Hemophilias

1
Hemophilias

• AHMG Fall 2004
• Juniata College

2
Hemophilia

• Affects about 1/5000-1/10000 males worldwide
• Hemophilias A and B are X-linked recessive
• A and B are indistinguishable phenotypically
• Symptoms spontaneous bleeding into joints and
  muscles/prolonged bleeding after accidents or
  surgery

3
Hemophilia
4
Hemophilia

• Hemophilia A mutations in the gene encoding
  Factor VIII
• Hemophilia B mutations in the gene encoding
  Factor IX.
• Hemo. B is 1/5 as common as A, and is usually
  slightly less severe.

Bolton-Maggs and Pasi. The Lancet. 361
1801-1809, 2003.
5
Hemophilia

• Factor VIII gene is longer (26 exons) than Factor
  IX gene (8 exons).
• Factor VIII gene is on Xq28 factor IX gene is on
  Xq27.
• Most severely affected have no Factor produced,
  mildly affected have malformed, dysfunctional
  protein produced.

Bolton-Maggs and Pasi. The Lancet. 361
1801-1809, 2003.
6
Hemophilia A
7
Hemophilia A
8
Hemophilia treatment

• There is no cure for hemophilia.
• Treatment
• During a bleeding episode, give replacement
  Factor (VIII or XI) that is absent in the patient
• Prophylaxis give hemophiliac boys replacement
  factor 2-3 times a week so that the factors
  there if an injury event or spontaneous bleeding
  occurs.
• Expensive in the short-term, but these boys live
  a full life. (I.e., arent confined to wheel
  chairs due to joint arthritis, can work, have
  normal life-expectancy.)
• 10-15 of patients treated with replacement
  factors develop inhibitor antibodies to the
  replacement factors, making treatment even more
  difficult.

9
Hemophilia treatment

• Source of Factors VIII and IX
• Until 1992 and 1999, respectively, sole source
  was purification from donated blood plasma.
• Problem until 1985 blood wasnt screened for
  virus, so hemophiliacs contracted hepatitis B and
  C and HIV from these plasma products
• Now, we have recombinant Factor VIII and Factor
  IX
• Dont come from patients, so theres no viral
  contamination.

10
Hemophilia

• Good candidate for gene therapy
• Only a 1-2 increase in the amount of Factor able
  to be produced would be enough to bring relief to
  patient and for patient to live normal life.
• Are several trial so far, but none successful
  yet
• Cant get the gene to the tissue that needs it.
• Cant get the gene to be expressed for as long as
  is necessary for relief of symptoms.
• Toxicity