Vitamin K- An overview

Professor (Dr. )Namrata Chhabra
27-Jan-18 1Biochemistry for medics- Lecture Notes- Namrata Chhabra

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
27-Jan-18 Biochemistry for medics- Lecture Notes- Namrata Chhabra 2

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")

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;
 and Menadione and menadiol diacetate, synthetic compounds that can
be metabolized to phylloquinone.

Vitamin K-Chemistry
27-Jan-18 5
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

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

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).

Conditions causing impaired absorption of
vitamin K
 Fat malabsorption
is associated with
impaired
absorption of
vitamin K and
other fat soluble
vitamins.

Impaired absorption of vitamin K
Absorption of
vitamin K may also
be decreased by
mineral oil, bile
acid sequestrants
(Cholestyramine,
Colestipol) and
Orlistat (weight
loss medication).

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)

Functions of Vitamin K
Coagulation
Bone Synthesis
Prevention of
atherosclerosis

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.
Glutamic acid

Vitamin K-dependent gamma-carboxylation
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).

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.

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.

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 the vitamin 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.

Vitamin K cycle
 Reduced lipoamide is required for the activity of
Epoxide reductase and NADPH is needed for the
action of vitamin K reductase.

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.

Role of vitamin K in blood coagulation

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

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 laboratory measurement of how long it takes
blood to form a clot) is used to determine the effects of oral
anticoagulants on the clotting system.
 In healthy people an INR of 1.1 or below is considered normal. An INR
range of 2.0 to 3.0 is generally an effective therapeutic range for people
taking warfarin.

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.
 Osteocalcin is a protein synthesized by osteoblasts.
 The synthesis of osteocalcin by osteoblasts is regulated by the active
form of vitamin D, 1,25(OH)2D3 or calcitriol.
 The mineral-binding capacity of osteocalcin requires vitamin K-
dependent gamma-carboxylation of three glutamic acid residues.

Synthesis of Bone Calcium-Binding Proteins
After gamma carboxylation
osteocalcein binds tightly to
calcium.
Treatment of pregnant women with Warfarin can lead
to fetal bone abnormalities (Fetal Warfarin syndrome)

Synthesis of Bone Calcium-Binding Proteins
 Matrix Gla protein- MGP has 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.

Vitamin K deficiency
Vitamin K
deficiency
Dietary
deficiency
Fat
malabsorption
Surgical
interventions
of intestine
Chronic liver
diseases
Prolonged
intake of
antibiotics

Vitamin K deficiency in the newborn
Maternal
medication
Anticonvuls
ants
Antibiotics
Antitubercul
ar drugs
Vitamin K
antagonists
Newborn
Vitamin K
deficiency
Maternal
medication
Inadequate
placental
transfer
Limited
storage in
liver
Inadequate
availability in
breast milk

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.

Hallmarks of vitamin K deficiency
Weak
bones

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

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.

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.

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.

Treatment
A vitamin K injection in the muscle is
recommended for all newborns to
reduce the risk of bleeding within the
brain after delivery.

Toxicity
 Toxicity from dietary phylloquinone and menaquinones has not
been described.
 High doses of vitamin K can impair the actions of oral
anticoagulants.

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.

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/

Thank you

Vitamin K- An overview

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