PHM226 Hemophilia A: Mechanism and History

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PHM226Hemophilia AMechanism and History

• Sajjad Giby (sajjad.giby_at_utoronto.ca)
• Mehrdad Pourzakikhani (mehrdad.pourzakikhani_at_utoro
  nto.ca)
• Nardin Samuel (nardin.samuel_at_utoronto.ca)
• Georges Farah (georges.farah_at_utoronto.ca)
• Sign-Up date Wednesday, January 23rd, 2008

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Presentation Outline

• Introduction and Background
• History
• Physiology and Pathophysiology
• Medication and Treatment Options
• Summary

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What is Hemophilia?

• Hemophilia is a rare but serious disease - type A
  affects about 2500 Canadians
• Etymology Greek haima meaning blood, philia
  meaning to love
• Essentially, missing coagulation factors prevent
  fibrin formation necessary for maintaining a
  blood clot
• Ranges from mild to severe

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• X-chromosome hereditary condition
• In the most common form, A, clotting factor VIII
  is absent
• Hemophilia B, 2nd most common, lacks factor IX
• Type C has a deficiency in factor XI
• Internal bleeding is much more serious than
  external
• External cuts will bleed for a longer amount of
  time
• Internal hemorrhaging can occur in muscles,
  joints and tissues, including the brain. It can
  impair function and even be life threatening

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History
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Ancient/Medieval Records

• Earliest recorded mention
• Talmud, Jewish religious text, 2nd century
• Male babies did not have to be circumcised if two
  brothers had previously died from bleeding in the
  procedure
• 11th century Arab physician Albucasis mentions in
  Al-Tasrif
• Andalusian family whose males died from bleeding
  after minor injuries

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Modern Times

• 1803 Philadelphia physician John Conrad Otto
  recognized a hereditary hemorrhagic disposition
  in certain families that affected males only.
• 1828 hemophilia coined for the condition by
  Hopff at University of Zurich

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20th Century

• Harvard doctors Patek and Taylor isolate
  anti-hemophilic globulin from plasma.
• Prove that problem not with vessel or platelet
  structures.
• Argentinean doctor Pavlosky clinically
  differentiated between types A and B.
• Blood from one could help another with a
  different protein deficiency.

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• I take all my pictures like this.

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The Royal Disease

• Queen Victoria was a mystery carrier either a de
  novo mutation or product of her mother having an
  affair with a carrier male.
• Passed it on to 3 of her 9 children, thus
  affecting the lives of many grand-children and
  the royal families of Germany, Spain and Russia
• Daughter Alice passed it to some of her children,
  including Alexandra

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• Alexandra married Nicholas II Tsar of Russia and
  passed it to only son Alexei
• The royal family was occupied with Alexeis
  disease and went to great lengths to help him,
  including alleged healer and infamous
  question-marked figure Rasputin, one of the many
  factors in fall of imperial Russia.
• Rasputin used hypnosis to relieve pain and/or
  slow hemorrhages, and sent away doctors who some
  claim were actually prescribing then wonder
  drug aspirin.

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• Would you like to talk here or in the private
  counseling area?

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Physiology and Pathophysiology
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Physiology and Pathophysiology

• Hemophilia A is caused by a recessive trait, with
  a defective gene (the HEMA gene) located on the
  X-chromosome
• HEMA gene codes for Factor VIII
• Human Factor VIII is a plasma glycoprotein 216
  amino acids long that performs a substantial role
  in blood-clotting
• However, Factor VIII circulates through the body
  as a complex paired with the von Willebrand factor

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• Once activated, factor VIII is released from the
  vWF and binds to phospholipid membrane surfaces
  such as those provided by activated platelets
• There it interacts with the Christmas Factor
  (IXa) to become the intrinsic system factor X
  activator
• Intrinsic factor X activation is a critical step
  in the early stages of coagulation

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• Along with Factor V, calcium and platelet factor
  3 (PF3) convert prothrombin to thrombin
• Thrombin then converts fibrinogen to fibrin,
  which then forms a stabilized meshwork, a fibrin
  clot, to occlude the damaged blood vessel

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• The origin of Hemophilia A may be in the original
  binding of factor VIII to von Willebrand factor.
• If factor VIII is not bound to vWf, the entire
  cascade of events leading to the conversion of
  prothrombin to thrombin is affected.
• This binding has been shown to be dependent upon
  the C2 region of factor VIII.
• Structurally destabilizing mutations in this area
  of the protein could cause factor VIII to become
  unable to bind with von Willebrand factor, as
  shown in the ribbon diagram.

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Treatment Options
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Treatment

• Goal of Therapy Normalize Factor VIII lab values
  to normal plasma levels
• No one-time cure at present
• In the past, whole blood/fresh plasma
  transfusions did not contain enough factor VIII
• Blood products were not screened for any diseases
  until 80s and 90s

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Main Treatment Option

• Factor VIII REPLACEMENT THERAPY
• IV infusions
• Purity (measured in activity units)
• Origin (Genetically engineered? Plasma derived?)
• Degree of viral attenuation
• Presence of foreign added protein
• Efficacies are equal! Product safety and costs
  are not
• Some brand names Recombinate, Kogenate FS,
  Refacto
• Dosing depends on the nature of injury
  (individualized)

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Adjunctive Therapy

• Desmopressin Acetate (DDAVP)
• Treatment of mild hemophilia A
• NOT for severe hemophilia (why?)
• Increases plasma levels of factor VIII x 4
• Side effects BP fluctuations, tachycardia and
  facial flushing

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• Antifibrinolytic Agents (e.g. EACA aka Amicar)
• Inhibits the activity of plasmin, which is
  responsible for the degradation of blood clots.
• Not for children

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Future Treatments

• Prophylactic Factor Replacement Therapy
• vs. post-injury treatment currently used
• Gene Therapy?

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Summary

• Hemophilia A is caused by a rare recessive trait,
  with the defective gene (the HEMA gene encoding
  Factor VIII) located on the X-chromosome. As a
  result males with a defective X chromosome
  exhibit hemophilia, while females (with 1 mutant
  copy) are carriers of the mutation (but do not
  exhibit overt hemophilia).
• This condition affects the blood's ability to of
  blood to clot due to a deficiency in Factor VIII
• Thus the disease is distinct from hemophilia B
  (also known as Christmas disease or von
  Willebrand disease).
• The severity of hemophilia A ranges from mild to
  severe.
• Hereditary roots of the disease were recognized
  and the disease named in the 1800s.
• Queen Victoria passed hemophilia to some of her
  children and grandchildren and affected royal
  families of Germany, France, Spain and Russia
• This has been thought to be due to the
  inefficient binding of Factor VIII to von
  Willebrand factor (v WF)due to mutations in the
  C2 region of the protein.
• Normally Factor VIII binds to vWFprotecting it
  from degradation. In the absence of effective
  binding factor VIII is rapidly degraded,
  resulting in a concomitant fall in factor VIII
  levels. Factor VIII is released from vWF factor
  by the action of thrombin.
• Human Factor VIII is a plasma glycoprotein 216
  amino acids long that performs a substantial role
  in blood-clotting
• However, Factor VIII circulates through the body
  as a complex paired with the von Willebrand
  factor
• Treatment Factor VIII Replacement Therapy (bolus
  or continuous infusion dosing depends on nature
  of injury)
• Secondary Treatments DDAVP to release stored
  factor VIII in patients with mild hemophilia A
  Antifibrinolytic Agent to inhibit plasmin
  activity

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Summary
Affected in Hemophilia type A
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Sources

• Colman, Robert W., et al. Clinical Manifestation
  and Therapy of the Hemophilias. Hemostasis and
  Thrombosis Basic Principles and Clinical
  Practice. 5th Edition. Lippincott Williams
  Wilkins, 2006.
• Page, David, Walker, Irwin. Hemophilia A and B.
  The treatment of Hemophilia. Canadian Hemophilia
  Society. 2006. McMaster University Medical
  Centre. January 19th 2008. ltwww.hemophilia.ca/en/2
  .1.7.phpgt
• Schaider, Jeffrey, et al. Hemophilia. Rosen
  Barkins 5-Minute Emergency Medicine Consult. 3rd
  Edition. Lippincott Williams Wilkins, 2007.
• Pratt, K.P., et al. Structure of the C2 domain of
  human factor VIII at 1.5 Å resolution. Nature.
  402439-441. 1999.
• Stoilova-McPhie S, et al. 3-Dimensional structure
  of membrane-bound coagulation factor VIII
  modeling of the factor VIII heterodimer within a
  3-dimensional density map derived by electron
  crystallography. Blood 991215-23. 2002.
• http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridgnd.
  section.95
• http//www.hemophilia.ca/en/
• http//encarta.msn.com

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