Vitamin K- An overview

Vitamin K- chemistry, metabolism, deficiency and vitamin K antagonists

1. Professor (Dr. )Namrata Chhabra
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Biochemistry for medics-Lecture Notes-Namrata Chhabra

2. Learning objectives
To understand:
1)Chemistry, and metabolism of vitamin K
2)Biological significance,
3)Vitamin K deficiency -Causes, and clinical implications
4)Mechanism of action of vitamin K antagonists
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3. Vitamin K
Vitamin K represents a group of lipophilic and hydrophobic
vitamins.
Originally identified for its role in the process of blood clot
formation
("K" is derived from the German word "koagulation")
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4. Vitamin K-Family
Three compounds have the biological activity of vitamin K
Phylloquinone (Vitamin K1),the normal dietary source, found in green
vegetables
Menaquinones (vitamin K2),synthesized by intestinal bacteria, with
differing lengths of side chain;
andMenadioneand menadiol diacetate, synthetic compounds that can
be metabolized to phylloquinone.
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5. Vitamin K-Chemistry
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Phylloquinone have a 20 C side
chain ,
Menaquinones have a 30 C side
chain.
The synthetic vitamin K
(menadione, menadiol diacetate)
have only hydrogen in place of
isoprenoid side chain that makes
these vitamin water-soluble.
Naphthoquinone
ring
Isoprenoid side chain

6. Dietary Sources
Green leafy vegetables such as kale and spinach,
Margarine and liver.
Vegetable oils and particularly olive, canola, and soybean oils.
Some amount is contributed by intestinal bacteria
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7. Absorption, Transportation and
Storage
Absorption takes place in small intestine
in the presence of bile salts.
The transportation from intestine is
carried out through chylomicrons.
Storage occurs in liver and from liver
transportation to peripheral cells is
carried out bound with beta lipoproteins
(VLDL).
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8. Conditions causing impaired absorption of
vitamin K
Fat malabsorption
is associated with
impaired
absorption of
vitamin K and
other fat soluble
vitamins.
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9. Impaired absorption of vitamin K
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Absorption of
vitamin K may also
be decreased by
mineral oil, bile
acid sequestrants
(Cholestyramine,
Colestipol) and
Orlistat (weight
lossmedication).

10. Recommended daily allowance
(RDA)
The average daily allowance is 50-120
mcg/day.
Requirement increases in –
Liver disorders
Patients on prolonged antibiotic therapy,
bile acid sequestrants (Cholestyramine,
colestipol) and Orlistat (weight loss
medication)
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11. Functions of Vitamin K
Coagulation
Bone Synthesis
Prevention of
atherosclerosis
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12. Mechanism of action of vitamin K
Vitamin K has an important role in post-
translational modification of calcium binding
proteins
Vitamin K-dependent gamma-carboxylation occurs
only on specific glutamic acid residues in a small
number of vitamin K-dependent proteins, it is critical
to the calcium-binding function of those proteins.
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Glutamic acid

13. Vitamin K-dependent gamma-carboxylation
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Vitamin K acts as a
cofactor for Carboxylase
enzyme that catalyzes
the carboxylation
glutamic acid, resulting
in its conversion to
gamma-carboxy
glutamic acid (Gla).

14. 1) Role of vitamin K in coagulation
Factors II (prothrombin), VII, IX, and X make up the core of the
coagulation cascade.
These factors are synthesized in the liver in the inactive form.
They undergo post translational modifications, gamma carboxylation of
glutamic acid residues.
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15. Role of vitamin K in coagulation
Gamma carboxylation imparts another negative charge to promote the
effective binding of these factors/proteins to calcium ions.
γ-Carboxyglutamates by chelating calcium ions, therefore, permit the
binding of the blood clotting proteins to membranes.
Prothrombin and several other proteins of the blood clotting system
(Factors VII, IX, and X, and proteins C and S) each contain 4–6 γ-
carboxyglutamate residues.
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16. 27-Jan-18 16

17. Vitamin K cycle
Vitamin K is a fat-soluble vitamin, the body stores very little of it, and its
stores are rapidly depleted without regular dietary intake.
Because of its limited ability to store vitamin K, the body recycles it
through a process called thevitamin K cycle.
The vitamin K cycle allows a small amount of vitamin K to function in the
gamma-carboxylation of proteins many times, decreasing the dietary
requirement.
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18. Vitamin K cycle
Reduced lipoamide is required for the activity of
Epoxide reductase and NADPH is needed for the
action of vitamin K reductase.
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19. Vitamin K Antagonists
Dicumarol and Warfarin, inhibit coagulation through antagonism
of the action of vitamin K.
These are competitive inhibitor of Epoxide reductase.
By preventing recycling of vitamin K inhibiting two important
reactions , these drugs create a functional vitamin K deficiency
In the presence of Warfarin, vitamin K epoxides cannot be reduced,
they accumulate and are excreted.
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20. Role of vitamin K in blood coagulation
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21. Indications for using vitamin K antagonists
The main indications for a patient to receive vitamin K antagonists (VKAs)
are the following:
Mechanical Heart Valves
Atrial Fibrillation
Deep Vein Thrombosis and Pulmonary Embolism
Myocardial infarction
Acute Ischemic Stroke
The pathological formation of a blood clot, or thrombosis, poses significant
health risks in such patients
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22. Some facts about Vitamin K Antagonists
Large quantities of dietary or supplemental vitamin K can overcome the
anticoagulant effect of vitamin K antagonists
The major side effect of Warfarin is bleeding. INR (international
normalized ratio-a laboratorymeasurementof how long it takes
blood to form a clot) is used to determine the effects oforal
anticoagulantson the clotting system.
In healthy people an INR of 1.1 or below is considered normal. An INR
range of2.0 to 3.0is generally an effective therapeutic range for people
taking warfarin.
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23. 2) Synthesis of Bone
Vitamin K is also important in synthesis of two proteins that contain γ-
carboxyglutamate that are present in bone-osteocalcin and bone matrix
Gla protein.
Osteocalcinis a protein synthesized by osteoblasts.
The synthesis of osteocalcin by osteoblasts is regulated by the active
form of vitamin D, 1,25(OH)
2D
3or calcitriol.
The mineral-binding capacity of osteocalcin requires vitamin K-
dependent gamma-carboxylation of three glutamic acid residues.
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24. Synthesis of Bone Calcium-Binding Proteins
After gamma carboxylation
osteocalcein binds tightly to
calcium.
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Treatment of pregnant women with Warfarin can lead
to fetal bone abnormalities (Fetal Warfarin syndrome)

25. Synthesis of Bone Calcium-Binding Proteins
Matrix Gla protein-MGPhas been found in bone, cartilage, and soft
tissue, including blood vessels.MGP prevents the calcification of soft
tissues and cartilages,while facilitating normal bone growth and
development.
Protein S-The vitamin K-dependent anticoagulant protein S is also
synthesized by osteoblasts, but its role in bone metabolism is unclear.
Children with inherited protein S deficiency suffer complications related
to increased blood clotting as well as decreased bone density.
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26. Vitamin K deficiency
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Vitamin K
deficiency
Dietary
deficiency
Fat
malabsorption
Surgical
interventions
of intestine
Chronic liver
diseases
Prolonged
intake of
antibiotics

27. Vitamin K deficiencyin the newborn
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Maternal
medication
Anticonvuls
ants
Antibiotics
Antitubercul
ardrugs
Vitamin K
antagonists
Newborn
Vitamin K
deficiency
Maternal
medication
Inadequate
placental
transfer
Limited
storage in
liver
Inadequate
availability in
breast milk

28. Clinical Manifestations
The main symptom is bleeding (hemorrhage)—into the skin (causing
bruises), from the nose, from a wound, in the stomach, or in the intestine.
Blood may be seen in the urine or stool.
In newborns, life-threatening bleeding within or around the brain may
occur.
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29. Hallmarks of vitamin K deficiency
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Weak
bones

30. Laboratory Studies
A Prothrombin time (PT)
Activated partial Thromboplastin time (aPTT),
Fibrinogen levels, and
A platelet count can be included in the initial workup for
vitamin K deficiency bleeding (VKDB) in a newborn.
Full coagulation profile
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31. Laboratory Studies
A prolonged PT is usually the
first laboratory test result to be
abnormal in vitamin K
deficiency bleeding due to
reduction in Prothrombin, FVII,
FIX, and FX levels.
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32. Laboratory studies
Patients with liver disease may have an elevated prothrombin
time because of liver cell destruction as well as vitamin K
deficiency.
If an elevated prothrombin time does not improve on vitamin K
therapy, it can be deduced that it is not the result of vitamin K
deficiency.
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33. Treatment of vitamin K deficiency
For patients with chronic
malabsorption, 1–2 mg/d of vitamin K
should be given orally,
or 1–2 mg/week can be taken
parenterally.
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34. Treatment
A vitamin K injection in the muscle is
recommended for all newborns to
reduce the risk of bleeding within the
brain after delivery.
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35. Toxicity
Toxicity from dietary phylloquinone and menaquinones has not
been described.
High doses of vitamin K can impair the actions of oral
anticoagulants.
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36. Summary
Vitamin K is a fat soluble vitamin
Phylloquinone, Menaquinone and Menadione are the members of vitamin K
family
Vitamin K acts as a coenzyme for the gamma carboxylation of glutamic residues
of Calcium binding proteins
Plays an important role in blood clotting, bone formation and prevention of
calcification of soft tissues
Deficiency of vitamin K is manifested in the form of bleeding tendencies and
hemorrhages
Oral or injectable vitamin K can be recommended depending upon the severity
of the disease.
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37. Further reading
http://www.namrata.co/vitamin-k-chemistry-and-functions-part-1/
http://www.namrata.co/category/vitamins/theory-notes-vitamins/
http://www.namrata.co/vitamin-k-chemistry-functions-and-clinical-
significance-a-power-point-presentation-2/
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38. Thank you
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