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Paul MM Van Haard
Reinier de Graaf Groep
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History
Vitamin K (VK) is an essential fat-soluble vitamin or micronutrient.
1895 Charles Towsend (Boston, USA) first described syndrome of Hemorrhagic Disease of the Newborn
(HDN).
1929 VK was discovered by Henrick Dam, the Danish biochemist. K stands for Koagulation.
1939 VK was synthesized for clinical use.
1974 Definite action of VK in carboxylation process was
known.
1995 One hundred year celebration of Dams birth: International Symposium on Vitamin K in Infancy in
Basel, Switzerland by Sutor, Hathaway et al(1).
Physiology and Metabolism of VK
Types of natural VK:
1. K1 Phyloquinone from plant, fat-soluble.
2. K2 Menaquinone from GI flora, water-soluble.
K2 has longer half-life in the liver storage than K1.
Adults receive VK half from diet and half from gastrointestinal (GI) flora. For newborn and infants the main source of
VK comes from diet (milk) and small amounts from GI flora.
Metabolism.
Vitamin K is an essential fat-soluble vitamin that is required
for the post-translational gamma carboxylation of the coagulation factors II, VII, IX, X and Proteins C and S. These
proteins contain the unique amino acid, gamma carboxyl
glutamic acid, which is necessary for calcium binding and
essential for their function. The process occurs in the liver
cells. The enzymes necessary for the vitamin K epoxide
cycle are vitamin K epoxide reductase and vitamin K
quinone reductase. Undercarboxylated vitamin K dependent proteins which are produced and released in the absence of VK are named protein induced by VK absence or
PIVKA II.
Vitamin K dependent proteins:
1. Clotting factors II, VII, IX, X or prothrombin complex
(PC).
2. Protein C inhibits Vlla, Va and increases fibrinolysis.
3. Protein S, cofactor of protein C.
4. Osteocalcin for calcium metabolism: increases calcium
deposition in bone, tissue and increases renal tubular
reabsorption and etc.
Physiologic deficiency of prothrombin complex in
newborn babies.
Newborn babies received VK in small amounts from the
Bangkok, Thailand
154
Classic HDN
Late HDN
or APCD
Secondary
PC deficiency
Age
days 2-7
(mostly days 3-5)
2 wk.- 6 mo.
(mostly wk. 2-8)
any age
Causes and
risk factors
- maternal medication
during pregnancy
- rarely idiopathic
- inadequate VK intake
- marginal VK content in
breast milk
- no VKP at birth
Incidence per
100,000 births
very rare
80 in Thailand
- 20-80 in Asia
- 4-7 in Europe
Prophylaxis
VKP antepartum
to mother
- VKP oral or IM
- adequate VK supply
- VKP IM
- adequate VK supply
biliary obstruction
hepatic disease
malabsorption, etc.
low intake, i.e.
parenteral nutrition
Age
Etiology
Risk factors
Common bleeding site
Mortality (%)
Sequelae
Bangkok, Thailand
Classic HDN
75 cases
Late HDN
691 cases
Secondary PC deficiency
31 cases
1-7 days
idiopathic
no VKP at birth, low VK intake
GI, skin
12
rare
2 wk 6 mo
idiopathic
no VKP at birth, low VK intake
intracranial 80%
25
50
2 wk 1 yr
malabsorption, bile obstruction, etc.
known cause
intracranial 65%
26
28
155
No. of cases
Year
Incidence
Age
to 2 month
>2 to 6 month
Sex M:F
Risk factors:
Infant feeding
Breast
Breast + formula
VK prophylaxis
Not receiving
Intramuscular
Oral
Undetermined
Clinical manifestation.
Hemorrhage
Intracranial
Skin and muscle
Gastrointestinal tract
Anemia
Convulsion
Outcome
Mortality
Sequelae
Bangkok, Thailand
Thailand
Other
Countries
691
1953-1995
922
1967-1988
85%
15%
2.5:1
75%
25%
2:1
91
9
80
3
7
10
96
4
100
82
24
17
74
64
100
91
24
26
90
24
50
17
50
Plasma K1 level
ng/mL
range
Normal adult
Pregnant woman at term
Cord blood
0.26
0.2
not detected (< 0.01)
0.10-0.66
0.01-0.29
2.5
2.3
4.9
33
<5
50-60
156
Country
VKP giving
Yes
1. Ungchusak K.(27)
2. Khanjanathiti P.(28)
3. Chuansumrit A and
Isarangkura P.
4. Nakayama K.(8)
5. Hanawa Y.(10)
6. Hanawa Y.(11)
7. Von Kries R.(18)
8. Victora CG.(18)
Bangkok, Thailand
1983
1977-78
1977-87
1988-95
1978-80
1981-85
1985-88
1998
1998
Thailand
Thailand
Thailand
Thailand
Japan
Japan
Japan
Europe
USA
(mostly)
Prevalence per
No
100,000 birth
35
80
80
4.2-7.8
25
20
6
4-10
4.4-7.2
157
Type of VKP
Prevalence
Rate/
per 100,000
total births
births
Intramuscular:
K1 1 mg at birth: single dose(19)
0:325,000
Oral route:
K1 1 mg x 3 D0, W1, W4-6(19)
32:1,200,000
K1 1 mg x 3 D0, D3, W3-4(19)
8:325,000
KMM 2 mg D1, D4(30)
4:83,000
K1 1 mg D0, 25 g/day x 3 mo. (19)
5:439,000
K1 2 mg: single dose Thailand(6)
4-7:100,000
No VKP Thailand(27,28)
35-80:100,000
Bangkok, Thailand
0
2.7
2.5
4.8
1.1
4-7
30-80
1 mg
5 mg
10 mg
10 mg
1 mg
K1 Mixed Micelles*
Vitamin K
Glycocholic acid
NaOH 1 N
Lecithin
HCI 1 N
NaOH 0.1 N, pH 6
Aq. inject. ad
10 mg
54.6 mg
123.2 l
75.6 mg
10 l
1 mg
158
Bangkok, Thailand
159