A brief about bleeding disorders: - Acquired, inherited - von Willebrand disease, Hemophilia

1. GENETICS OF
INHERITED
BLEEDING
DISORDERS

2. Vitamin K
deficiency, Warfarin
therapy, liver
diseases, DIC,
massive tranfusion
vWD,
Hemophilia A &
B
Acquired Inherited
Bleeding
Disorders

3. Genetic Factors:
• Mutations in single gene: causing loss of function.
• Variants in genes: causing alteration of function.
• Chromosomal imbalance: causes alteration in gene dosage.

4. Dominant
Heterozygotes with
one copy of the
altered gene are
affected
Recessive
Homozygotes with
two copies of the
altered gene are
affected
X-linked recessive
Males with one copy of the
altered gene on the X-
chromosome are affected

5. VON WILLEBRAND DISEASE
• A common inherited bleeding disorder (autosomal dominant) characterized by decreased
Von Willebrand Factor.
• vWFgene is located on chromosome 12 containing 52 exons.
• >500 mutations causing vWD have been identified in the vWF gene.
Laboratory investigation:
– Defective platelet adherence (PFA-100) or long bleeding time.
– Subnormal levels of von Willebrand antigen and factor VIII in
plasma.
– Low Ristocetin cofactor activity or vWF activity.

6. COMMON BLEEDINGS IN VWD
Gyn/Obs 60% →menorrhagia has a good sensitivity but low specificity. Abnormal
menstruation is characterized by:
• 80 ml/month
• Clots greater than 1 inch in diameter.
• Low serum ferritin.
• Changing the pad every one hour.
Nose 60% (common in children)
Teeth 50%
Ecchymosis 50% (easy bruising)

7. Type 1 (quantitative):
production of vWF
(levels 20%-50%)
2N: decreased
binding of FVIII to
vWF
Type 2 (qualitative):
missense mutation
Type 3 (quantitative):
severe deficiency
(levels <10%), AR,
hemophilia-like
phenotype
vWD Types
2M: decreased vWF
function, no loss of
large multimers
2B: increased affinity
for platelet GpIb
2A: selective
deficiency of high-
molecular-weight
multimers

8. HEMOPHILIA
• Recessive X-linked, males than females
Hemophilia A factor VIII deficiency
Hemophilia B factor IX deficiency
Factor level & severity:
>1% : sever, bleeding after minimal injury.
 1%-5%: moderate, bleeding after mild injury.
5%: mild, bleeding after significant trauma or surgery.

9. • Most hemophilia A cases due to an inversion mutation in intron 1 or 22, remainder
genetically heterogeneous
– Nonsense/stop mutations: preventing factor production
– Missense mutations: affecting factor activity not production
• 15-20% of cases due to new mutations

10. Other inherited factor deficiencies:
• Factor XI: mostly in Ashkenazi Jews. Bleeding is usually mild except after surgery or
significant injury.
Diagnosis is based on:
• The Factor level and the history
• Replacement of factor is the main thing
• Remember antibodies