Hemophilia A

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Hemophilia A

General background information

Mode of inheritance

  • X-linked recessive

Single important gene

  • The FVIII gene makes the clotting cascade enzyme Factor VIII.
  • The gene is large: 186 kb with 26 exons.

Etiology

  • There are a variety of mutations and mutation types (large / small deletions, insertions, missense, etc.) that cause hemophilia A.
    • We will use Hemophilia A specifically as an example of unusual crossing over.
      • Occurs in 40-50% of Hemophilia A cases


  • Unusual crossing over:
    • In hemophilia A, an inversion within the gene arising from crossing over causes disruption of the gene.
    • The inversion in Hemophilia A usually occurs during male meiosis.
    • Recall that exons are numbered for their position (starting with 1) as one moves in the direction of transcription.
    • The wild-type order is 1->26.
    • There are, however, inverted repeats downstream of the first exon and upstream of the 22nd exon that can pair to allow inversion.
    • The inversion flips exons 1-22 over, leaving the final order 22->...->1->23->...->26

Pathogenesis

  • Pts with > 25% function of factor VIII of the clotting cascade will have no symptoms.
    • As the amount of factor VIII function approaches 5% of normal, symptoms begin to manifest.
    • < 1% factor VIII function manifests severe disease: frequent bleeding (even spontaneously), bleeding into joints

Phenotypic information

  • External bleeding episodes
  • Prolonged bleeding from a circumcision wound or a venepuncture or heelprick is another common early sign of haemophilia
  • Prolonged bleeding from common injuries, or in severe cases bleeds may be spontaneous and without obvious cause.
  • The most serious sites of bleeding are: joints, muscles, digestive tract, and brain
    • The muscle and joint haemorrhages are indicative of haemophilia
    • Digestive tract and cerebral haemorrhages are also germane to other coagulation disorders
  • Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability.
    • Joint damage is not a result of blood in the capsule but rather the healing process.
    • When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded.

Diagnosis

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers

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