • http://chemistry.about.com/library/graphics/blvitamink1.htm • http://media-2.web.britannica.com/eb-media/28/98328-004-5514AFAC.jpg • http://www.frca.co.uk/images/clotting_cascade.gif