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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

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.

1-Overview of clotting mechanisms

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

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 .

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 .

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

Normal values for blood cells

Cell Normal range (cells/µL)

Total WBC 4000- 11000 (% of total WBC)

NeutrophilsEosinophilsBasophilsLymphocytesMonocytes

3000- 6000150- 3000- 1001500- 4000300- 600

50- 70

1- 4

0.420- 40

2- 8

RBC Females Males

~ 4.8 x 106

~ 5.4 x 106

Platelets 200,000- 500,000

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

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

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

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

different lab investigation for bleeding disorder :

Tests for Bleeding Disorders

Con . Tests for Bleeding Disorders

• hemophilia, clinical presentation and its types.

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%.

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.

Signs and SymptomsExternal 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

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

Molecular basis and inheritance of hemophilia

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

Father with Hemophilia and Mother Carrier Genetics

Carrier Mother Genetics

mechanisims of family and patient pedigree

Goals of Pedigree Analysis1. 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 SymbolsA 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.

More Symbols

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

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

Thank you – Asem Shadid