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Vitamin K- Chemistry functions and Clinical significance
1. By- Professor (Dr. )Namrata Chhabra
Biochemistry For Medics- Lecture notes
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Biochemistry for medics- Lecture Notes- Namrata
Chhabra
2. Vitamin K- Chemistry
Vitamin K represents a group of lipophilic and
hydrophobic vitamins.
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.
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Biochemistry for medics- Lecture Notes- Namrata
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4. Vitamin K- Chemistry
Vitamin K family are naphthoquinone derivatives .
Phylloquinone and menaquinones, both have a long
isoprenoid side chain.
The length of the side chain differs.
Phylloquinone have a 20 C side chain , whereas
menaquinones have a 30 C side chain.
The isoprenoid chain makes these vitamin hydrophobic or
lipophilic.
The synthetic vitamin K (menadione, menadiol diacetate)
have only hydrogen in place of isoprenoid side chain that
makes these vitamin water-soluble.
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Biochemistry for medics- Lecture Notes- Namrata
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5. Dietary Sources
Vitamin K is found in green leafy vegetables such as
kale and spinach, and
Appreciable amounts are also present in margarine
and liver.
Vitamin K is present in vegetable oils and is
particularly rich in 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 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.
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8. Impaired absorption of vitamin K
Fat malabsorption is associated with impaired
absorption of vitamin K and other fat soluble
vitamins.
Vitamin K is important for the coagulation process.
In its deficiency coagulation process is grossly
affected resulting in tendency for bleeding and
hemorrhages.
Absorption of vitamin K may also be decreased by
mineral oil, bile acid sequestrants (Cholestyramine,
Colestipol) and Orlistat (weight loss medication).
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9. Impaired absorption of vitamin K
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10. Recommended daily allowance
The average daily allowance is 50-100 mg/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
Carboxylation of Glutamate in post synthetic
modification of calcium binding proteins
The only known biological role of vitamin K is as a cofactor
for an enzyme (Carboxylase) that catalyzes the
carboxylation of the amino acid, glutamic acid, resulting in
its conversion to gamma-carboxy glutamic acid (Gla).
Although 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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13. Functions of vitamin K
Calcium binding proteins
Vitamin K–dependent proteins are a heterogeneous
group, including =
clotting factor proteins and proteins found in
bone
lung
kidney, and
placenta.
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14. 1) Role of vitamin K in coagulation
The ability to bind calcium ions (Ca2+) is acquired by the
activation of the vitamin K-dependent clotting factors, or
proteins, in the coagulation cascade.
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.
This process of gamma carboxylation of glutamic acid
residues imparts another negative charge, so as to promote
the effective binding of these factors/proteins to calcium
ions.
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16. 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.
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17. Vitamin K cycle
Reduced lipoamide is required for the activity of
Epoxide reductase whereas NADPH is needed for the
action of vitamin K reductase.
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18. Vitamin K cycle
Vitamin K hydroquinone (active form) is oxidized to
the Epoxide form during the process of enzymatic
reaction.
The initial form (hydroquinone form) is regenerated
by two steps process.
Vitamin K Epoxide is reduced to the quinone by a
Epoxide reductase, and the quinone is reduced to the
active hydroquinone by either the same reductase or
by a vitamin K reductase(quinone reductase).
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19. Role of vitamin K in coagulation
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.
γ-Carboxyglutamate chelates calcium ions, and so
permits the binding of the blood clotting proteins to
membranes.
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20. Vitamin K Antagonists
Dicumarol and Warfarin, inhibit coagulation
through antagonism of the action of vitamin K.
Warfarin prevents the recycling of vitamin K by
inhibiting two important reactions and creating a
functional vitamin K deficiency
Warfarin is a competitive inhibitor of Epoxide
reductase.
In the presence of Warfarin, vitamin K epoxides
cannot be reduced, they accumulate and are
excreted.
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21. Vitamin K Antagonists
Abnormal precursor of prothrombin
(preprothrombin) containing little or no
carboxyglutamate, and incapable of chelating
calcium, is released into the circulation
Thus, in the presence of Warfarin or in vitamin K
deficiency the process of coagulation is inhibited,
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22. Vitamin K Antagonists
Large quantities of dietary or supplemental vitamin K
can overcome the anticoagulant effect of vitamin K
antagonists
patients taking these drugs are cautioned against
consuming very large or highly variable quantities of
vitamin K in their diets.
Like all anticoagulants, the major side effect of
Warfarin is bleeding.
Treatment of pregnant women with Warfarin can lead
to fetal bone abnormalities (Fetal Warfarin syndrome)
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23. Synthesis of Bone Calcium-Binding
Proteins
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.
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24. Synthesis of Bone Calcium-Binding
Proteins
After gamma carboxylation osteocalcein binds tightly
to calcium.
Osteocalcin also contains hydroxy proline, so its
synthesis is dependent on both vitamins K and C; in
addition, its synthesis is induced by vitamin D.
The release into the circulation of osteocalcin
provides an index of vitamin D status.
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25. 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.
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26. Synthesis of Bone Calcium-Binding
Proteins
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28. Vitamin K deficiency
Causes
Lack of vitamin K in the diet
Fat malabsorption and that thus reduce the absorption
of vitamin K
Disease or surgical interventions that affect the ability
of the intestinal tract to absorb vitamin K
Chronic liver diseases
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29. Vitamin K deficiency in the
newborn
• Maternal medications that interfere with vitamin K stores
or function (e.g., carbamazepine, phenytoin, barbiturates,
some Cephalosporins, rifampin, Isoniazid, Warfarin or
Warfarin like drugs) can result in vitamin K deficiency
bleeding in the infant.
•Transplacental transfer of vitamin K is very limited during
pregnancy,
•The storage of vitamin K in neonatal liver is also limited.
•Breast milk is a poor source of vitamin K.
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30. Vitamin K deficiency in infants
Diarrhea
Hepatitis
Cystic fibrosis
Celiac disease
Short bowel syndrome
Chronic exposure to broad spectrum antimicrobials
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31. 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.
Having a liver disorder increases the risk of bleeding
because proteins that help blood clot (clotting factors)
are made in the liver.
Vitamin K deficiency may also weaken bones.
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32. Clinical Manifestations
Most newborn infants are healthy upon examination,
however, intracranial hemorrhage can occur during
the delivery process and can lead to severe
complications.
Internal hemorrhage of organs other than the brain
may be difficult to detect; however, if they are
suspected, careful physical monitoring and serial
imaging after birth are indicated.
Soft tissue hemorrhages may be there.
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33. Clinical Manifestations
A deficiency of
vitamin K can
lead to extreme
bleeding, which
can begin as a
gum or nose
discharge or
bruising
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34. Laboratory Studies
A Prothrombin time (PT),
activated partial
Thromboplastin time
(aPTT), fibrinogen levels,
and a platelet count should
be included in the initial
workup for vitamin K
deficiency bleeding (VKDB)
in a newborn.
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35. 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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36. Laboratory Studies
The diagnosis of vitamin K deficiency bleeding is
confirmed if administration of vitamin K halts the
bleeding and reduces the PT value.
Infants with vitamin K deficiency bleeding typically
have a prolonged PT with platelet counts and
fibrinogen levels within the normal range for
newborns.
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37. Imaging Studies
MRI exposes the neonate to no radiation and is
becoming the preferred way to study the brain
because tissue damage can be better defined.
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38. Other Tests
A full coagulopathy work-up and hematology
consultation are required if clinical and laboratory
findings are suggestive of non–vitamin K deficiency
bleeding.
A work-up that includes functional tests and imaging
are mandatory if liver disease is suspected.
Hereditary defects in the coagulation system must
always be considered among the differential diagnoses.
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39. 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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40. Treatment
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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41. Treatment
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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42. Treatment
People who have vitamin K deficiency and a severe
liver disorder may also need blood transfusions to
replenish the clotting factors.
A damaged liver may be unable to synthesize clotting
factors even after vitamin K injections are given.
The reversal of excessive anticoagulant therapy with
Warfarin or Warfarin-like drugs can be achieved by
minimal doses of vitamin K (1 mg orally or by
intravenous injection) for asymptomatic patients.
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43. 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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44. Prevention
Intramuscular (IM) vitamin K prophylaxis at birth is
the standard of care.
Commercial infant formulas contain supplemental
vitamin K.
These measures have served to make vitamin K
deficiency bleeding a rarity.
However, parental refusal of prophylaxis and an
increasing frequency of breastfeeding may cause a
resurgence of vitamin K deficiency bleeding in
developed countries.
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45. Prognosis
In the absence of intracranial hemorrhage, the
prognosis for vitamin K deficiency bleeding in an
otherwise healthy infant is excellent.
Prognosis after intracranial hemorrhage depends on
the extent and location of the hemorrhage.
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46. 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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