Presentation Outline

 Introduction and Background

 History
 Physiology and Pathophysiology
 Medication and Treatment Options
 Summary

What is Haemophilia?

 Haemophilia 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

National Haemophilia Foundation Mission Statement

The National Haemophilia Foundation is dedicated

to finding the cures for inherited bleeding

disorders and to preventing and treating the

complications of these disorders through

education, advocacy, and research.

 X-chromosome hereditary condition

 In the most common form, A, clotting factor VIII
is absent
 Haemophilia 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

History

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

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

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.

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

 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.
Types – Clotting Factors

• I Fibrinogen – Easy bruising

• II Prothrombin – Nosebleeds and bruising
• III Tissue Extract
• IV Calcium
• V - Joint bleeding and other symptoms
• VII – Mild effects
• VIII – Most common type (Hemophilia A)
• IX Christmas factor – The Christmas disease (Hemophilia B)
• X Plasma Thromboplastin Antecedent (PTA) – Joint bleeding
• XI Hageman factor – High occurrence in Jewish population
• XII – Little to no trouble clotting
• XIII Fibrin Stabilizing Factor – No trouble clotting, but after the clot is formed it is
very weak

 Haemophilia 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

 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

 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
  The origin of Haemophilia 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.

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

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)

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

 Antifibrinolytic Agents (e.g. EACA aka Amicar)

 Inhibits the activity of plasmin, which is
responsible for the degradation of blood clots.
 Not for children

Future Treatments

 Prophylactic Factor Replacement Therapy

 vs. post-injury treatment currently used
 Gene Therapy?

Summary

 Haemophilia 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