Vitamin K and its clinical applications

Dr. Rohini C Sane

VITAMIN K “K ” is the abbreviation of the German word “Koagulation ”

VITAMIN K are Naphthoquinone derivatives and have long side

Isoprenoid chain.

1929 – Henrick Dam – isolation of Vitamin K1 –(Noble Prize )

1939 – Edward Doisy – isolation of Vitamin K2 –(Noble Prize 1943 )

Properties of Vitamin K

A. Anti hemorrhagic factor = coagulation vitamin K

B. Yellow oil

C. With Low Melting point

D. Optically active

E. Thermostable

F. Labile for light and alkali

G. Absorbs UV light

H. Synthesis by intestinal bacteria

I. Daily dietary requirement nil (dietary factors and synthesis by intestinal

bacteria 70-140 micrograms /day )

CHEMISTRY OF VITAMIN K

VITAMIN K1 VITAMIN K2 VITAMIN K3

NAME OF SIDE

CHAIN

PHYLOQUINONE

( 20C )

FARNO QUINONE

( 30C )

MENADIONE

SOURCES (ALPHA –ALPHA)

CABBAGE

SOYABEAN

BACTERIA ,FISH ,MEAT SYNTHETIC

-USED IN CLINICAL

PRACTICE

CHEMISTRY 3 PHYTYL

1,4 NAPHTHQUINONE

2 METHYL 3 DIFARNESYL

1,4 NAPHTHQUINONE

2 METHYL

1,4 NAPHTHQUINONE

SOLUBILITY FAT SOLUBLE FAT SOLUBLE WATER SOLUBLE

Comparison of types of vitamin k

Chemistry of Vitamin K

Isoprenoid chain

Isoprenoid chain

Isoprenoid chain

Naphthoquinone

Naphthoquinone

Dietary sources of vitamin k for vegetarians

Dietary sources of vitamin k for non-vegetarians

Metabolism : Absorption and transport of Vitamin K

Dietary/ Intestinal Vitamin K

Small intestine

Target Tissue

Bile salts

LDL

1. storage in Liver

2. Transportation in

plasma by

Beta Lipoproteins

1. No excretion in

urine

2. Excretion in feces

in large quantities

(bacterial origin)

Absorption along with Chylomicrons

Transport

MORAWITZ THEORY OF BLOOD COAGULATION

THROMBIN

PROTHROMBIN

FIBRINFIBRINOGEN BLOOD

COAGULATION

INTRENSIC AND EXTRENSIC FACTORS

Factors of blood coagulation dependent on VITAMIN K

Factor II = PROTHROMBIN

Factor VII = SPCA

Factor IX = CHRISMAS FACTOR

Factor X = STUART PROWER FACTOR

All of them are synthesized in the liver as inactive zymogens.

They undergo post translational modification : Gamma carboxylation of Glutamic

acid residue.

Gamma carboxylation of Glutamic acid (GCG ) synthesis needs Vitamin K as a

cofactor.

Vitamin k dependent carboxylation of the precursors of clotting factors

PROTEIN* -----NH--- CH---CO + O2 + CO2

Ι

CH2

Ι

CH2 (PROTEIN * : PRECURSORS OF CLOTTING FACTORS II ,VII,IX,X)

Ι

COOH

DICUMAROL &

WARFARIN CARBOXYLASE and VITAMIN K

PROTEIN -----NH ----CH---CO

Ι

CH2

Ι

CH2

COO⁻ COO ⁻ ( CARBOXYLATED CLOTTING FACTORS II ,VII,IX,X) Ca ²⁺

Osteocalcin and Vitamin K

Osteocalcin is

1. A small protein ( 40-50 amino acids )

2. synthesized by osteoblasts of bone and its synthesis is induced by Vitamin D

3. Structural protein of kidney ,lung and spleen

4. Functional activity dependent on Vitamin K for gamma carboxylation of Glutamic acid residue at active site

5. Binds to hydroxy apatite crystals of bone- dependent on Vitamin K for gamma carboxylation of Glutamic acid residue at active site

6. Contains hydroxyproline - dependent on Vitamin K and C.

Functions of vitamin K

GLUTAMIC ACID OF CALCIUM BINDING PROTEINS (FACTOR II,VII,IX,X OSTEOCALCIN )

GAMMA CARBOXY GLUTAMIC ACID (Glu-Coo- )

CALCIUM BINDING (Ca2+) to PROTEINS

(in Organs dependent on Calcium binding proteins)

VITAMIN K DEPENDENT carboxylase oxygen , CO2 ,NADH and Vitamin K

Organ dependent on calcium binding protein and Vitamin K

Organ dependent on calcium binding protein and Vitamin K are

1. Bone

2. Spleen

3. Placenta

4. Kidney

Vitamin K dependent carboxylase

Vitamin K dependent carboxylase is

1. A microsomal enzyme

2. needs oxygen , CO2 ,NADH and Vitamin K

3. Undergoes cyclic process which is Vitamin K dependent and process is

inhibited by Dicumarol/ Warfarin

VITAMIN K CYCLE IN CARBOXYLATION REACTIONS

PROTEIN-GLUTAMIC ACID CARBOXYLASE PROTEIN- CARBOXY GLUTAMIC ACID

VITAMIN K 2,3 EPI OXIDE FORM

(HYDRO QUINONE FORM)

REDUCTASE REDUCTASE

DICUMAROL/ WARFARIN

QUINONE FORM

Fetal Warfarin syndrome :

Treatment of pregnant women with Warfarin leads to fetal bone malformation

Role OF Vitamin K and Warfarin

warfarin as an anti- Coagulant

Mechanism of action of Vitamin K and Warfarin in coagulation

Deficiency of vitamin K

RDA of vitamin K = 70 -140 Micrograms /day( This is available in a normal diet )

Intestinal bacterial synthesis of vitamin K is sufficient to meet needs of the

body.

Deficiency of vitamin K is very RARE and occurs when intestinal flora of

microorganism is disturbed and vitamin K synthesis is inhibited .

Causes of Deficiency of vitamin K

1. Prolonged antibiotic therapy(killing intestinal bacteria)

2 . Malabsorption of lipids due to

A. Sprue

B. Steatorrhea

C. Coeliac diseases

D. Obstructive jaundice ( unavailability of bile salts –when fat and fat soluble vitamins not absorbed)

E. Chronic pancreatitis

3. Short circulation bowel as a result of surgery

4. Consumption of Spoilt Clover Hay ( contains Dicumurol = Vitamin K Antagonist )

5. HEMORRHAGIC DISEASE OF NEWBORNS (intestinal flora not formed after placental detachment)

Causes and consequences of Deficiency of vitamin K :1. ( Prolonged antibiotic therapy(killing intestinal bacteria)

Prolonged antibiotic therapy(killing intestinal bacteria)

Lack of active prothrombin

Prolonged prothrombin time

Delayed coagulation/clotting time

Spontaneous hemorrhages

Profuse bleeding with minor injuries

Hemorrhagic disease of newborns and Deficiency of vitamin K

Hemorrhagic disease of newborns is attributed by Deficiency of

vitamin K.

Causes of Hemorrhagic disease of newborns leading to Deficiency of

vitamin K are

1. Lack of hepatic stores of vitamin K

2. Absence of Intestinal flora ( synthesis of vitamin K inhibited )

3. Limited oral intake ( if breast milk has low levels of vitamin K : less

than 15 mg /liter )

Management of Hemorrhagic disease of newborns : Premature/preterm

infants –prophylactic doses of 1mg Menadione ( synthetic vitamin K )

Clinical manifestation of Deficiency of vitamin K

In adult and children ,deficiency of vitamin K is manifested as

1. Bruising tendency

2. Enchymotic patches

3. Mucous membrane hemorrhage

4. Post traumatic/ internal bleeding

5. Hemorrhagic disease of newborns

Prolonged prothrombin time

Delayed coagulation/clotting time

Management of Deficiency of vitamin K

Management of Deficiency of vitamin K includes

1. Water Soluble Vitamin K3 Injection 1mg Menadione

( synthetic vitamin K )

Oral Doses Of Vitamin K Not Effective

Function of Vitamin K in Oxidative Phosphorylation :

Function of Vitamin K in Oxidative Phosphorylation is demonstrated as follows :

MITOCHONDRIA

UV RAYS

OXIDATIVE PHOSPHORYLATION INHIBITED

UV EXPOSED MITOCHONDRIA + VITAMIN K OXIDATIVE PHOSPHORYLATION RESTORED

DICUMUROL = UNCOUPLER OF OXIDATIVE PHOSPHORYLATION

Antagonists of Vitamin K1.Heparin : used in treatment of heart diseases as it prevents clotting

Prothrombin time (PT) increases after administration of VITAMIN K

(Normal Prothrombin time : 11 seconds)

Heparin administration needs close monitoring

2. Dicumarol / Warfarin : Structural similarity with vitamin K - inhibits

conversion of prothrombin to thrombin

3.Salicylates

DICUMAROL/ WARFARIN

Dicumarol/ Warfarin are

1. Structural analogs of vitamin K

2. Competitive inhibitors of Vitamin K dependent carboxylase therefore

inhibit gamma carboxylation of Glutamic acid residue at active site of

coagulation factors (FACTOR II,VII,IX,X, OSTEOCALCIN)

3. Wildly used as an anticoagulant for therapeutic purpose

Hypervitaminosis K

Hypervitaminosis K leads to

1. Hemolytic anemia

2. Jaundice ( hyperbilirubinemia and kernicterus-leading to brain damage)

Prothrombin time and vitamin K

Prothrombin time is index of liver function is and

prolonged in cases of abnormalities liver functions .

Criteria Defective liver

functions

Vitamin K deficiency

Prothrombin time (PT) * Prolonged Prolonged

Cause of prolongation of

prothrombin time

Lack of synthesis of

coagulation factors

/Unavailability of bile

salts

Unavailability of vitamin K for

activation of prothrombin

After administration of

vitamin K ( Menadione )

Failure to restore PT restore PT

Measurement of (PT) * before and after surgery is essential.

FAT SOLBLE VITAMIN AND THEIR FUNCTIONS