ERBIL POLYTHECNIC UNIVERSITY

SORAN TECHNICAL INSITITUTE

MIDWIFERY DIPARTMENT

FIRST STAGE(M)
 (VITAMIN K)

Prepared by :Narmin Salh Muhammad

Supervisor :Rzgar Mahir

2019-2020

CONTENT

Abstract ..............................................................…….3

Definition and introduction……………....................3

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Source of vitamin k………………………………….4

Biochemistry ………………………………………...5

Medical uses ………………………………………....9

Toxicity ……………………………………………...11

Food source ………………………………………….11

ABSTRACT Vitamin K has important functions within the body, some of which are still
being discovered. Research has shown that vitamin K is an anticalcification, anticancer,
bone-forming and insulin-sensitising molecule. Recent data indicate that subclinical vitamin
K deficiency is not uncommon. Additionally, vitamin K antagonists such as warfarin may
cause detrimental side effects, which may partly be blunted through vitamin K
supplementation.

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Definition and introduction

Vitamin K is a group of fat-soluble vitamins necessary for the

synthesis of proteins needed for blood coagulation and calcium
binding in bones and other tissues. These proteins are modified
by vitamin K, which enables calcium ions to be binded. This is
essential to control bleeding and hemorrhage disorders occur
without vitamin K. The bones may also become weak and the
arteries and other tissues are susceptible to
calcification.Vitamin K is so named because its discovery was
first reported in a German journal, where it was referred to as
“Koagulations vitamin.Chemically, the vitamin K family is made up of 2-methyl-1
derivatives. There are two natural forms of vitamin K, that are vitamin K1 and vitamin K2.
Vitamin K1 is also called phylloquinone, phytomenadione, or phytonadione and is
synthesized in plants because it is involved in photosynthesis, particularly green, leafy
vegetables. Vitamin K2, the main form stored in animals, has a number of subtypes called
menaquinones, vitamin counterparts that are characterized by the different lengths of their
isoprenoid side chains. Bacteria in the large intestine can convert vitamin K1 to vitamin K2
as well as lengthen the isoprenoid side chains of vitamin K2 to give a range of homologous
vitamin K2. People are usually able to get their daily vitamin K requirement by a safe and
balanced diet and it's unusual to have a lack. In addition, all fat-soluble vitamins, such as
vitamins A, D, E and K, are retained in the fat tissues of the body and extracted at a much
slower rate than water-soluble vitamins. Also, there are three synthetic forms of vitamin K
(vitamins K3, K4, and K5), but in some studies vitamin K3 has shown toxic effects. Dietary
Comparison Intake, a 25-year-old man needs 120 micrograms of vitamin K intake per day.
The volume is 90 micrograms / day for a woman; 10–20 micrograms / day for infants and for
children and teens. The daily demand is 15–100 micrograms per day. Although an allergic
reaction to supplementation with vitamin K may occur, there is no known risk of toxic effects
of vitamin K1 or vitamin K2, and therefore no tolerable upper intake limit has been
established.

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 Figure(1): Chemical Structure of Vitamin K

Sources of Vitamin K

Vitamin K is a group of fat-soluble vitamins involved in the synthesis of proteins required to

coagulate the blood and to bind calcium in bones and other tissues. Chemically, the vitamin
K family is made up of 2-methyl-1 derivatives. Vitamin K has two natural forms, namely
Vitamin K1 and Vitamin K2. Also called phylloquinone, phytomenadione or phytonadione,
vitamin K1 is synthesized in plants, particularly green, leafy vegetables, because it is
involved in photosynthesis. Also, vitamin K1 is abundant in various fruits such as avocado
and kiwi and some herbs contain very high amounts of vitamin K.For example , it is known
that two tablespoons of parsley contain more than 150 per cent of the recommended daily
vitamin K level. Vitamin K2, which is the main form stored in animals, has a variety of
subtypes called menaquinones, vitamin homologues that are distinguished by the varying
lengths of their side chains with isoprenoids. Bacteria in the large intestine can convert
vitamin K1 into vitamin K2, as well as lengthen the vitamin K2 side chains of isoprenoids to
give a range of vitamin K2 counterparts.

There are also three synthetic forms of vitamin K, which are K3, K4, and K5, although some
studies have shown toxic effects of vitamin K3.

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 Figure (2): types and source of vitamin k

Biochemistry

1- Function in animals

The function of vitamin K2 in the animal cell is to add a functional group of carboxylic acid
to a residue of glutamate (Glu) amino acid in a protein, and to form a residue of gamma-
carboxyglutamate (Gla). This is a somewhat uncommon posttranslational protein
modification, then known as a "Gla protein." The presence of two −COOH (carboxylic acid)
groups on the same carbon in the gamma-carboxyglutamate residue helps it to chelate
calcium ions. The binding of calcium ions in this way very often triggers the function or
binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors
discussed below. Within the cell, vitamin K undergoes electron reduction to a reduced form
called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase
(VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow Glu to carboxylate
to Gla; this enzyme is called gamma-glutamyl carboxylase or carboxylase dependent on
vitamin K. The carboxylation reaction only occurs if at the same time the carboxylase
enzyme is capable of oxidizing vitamin K hydroquinone to the vitamin K epoxide. It is said
to be combined with the carboxylation and epoxidation reactions. Then VKOR reconverts

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vitamin K epoxide to vitamin K. The vitamin K cycle is known as the reduction and
subsequent reoxidation of vitamin K coupled with Glu carboxylation. People rarely have a
vitamin K deficiency because vitamin K2 is stored continuously in cells in part.

Fıgure (3): Mechanism of action of vitamin K1

2- Gamma-carboxyglutamate proteins

The following human Gla-containing proteins ("Gla Proteins") were characterized to the
primary structure level: blood coagulation factors II (prothrombin), VII, IX , and X,
anticoagulant protein C, and protein S, and factor X-targeting protein Z. The osteocalcin
bone Gla protein, the calcification-inhibiting matrix Gla protein (MGP), the growth-
regulating cell growth arrest specific gene 6 protein (Gas6), and the four transmembrane
Gla proteins (TMGPs), whose function is currently unknown. Gas6 can function as a
growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation
or prevent apoptosis in some cells.Gas6 can function as a growth factor to activate the
Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some
cells. In all cases in which their function was known, the presence of the Gla residues in
these proteins turned out to be essential for functional activity. Gas6 can function as a
growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation
or prevent apoptosis in some cells. The presence of the Gla residues in these proteins
turned out to be important for functional activity in all cases in which their function was
identified. In a wide range of vertebrates, gla proteins are known to occur: mammals ,
birds, reptiles, and fish. A number of Australian snakes' venom acts by activating the
human blood coagulation system. In certain cases, snake Gla activates enzymes that bind

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to the endothelium of human blood vessels and catalyze the conversion of procoagulant
clotting factors into activated ones, which leads to unwanted and potentially deadly
coagulation.

The fish-hunting snail Conus geographus is synthesized with another important class of
invertebrate Gla-containing proteins. These snails produce a venom that contains
hundreds of neuroactive peptides, or conotoxins, that are toxic enough to destroy an adult
person. Several of the conotoxins contain two to five Gla residues.

Figure(4): Gamma-carboxyglutamate proteins

3- Methods of assessment

An rise in prothrombin time, a coagulation assay, has been used as a vitamin K status
indicator but this test lacks adequate sensitivity and specificity. The most widely used
marker of the vitamin K level is serum phylloquinone (K1). Concentrations of < 0.15 μg /
L show a deficiency. Disadvantages include exclusion of other vitamin K vitamins and
interference from recent dietary intake. Gamma-carboxylation of unique glutamic acid
residues within the Gla domain of the 17 vitamin K-dependent proteins (VKDPs) is
necessary for vitamin KThus, an increase in uncarboxylated VKDPs is an indirect, but
responsive, and precise marker for vitamin K deficiency. If uncarboxylated prothrombin
is assessed, this "Protein Caused by Vitamin K Absence / antagonism (PIVKA-II)" is
elevated to vitamin K deficiency. The test is used to determine the risk of deficient

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bleeding from vitamin K in newborn infants. Osteocalcin is a VKDP involved in bone
tissue calcification. The ratio of uncarboxylated osteocalcin to carboxylated osteocalcin
(ucOC / OC) increases with vitamin K deficiency. Vitamin K2 has been shown to
decrease ucOC / OC and increase bone mineral density of the lumbar vertabrae. Matrix
Gla Protein (MGP) is another VKDP. MGP needs to undergo vitamin K dependent
phosphorylation and carboxylation to become biologically active. High plasma
concentration of uncarboxylated, dephosphorylated MGP (dp-ucMGP) is indicative of
vitamin K deficiency. It associates elevated dp-ucMGP with vascular calcification. Meta-
analysis has shown that elevated dp-ucMGP was associated with increased risk of all-
cause death and cardiovascular mortality in adults.

Figure (5):types of Assessment Methods

4- Function in bacteria

Many bacteria found in the large intestine such as Escherichia coli can synthesize vitamin
K2 (MK-7 up to MK-11), but not vitamin K1 (phylloquinone). In these bacteria,
menaquinone transfers two electrons between two separate small molecules during
oxygen-independent processes of metabolic energy production (anaerobic respiration).
For example, a small molecule with an excess of electrons (also known as an electron
donor) such as lactate, format or NADH transfers two electrons to menaquinone with the
aid of an enzyme. Then, with the help of another enzyme, the menaquinone transfers
these two electrons to an appropriate oxidant, such as fumarate or nitrate (also called an

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acceptor of electrons). Using two electrons to fumarate or nitrate transforms the molecule
to succinate or nitrite plus water , respectively. Both of these reactions produce a cellular
energy supply, ATP, in a manner similar to eukaryotic cell aerobic respiration, but the
final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic
respiration the final oxidant is molecular oxygen (O2), which accepts four electrons to be
converted into water from an electron donor such as NADH. E. Coli can conduct both
aerobic respiration and menaquinone-mediated anaerobic respiration as facultative
anaerobes.

Medical uses

Vitamin K is also part of the recommended treatment plan for

poisoning by rodenticide (coumarin poisoning). Treatment with
vitamin K may only be appropriate in persons who have
intentionally ingested significant quantities of rodenticide or
ingested an uncertain amount of rodenticide. Patients are given oral
vitamin K1 to prevent the negative effects of rodenticide
poisoning, and in cases of poisoning with "superwarfarin" rodenticides such as
brodifacoum, this dosing must sometimes be continued for up to nine months. Oral
vitamin K1 is compared to other routes of administration of vitamin K1, since it has less
side effects.

1- Treating newborns

Vitamin K is administered to newborns as an injection to prevent bleeding with a vitamin

K deficiency (VKDB). Newborn babies 'blood clotting factors are around 30–60 percent
those of adult values; this may be attributed to the decreased production of precursor
proteins and their guts' sterility, i.e., lack of intestinal bacteria to synthesize vitamin K.
The incidence of vitamin K bleeding deficiency is estimated at 0.25–1.7 percent in the
first week of the infant's life, with a frequency of 2–10 cases per 100,000 births. Human
milk contains 1–4 μg / L of vitamin K1, while the formula for infants can contain up to
100 μg / L. Late start VKDB may be the product of exclusive breast feeding, Especially
when the treatment was not preventive. In infants who had not obtained prophylaxis at
birth, the median incidence of late onset VKDB was 35 cases per 100,000 live births.

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Bleeding can be severe in infants due to a vitamin K deficiency, resulting in
hospitalization, brain damage and death. Intramuscular injection, typically given shortly
after birth, is more effective in preventing bleeding with a vitamin K deficiency than oral
administration, which requires up to three months of age for weekly dosing.

2- Managing warfarin therapy

The effective anticoagulant action of the anticoagulant drug warfarin is a function of the
intake of vitamin K and the dosage of the drug, and must be individualized for each
patient because of different absorption. Vitamin K is a treatment for the symptoms of
bleeding caused by drug overdose. The vitamin may be supplied by mouth, intravenously
or by subcutaneous administration. Oral vitamin K is used in situations where the
International Standardized Ratio (INR) of a person is greater than 10 but the active
bleeding is not present. The newer apixaban, dabigatran, and rivaroxaban anticoagulants
are not antagonists of vitamin K.

3- Treating coumarin (rodenticide) poisoning

In the pharmaceutical industry coumarin is used as a precursor reagent in the synthesis of

a variety of pharmaceutical synthetic anticoagulants. One type, 4-hydroxycoumarins, acts
as antagonists of vitamin K. They block vitamin K from regeneration and recycling.
Some of the chemicals class of anticoagulant 4-hydroxycoumarin are designed to have
high potency and long residence times in the body, and these are specifically used as
rodenticides of second generation ("rat poison"). Death occurs several days to two weeks
later, usually from internal hemorrhaging. For humans, except for animals that have either
eaten rodenticide or rodenticide-poisoned rodents, Treatment requires repeated
administration of vitamin K in significant quantities.

4- Side effects

No known toxicity is associated with high doses of phylloquinone (vitamin K1) or

menaquinone (vitamin K2) types of vitamin K, so no tolerable upper intake (UL) levels
were set. However, when administered intravenously as opposed to orally, vitamin K1
was associated with serious adverse reactions such as bronchospasm and heart arrest.

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 Studies of blood clotting (coagulation) in humans using 45 mg of vitamin K2 (as MK-4)
per day and up to 135 mg of K2 (as MK-4) per day (45 mg three times a day) showed no
rise in the risk of blood clots. A synthetic form of vitamin K, vitamin K3 (menadione), is
demonstrably toxic at high doses, unlike the healthy natural forms of vitamin K1 and
vitamin K2 and its various isomers. The U.S. FDA has banned this form from over-the-
counter sales in the U.S. because it has been shown that high doses cause allergic
reactions, hemolytic anemia and cytotoxicity in liver cells.

Toxicity

Although no adverse effects have been observed from the ingestion of vitamin K from natural
sources, overdose of this vitamin through supplements may exhibit allergic reaction. As it
actively participates in reversing the effects of antibiotics or blood thinners, over-
consumption of vitamin K supplements can interfere with the effects of those medicines that
are taken by individuals to prevent blood clotting in the blood supplying arteries to the heart
or brain. Vitamin K's Recommended Dietary Intake (RDA) is 55 mcg per day for both men
and women aged 19 and over. Anything above the prescribed dosage can cause toxicity, such
as reduced appetite, increased liver, trouble breathing , muscle weakness, paleness and body
swelling.

Therefore, it is often strongly recommended to increase your body's vitamin K levels by

natural dietary choices and consume the supplements only after careful consultation with
your doctor or doctor.

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 Figure (6): toxicity and adverse effect of vitamin k

Food Sources

The adequate number of dietary sources that Mother Nature offers is sufficient to satisfy
one's K vitamin requirement. Vitamin K1 is commonly present in most greeneries while most
foodstuffs dependent on animals are rich sources of vitamin K2.

The food sources that are loaded with vitamin K are given
below:

Green Vegetables:

Kale, spinach, green turnip, parsley, lettuce,

cauliflower, broccoli, cabbage, brussels etc.

Kale, spinach, parsley, lettuce, cauliflower, broccoli ,

cabbage, brussels and so on.

Fruits:

Kiwi, Blueberry, Avocado etc.

The Sources of Dairy:

From cheese to milk and yogurt.

Such Other Sources:

Fermented dishes such as natto, miso, sauerkraut, eggs and meat.

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Reference:

1-  "The discovery of vitamin K, its biological functions and therapeutical application" (PDF). Nobel

Prize Laureate Lecture.
2- Bentley R, Meganathan R (September 1982). "Biosynthesis of vitamin K (menaquinone) in
bacteria". Microbiological Reviews.
3- Hafizi S, Dahlbäck B (December 2006). "Gas6 and protein S. Vitamin K-dependent ligands for the
Axl receptor tyrosine kinase subfamily". The FEBS Journal. 
4-  Stenflo J, Fernlund P, Egan W, Roepstorff P (July 1974).  "Vitamin K dependent modifications of
glutamic acid residues in prothrombin
5- Maresz K (February 2015). "Proper Calcium Use: Vitamin K  as a Promoter of Bone and
2

Cardiovascular Health". Integrative Medicine.

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