3. ďśGenetic 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.
ďśLaboratory investigation:
â Defective platelet adherence (PFA-100) or long bleeding time.
â Subnormal levels of von Willebrand antigen and factor VIII in
plasma.
â Low Ristocetin cofactor activity or vWF activity.
6. COMMON BLEEDINGS IN VWD
ďśGyn/Obs 60% âmenorrhagia 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.
ďśNose 60% (common in children)
ďśTeeth 50%
ďśEcchymosis 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
ďźHemophilia A factor VIII deficiency
ďźHemophilia B factor IX deficiency
ďśFactor level & severity:
ďą>1% : sever, bleeding after minimal injury.
ďą 1%-5%: moderate, bleeding after mild injury.
ďą5%: 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
â Nonsense/stop mutations: preventing factor production
â 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.
ďśDiagnosis is based on:
⢠The Factor level and the history
⢠Replacement of factor is the main thing
⢠Remember antibodies