1-Overview of clotting mechanisms. 2-different lab investigation for bleeding disorder. 3-hemophilia, clinical presentation and its types. 4-Molecular basis and inheritance of hemophilia. 5-mechanisims of family and patient pedigree.

1. Pbl3-mbod
Hemophilia,Clinical Presentation, Types,molecular Basis And
Inheritance,overview Of Clotting Mechanisms , Different Lab
Investigation For Bleeding Disorder And Mechanisims Of
Family And Patient Pedigree.
Asem shadid

2. Objectives:
1-Overview of clotting mechanisms.
2-different lab investigation for bleeding disorder.
3-hemophilia, clinical presentation and its types.
4-Molecular basis and inheritance of hemophilia.
5-mechanisims of family and patient pedigree.

3. 1-Overview of clotting mechanisms

4. What is Haemostasis?
The process of blood clotting and then the subsequent
dissolution of the clot, followed by repair, is termed
haemostasis
Don’t confuse the terms:
 Homeostasis - equilibrium between interdependent elements
 Haemopoiesis - the production of blood cells and platelets, which
occurs in the bone marrow.
 Haemostasis or hemostasis - blood clotting

5. Key Points
 • Hemostasis requires the
interaction of platelets,
coagulation and fibrinolysis
factors, endothelium,pro-
inflammatory and anti-
inflammatory mediators, and
leukocytes .
• • Physiologic anticoagulants
such as AT-III and Activated
Protein C oppose thrombosis,
serving to localize it to sites of
vascular injury .
• • Clot formation is balanced by
plasmin-mediated fibrinolysis .

6. Basic Theory
• More than 50 substances that affect blood coagulation have been
found, some that promote coagulation, called procoagulants,
and others inhibit coagulation, called anticoagulants .

7. Clotting factors :
A series of different plasma proteins called blood-clotting
factors

8. Normal values for blood cells
Cell Normal range (cells/µL)
Total WBC 4000- 11000 (% of total WBC)
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
3000- 6000
150- 300
0- 100
1500- 4000
300- 600
50- 70
1- 4
0.4
20- 40
2- 8
RBC
Females
Males
~ 4.8 x 106
~ 5.4 x 106
Platelets 200,000- 500,000

9. Vascular Constriction
Platelet Plug
Fibrous Growth
To reduce the blood flow near
the site of injury
To temporarily stop the blood loss
from the site of injury
To permanently stop the blood loss
from the site of injury
To permanently close the hole in the
blood vessel
Clot Dissolution
Blood Clot
To remove the clot so that normal
blood flow can resume
Events in Haemostasis

10. General Mechanism
 Immediately after a blood vessel has been cut or
ruptured, the smooth muscles in vessel wall
contract, To temporarily stop the blood loss from the
site of injury .
 Platelets also play a role in vasoconstriction by
releasing a powerful vasoconstrictor thromboxane
A2.
 platelets adhere, swell and release many
substances that activate the whole process of blood
clotting , They form a platelet plug and stop the
bleeding .
 platelets Contain large amount of enzymes and
calcium ions ,Secrete a growth factor that causes
growth of vascular endothelial cells and fibroblasts
,Also contain an important protein called fibrin-
stabilizing factor .
Vascular Constriction
Platelet Plug
Blood Clot
Fibrous Growth
Clot Dissolution

11. General Mechanism
 Formation of Prothrombinase (Prothrombin Activator ) :
 Intrinsic System:
This is initiated by liquid blood making contact with a foreign surface, Trauma to the blood
itself or exposure of the blood to collagen .
 Extrinsic System:
This is initiated by liquid blood making contact with damaged tissue. Traumatized vascular
wall or traumatized extravascular tissues .
 In response to rupture of the vessel , a complex
cascade of chemical reactions occurs in the
blood. The net result is formation of a complex of
activated substances collectively called
prothrombin activator
 The prothrombin activator catalyses conversion
of prothrombin into thrombin
 The thrombin acts as an enzyme to convert
fibrinogen into fibrin fibers that enmesh platelets,
blood cells, and plasma to form the clot

12. Common Pathway
After clot has formed… Fibrinolysis
• The plasma contains plasminogen (or profibrinolysin) that, when activated,
becomes a substance called plasmin (or fibrinolysin).
• Plasmin is a proteolytic enzyme. It digests fibrin fibers and some other
coagulants such as fibrinogen, Factor V, Factor VIII, prothrombin, and Factor
XII
fibrin-stabilizing factor from platelet :
• This acts as an enzyme to cause covalent
bonds between more and more of the fibrin
monomer molecules, adding tremendously to
the three-dimensional strength of the fibrin
meshwork

13. different lab investigation for
bleeding disorder :

14. Tests for Bleeding Disorders

15. Con . Tests for Bleeding
Disorders

16. • hemophilia, clinical
presentation and its types.

17. What is Hemophilia?
 Hemophilia is an inherited bleeding disorder that almost always affects males.
 Hemophilia, a recessive trait associated with the X-chromosome, is manifested almost
exclusively in males.
 A person with hemophilia has low or non-existent levels of blood clotting factor.
 There are 13 blood clotting proteins (coagulation factor) along with platelets and fibrin
necessary for clotting blood.
 If one factor is missing or present at low levels, this causes blood clotting problems and a
proper clot will not form.
 What is Hemophilia severity?
 Severe 0% - 1% factor level. About 80% of hemophilia sufferers are considered severe.
Moderate 1% - 5% factor level. About 10% of hemophilia sufferers are considered
moderate.
Mild 5% - 50% factor level. About 10% of hemophilia sufferers are considered mild.
 Severity levels do not change, as in get better or worse. These levels are genetic and tend to
run the same in a given family. "Normal" levels of clotting protein are 50 - 150%.

18. Types of Hemophilia and other
bleeding disorders :
 Hemophilia A: This person has low levels of or is missing completely
factor 8 (Also called FVIII or factor VIII deficiency) 80% of people with
hemophilia have Type A Hemophilia. Factor VIII deficiency usually only
manifests in males.
 Hemophilia B: This person has low levels of or is missing completely
factor 9 (Also called FIX or factor IX deficiency) 20% of people with
hemophilia have Type B Hemophilia. Factor IX deficiency usually only
manifests in males.
 Hemophilia C: This person has low levels of or is missing completely
factor 11 (Also called FXI or factor XI deficiency) Hemophilia C is 10
times rarer than type A. Factor XI deficiency is different because it can
show up in both males and females.
 Von Willebrands Disease: a bleeding disease similar to Hemophilia that
affects both males and females equally. Von Willebrand factor circulates
attached to factor VIII and is necessary to form a clot.

20. Signs and Symptoms
External bleeding may include:
 Bleeding in the mouth from a cut or bite or from cutting or losing a tooth.
 Nosebleeds for no obvious reason.
 Heavy bleeding from a minor cut.
 Bleeding from a cut that resumes after stopping for a short time.
Internal bleeding may include:
 Blood in the urine (from bleeding in the kidneys or bladder).
 Blood in the stool (from bleeding in the intestines or stomach).
 Large bruises (from bleeding into the large muscles of the body).
Bleeding in the Joints
 Bleeding in the knees, elbows, or other joints is another common form of internal bleeding in
people who have hemophilia.
 The bleeding causes tightness in the joint with no real pain or any visible signs of bleeding. The
joint then becomes swollen, hot to touch, and painful to bend.
Bleeding in the Brain
 Long-lasting, painful headaches or neck pain or stiffness
 Repeated vomiting
 Sleepiness or changes in behavior
 Sudden weakness or clumsiness of the arms or legs or problems walking
 Double vision
 Convulsions or seizures

21. Summary :
 Factor IX deficiency
 Factor XI deficiency
 Factor VIII deficiency
 Inherited as an X-linked recessive trait
 What causes hemophilia?
 Hemophilia A and B are caused by a flaw in a part of a gene. acquired hemophilia,
clotting factors don't work right because the body makes antibodies that attack
them.
 Symptoms of hemophilia include:
 Bleeding into a joint or muscle, which causes pain and swelling.
 Bleeding that is not normal after an injury or surgery.
 Easy bruising.
 Frequent nosebleeds.
 Blood in the urine.
 Bleeding after dental work.
 most of the time, hemophilia symptoms are noticed during infancy or childhood

22. Molecular basis and inheritance of
hemophilia

23. General
 To explain the hemophilia
genetics, first you will need to
know a little about basic
genetics.
 When a Father and a Mother
create a child the Mother
gives one of the two X
chromosomes that she has.

 The Father gives either the X
or the Y chromosome, an X
produces a girl, a Y produces
a boy.
 So as illustrated above they
have a 50% chance of having
a boy and a 50% chance of
having a girl.
Father with Hemophilia Genetics

25. mechanisims of family and patient
pedigree

26. Goals of Pedigree Analysis
1. Determine the mode of inheritance:
1. Dominant
2. Recessive
3. Sex-linked
4. Autosomal
5. mitochondrial, maternal effect.
2. Determine the probability of an affected offspring
for a given cross.
Basic Symbols
A genetic pedigree is an easy way to track
family traits.
It looks like a family tree, but also contains
information about the mode of inheritance
(dominant, recessive, etc.) of genetic diseases.

27. More Symbols
 The red line (dashed)
“children lines” to denote a
child that is not related
biologically (adopted).

28. Steps in Pedigree Analysis
1. Autosomal . Both boys and girls will be involved.
 Dominant
 Disease must be in multiple generation.
 Disease person must have an affected parents.
 Male & female are equally affected
 Recessive
 Disease have skip generation.
 Disease person must not have an affected parents.
 Because autosomes are involved , Male & female are equally affected
2. X-linked
 Dominant
 Affected male will transmit the character to all daughters but not to sons
 Affected female will transmit the character to Half sons and Half daughters.
 Recessive
 No male to male transfer
 Affected male will be more than female

29. Thank you – Asem Shadid