Vitamin K

Ruchi, Doreen, Khatia, Alicia, Ekaterina

 Presentations
1. Ruchi Shah - Vitamin K Deficiency in Newborns

Case Study: Late Vitamin K Deficiency Bleeding After Intramuscular Prophylaxis at

Birth

2. Doreen Zehavi - Vitamin K Deficiency Secondary to Cystic Fibrosis

Case Study: Vitamin K Deficiency in an Infant with Cystic Fibrosis

3. Khatia Nanobashvili - Vitamin K Deficiency During the Pregnancy.

Case Study: Vitamin K Deficiency Embryopathy from Hyperemesis Gravidarum

4. Alicia Gould - Warfarin Embryopathy

Case Study: Severe Cervical Dysplasia and Nasal Cartilage Calcification Following
Prenatal Warfarin Exposure

5. Ekaterina Fitzgerel-Vitamin K epoxide reductase genetic deficiency.

Case study: Warfarin Dosing in a Patient with CYP2C9*3*3 and VKORC1-1639 AA

Genotypes.
 Late Vitamin K Deficiency Bleeding After Intramuscular
Prophylaxis at Birth

Ciantelli, M., Bartalena, L., Bernardini, M., Biver, P.,

Chesi, F., Boldrini, A., & Sigali, E. (2009). Late vitamin
K deficiency bleeding after intramuscular prophylaxis at
birth: a case report. Journal of Perinatology, 29(2),
168-169.
By: Ruchi Shah
 Late Vitamin K Deficiency Bleeding in Newborns

- Rare syndrome
- Defined as: unexpected bleeding due to a reduction
in Vitamin K coagulation factors in infants 2 to 12
weeks of age
- Usually occurs in breastfed newborns who have not
received vitamin K at birth
- characterized by intracranial hemorrhage
- Intramuscular administration of Vitamin K can
theoretically prevent late VKDB
 Case Study

- 6 week old, baby girl - admitted due to irritability,

axial hypertonus and exotropia
- 1 mg of vitamin K was given to her at birth
- Exclusively breastfed, with no vitamin K supplementation
- No post birth complications - healthy newborn
- Physical examination: bulging anterior fontanelle,
paleness, and partial seizures
- Blood examination: abnormal clotting function - low
levels of Vitamin K -dependent clotting factors
 Research Question: Data Collected:
Is an injection of a single
dose (1 mg) of Vitamin K, at
birth, enough to prevent late
VKDB in infants?

Intervention:
- 2mg of Vitamin K
administered, followed by
assessment of progression of
intracranial bleeding
- Ventriculoperitoneal shunt
- Daily dose of 25 µg of oral
Vitamin K prescribed
Major Finding:
No progression of
intracranial bleeding
due to administration of
2 mg of Vitamin K -
confirming late VKDB
 Conclusion and Significance:

- Prophylaxis of a single dose of 1 mg vitamin K at birth may

NOT be sufficient enough to prevent late VKDB
- Although the American Academy of Pediatrics suggests a single
dose of 1mg of Vitamin K at birth to prevent VKDB, cases
still occur in exclusively breastfed infants
- Vitamin K levels are lower in breast milk than in infant
formulas
- Some authors suggest Vitamin K to lactating mothers to
increase levels of Vitamin K in breast milk
- Further studies to assess the safety of this suggestion are
necessary
 Vitamin K Deficiency In An Infant With Cystic Fibrosis

Popova A, Foley J, Nasr SZ. Bleeding diathesis due to

vitamin K deficiency in an infant with cystic fibrosis.
Respiratory Medicine CME. 2010;3(3):165-166.

By: Doreen Zehavi

 Vitamin K Deficiency and Cystic Fibrosis (CF)
Vitamin K functions in the biosynthesis of clotting
factors necessary for coagulation
- CF characterized by a sticky mucus affecting both
the the lungs and the pancreas
- Vitamin K deficiency in CF infants due to:
1. Blockage of enzymes released from pancreas=>
fat and ADEK maldigestion and malabsorption
2. ↓ intake in breastfed infants
3. ↓ synthesis of vitamin k2 by the bacteria due
to chronic diarrhea and antibiotics
- 4 wk old M Caucasian infant dx with CF
- Intramuscular Vitamin K injection at birth
- 24 DOL: Gassy, Steatorrhea x10/d, normal growth
- Bronchodilator, pancreatic enzymes and ADEK
supplementation prescribed
- 29 DOL: Blood in stool, brown streaks in vomit
- Gastroesophageal reflux with frequent spitting
up and fussiness after feeding
 Research Question: Data Collected:
Should screening for
Vitamin K deficiency be
required upon diagnosis of
Cystic Fibrosis in
infants, regardless of
intramuscular injection at Factor VII and X activity = <
birth? 5%

Intervention: Factor V activity = 91%

- 1mg injection of Major Finding:

vitamin K Improvement in clotting
- Daily ADEK + Oral factor function post
Vitamik K x3/wk administration of 1 mg
Vitamin K.
 Conclusion and Significance:

- Vitamin K injection at birth may not prevent

pathocoagulation in all infants
- Maldigestion in Cystic fibrosis may lead to a
Vitamin K deficiency, resulting in bleeding
- This case report highlights the importance of
constant monitoring of Vitamin K levels and
supplementation in infants with Cystic Fibrosis
 Vitamin K Deficiency Embryopathy from Hyperemesis Gravidarum
Andrew S. Lane, Jennifer L. Stallworth, Kacey Y. Eichelberger, and Kenneth F. Trofatter (2015). “Vitamin K deficiency
embryopathy from hyperemesis gravidarum,” Case Reports in Obstetrics and Gynecology, vol. 2015, Article ID 324173, 3
pages. http://dx.doi.org/10.1155/2015/324173

By Khatia Nanobashvili
 Hyperemesis Gravidarum, Vitamin K & Binder Phenotype
Hyperemesis gravidarum - Persistent nausea and vomiting
during the pregnancy.

● Mother - dehydration, vitamin and mineral deficit,

and loss more than 5% of original weight.
● Baby - Binder phenotype (nasal hypoplasia) due to
vitamin K deficiency.

Vitamin K - deficiency can be screened with PT and INR.

Sensitive marker - PIVKA-II (protein induced vitamin K

absence)
 Case Study
21 y/o primigravida, 14-week
gestation. Complains of nausea & Diagnosis - Hyperemesis
vomiting since 7-week gestation. gravidarum
Physical findings - loss 18%
(17kg) of original weight,
persistent nausea & vomiting
Lab values - ketosis (in urine)
Ultrasound - prominent forehead
and flattened facial profile, no
evidence of bleeding or other
abnormalities
 Data Collected:
15-week - surgeon placed PEG-J
tube for enteral feeding
21-week - ultrasound showed
nasal hypoplasia, flat facial
profile, and prominent
forehead. Vitamin k - 245
pg/ml(80-1160 pg/ml). Fetal
DNA test - showed XY male with
low risk of trisomy 21, 18,
and 13.
At birth - hypoplastic nose,
high arched palate without
cleft, and flat face. Bone
scan didn’t show
chondrodysplasia punctata.
Diagnosis After Birth -
Vitamin K deficiency
embryopathy.
Research Question:
What kind of complications
does vitamin K deficiency
cause due to hyperemesis
gravidarum ?
Major Finding:
Hospitalized patients who
have hyperemesis
gravidarum should screen
with PT and PIVKA II to
avoid vitamin K deficiency
embriopathy.
 Conclusion and Significance
● Vitamin K deficiency
during the pregnancy can
cause rare disease -
nongenetic Binder
phenotype.
● Hyperemesis gravidarum,
warfarine use, or
malabsorption can cause
vitamin K deficiency.
● Screen all patients with
PT & PIVKA-II.
Severe Cervical Dysplasia and Nasal Cartilage Calcification Following
Prenatal Warfarin Exposure
Howe, A.M., Lipson, A.H., de Silva, M., Ouvrier, R., Webster, W.S. (1997). Severe Cervical Dysplasia and Nasal Cartilage
Calcification Following prenatal Warfarin Exposure. American Journal of Medical Genetics, 71, 391-396.
 Fetal Warfarin Syndrome
- Fetal Warfarin Syndrome or Warfarin embryopathy is
a rare condition characterized by fetal exposure to
warfarin during pregnancy
- Increased risk of exposure during first trimester
of pregnancy
- Reported clinical symptoms include nasal bone
hypoplasia,depressed nasal bridge, and distal
digital hypoplasia
- Warfarin inhibits the Vitamin K cycle resulting in
interference with vitamin K-dependent proteins
 Case Study
- Patient is first child of an 18-year old women
diagnosed with antithrombin III deficiency
- Women had been treated with warfarin since
diagnosis and was kept on warfarin throughout
pregnancy
- Initial dosage 11 mg per day
- Reduced to 6 mg per day mid-gestation
- Suspended 2 weeks before delivery
- On day 2, the child was transferred to a
children’s hospital and upon examination was
diagnosed with warfarin embryopathy
Data Collected: Research Question:
- Day 2:
Does warfarin interfere
- Maxillary hypoplasia with the development and
- Hypoplasia of the nose growth of cartilage by
- Hypoplasia of the vertebrae in the
inhibiting the normal
cervical region
formation of
- 2 Months: embryo-matrix gla
- Head ultrasound normal
protein (MGP)?
- Anti-thrombin III deficiency was
diagnosed and confirmed Major Finding:
- 20 Months: Calcification visible in
- Calcification in the nasal septum the septal and alar
- Voluntary movement was confined and
cartilages - consistent
limited
with findings that suggest
- Child considered quadriplegic
warfarin interferes with
prenatal growth of
cartilaginous nasal septum
 Conclusion and Significance
- Fetal exposure to warfarin in the first trimester
has severe effects in the development of nasal
cartilage and normal formation of vitamin
K-dependent proteins
- Warfarin embryopathy should be determined
radiologically and neurologically
- If major cervical abnormalities are present, MRI of
the spinal cord is an appropriate tool
Warfarin Dosing in a Patient with CYP2C9*3*3 and
VKORC1-1639 AA Genotypes

Johnson, M., Richard, C., Bogdan, R., Kidd, R. (2014). Warfarin Dosing in a Patient with CYP2C9*3*3
and VKORC1-1639 AA Genotypes. Case Reports in Genetics, 2014, 1-4.
 Genetic Variants
-Cytochrome P450 2C9 (CYP2C9) is the
primary enzyme responsible for
inactivation of warfarin
-Variant Allele 3 decreases activity of
the enzyme by 80%
-VKORC1 gene codes for Vitamin K epoxide
reductase
-VKORC1-1639 A variant decreases gene
transcription by 50%
-Homozygous patients in AA alleles are
extremely sensitive to warfarin. http://bio.unc.edu/people/faculty/tie-jianke/
 Case Study – Patient Introduction

74 year old white female of Ashkenazi Jewish descent

History of multiple diseases:

-CVD: atrial fibrillation, hypertension, coronary artery

disease, cardiomyopathy, cerebrovascular accident
peripheral vascular disease and pulmonary hypertension
-diabetes mellitus
-Other: hypothyroidism, myelodysplastic syndrome with
chronic anemia, chronic kidney disease, peptic ulcer
disease
 Research Question: Data Collected:
Is it safe to administer warfarin to sensitive
patients?

Intervention:
-Due to recurrence of atrial
fibrillation, she was
administered warfarin at 2 mg
-After 6 days, she was Major Finding:
administered vitamin K After genetic tests, her
(phytonadione) at 2.5 mg phenotype was CYP2C9*3*3 and
-Vitamin K was given repeatedly VKORC1-1639 AA
every 3-4 days in amounts of
2.5-5 mg
 Implications and Clinical Significance

- Majority of patients could benefit from genetic testing

before the initiation of warfarin therapy as VKORC1-1639
AA occurs in 32.5% of genotypes

- Find the right dosing of warfarin on the first

administration

- Decrease adverse effects of the warfarin with lower dose

for sensitive people
 Summary

- Prophylaxis of 1mg of Vitamin K at birth is NOT

necessarily sufficient in preventing Vitamin K
deficiencies

- Vitamin K deficiency during pregnancy can cause the

binder phenotype

- Fetal exposure to warfarin interferes with Vitamin

K dependent proteins
QUESTIONS?