Genetics of hemophilia A - MSc Diagnostic Hematology

1. Fibrin Clot.

2. The Molecular Genetics of
Haemophilia A
Ahmad A. Al-Qudah
Supervisor :
Dr. Laila F. Nimri

3. Genetics of Haemophilia A
- Hematology & Coagulation Cascade .
- Coagulopathies .
- Haemophilia A :
- Genetics .
- Diagnosis .
- Treatment ( Management ) .
- Acquired Haemophilia
- Abstract .
- ‘’ The Royal Disease ‘’ .
- Bibliography .

4. Hematology & Coagulation Cascade
Hematology :
is the study of blood and it’s components .

5. Hematology & Coagulation Cascade
Coagulation Cascade :
is the process by which blood forms clots , prevention
of blood loss from a damaged vessel .
I – fibrinogen
II – Prothrombin
III – Tissue thromboplastin/tissue factor
IV – Calcium
V – Proacelerin
VII – Proconvertin
VIII – Hemophilia A (antihemophilic factor)
IX – Hemophilia B (Christmas factor)
X – Stuart-Prower factor
XI – Plasma thromboplastin antecedent (PTA)
XII – Hageman factor
XIII – Fibrin stabilizing factor
Prekallikrein/Fletcher factor
High molecular weight kininogen (HMWK)/Fitzgerald factor

6. Hematology & Coagulation Cascade

7. Coagulopathies
is a condition in which the blood’s ability to clot is impaired. This
condition can cause prolonged or excessive bleeding, which may
occur spontaneously or following an injury or medical and dental
procedures.
Genetic disorder or Acquired , Resulting in :
1- insufficient amount of Plt or Coagulation factor .
2- nonfunctional Plt or Coagulation factor .
3- vessel wall damage .

8. Coagulopathies
Also we can classify Coagulopathy into :
Hyper-Coagulobility : ( thrombophilia )
is an abnormality of blood coagulation that increases the
risk of thrombosis .
- DIC , Antithrombin III deficiency , Thrombocytosis .
Hypo-Coagulobility :
is an unusual susceptibility to bleeding due to an
abnormality in coagulation.
- Thrombocytopenia , Haemophilia , vWD .

9. Haemophilia
is a group of hereditary genetic disorders that
impair the body's ability to control blood clotting
or coagulation .
Haemophilia A (clotting factor VIII deficiency)
Haemophilia B (clotting factor IX deficiency)
Haemophilia C (clotting factor XI deficiency)

10. Haemophilia A
clotting factor VIII deficiency
- Most common type ( 85 % )
- Frequency of 1 per 10,000 males
- In 1/3 of cases there is no family history
- Inherited as an X-linked recessive disorder
- Commonly an inversion of intron 1 and 22

11. Haemophilia A
Molecular Genetics
The factor VIII gene is situated near the tip of the long arm of
the X chromosome (Xq28 region). It is extremely large and
consists of 26 exons.
Commonly an inversion of intron 1 and 22.

12. Haemophilia A
Signs and symptoms
Characteristic symptoms vary with severity. In general
symptoms are internal or external bleeding episodes.
Patients with more severe hemophilia suffer more severe
and more frequent bleeds, while patients with mild
hemophilia typically suffer more minor symptoms except
after surgery or serious trauma.

13. Haemophilia A
Bleeding may occur anywhere in the body. Superficial
bleeding, or shallow.
Most serious sites of bleeding are :
- Joints
- Muscles
- Digestive tract
- Brain
The muscle and joint hemorrhages are indicative of
hemophilia.

14. Haemophilia A
Genetics

15. Haemophilia A

16. Haemophilia A

17. Haemophilia A

18. Haemophilia A

19. Haemophilia A
Diagnosis
Clinical Diagnosis
A specific diagnosis of hemophilia A cannot be made on
clinical findings , but The muscle and joint hemorrhages
are indicative .
Testing
Coagulation screening tests. Evaluation of an individual with a suspected
bleeding disorder includes: platelet count and platelet function analysis (PFA
closure times) or bleeding time; activated partial thromboplastin time (APTT);
and prothrombin time (PT),
In Haemophilia , PTT and APTT is prolonged . This
Prolongation is vary according to the severity of the case .

20. Haemophilia A
Management
- There is no cure for haemophilia
- Controlled with regular infusions of the deficient
clotting factor.
- Factor replacement can be either isolated from
human blood serum, recombinant, or a
combination of the two.

21. Haemophilia A
- Some haemophiliacs develop antibodies (inhibitors)
against the replacement factors given to them, so the
amount of the factor has to be increased or non-human
replacement products must be given, such as porcine
factor VIII.

22. Acquired Haemophilia A
- Due to antibody to factor VIII (most common autoimmune
factor deficiency)
- Most patients elderly
- Often presents with severe soft tissue or mucosal bleeding
(different bleeding pattern than inherited hemophilia)

23. Abstract
Hemophilia A is an X-linked bleeding disorder resulting from a defect in
coagulation factor VIII. Clinical severity, the level of factor VIII activity and
coagulant antigen vary widely.
However the phenotypic expression directly reflects the genetic defect.
In about 5%, hemophilia A results from partial deletion of the factor VIII
gene and is clinically severe. In another 5% single base mutations have been
found, which destroy the binding sites for the restriction enzyme TaqI. They
can be "nonsense" mutations resulting in stop codons and clinically severe
hemophilia, or "missense" mutations resulting in amino acid changes and
milder forms of hemophilia. By the use of the polymerase chain reaction
and denaturing gradient gel electrophoresis we have detected several point
mutations.
The formation of anti-factor VIII antibodies appears to be more
frequent in patients with defects resulting in absence of factor VIII protein.
Carrier detection and prenatal diagnosis can be made with 100% certainty
in families with identified mutations. In the absence of any informative
polymorphism the conventional methods for carrier detection are still
helpful

24. Haemophilia
“ The Royal Disease “
- Queen Victoria , through two of her five daughters
- passed the mutation to various royal houses across the continent,
including the royal families of Spain, Germany and Russia
- Her son Leopold suffered from frequent hemorrhages
before dying from a brain hemorrhage at 31

25. Genetics of Haemophilia A
Bibliography
• THROMBIN GENERATION AND BLEEDING IN HEMOPHILIA A
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395070/
• A homozygous female hemophilia A
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385172/
• Molecular genetics of hemophilia A
http://www.ncbi.nlm.nih.gov/pubmed/2508218
• Porcine model of hemophilia A
http://www.ncbi.nlm.nih.gov/pubmed/23209578
• A Strategy for the Molecular Diagnosis in Hemophilia A in Chinese
Population
http://www.ncbi.nlm.nih.gov/pubmed/23111982
• The gene therapy journey for hemophilia: are we there yet?
http://www.ncbi.nlm.nih.gov/pubmed/22829631
• Acquired Haemophilia A
http://www.ncbi.nlm.nih.gov/pubmed/23067181