1. Lec. 12…

2. Prevention of Blood Clotting in the Normal Vascular system
I-Endothelial Vascular Factors: :The smoothness of the endothelial cell surface prevent clotting :Layer of glycocalyx mucopolysacc haride repels clotting factors & platelets :Thrombomodulin remove thrombin thrombin-thrombomodulin complex activate protien-C which act as anti- coagulant inactivate Va, VIIIa & increases the activity of tissue plasminogen activator t-PA.

3. Thrombin

4. II --Anti– clotting mechanism
The tendency of blood to clot is balanced in vivo by limiting reactions that tend to prevent clotting inside the blood vessels and to break down any clots that do form when a vascular injury occurs.
The activated coagulation (clotting) factors must remain contained in a localized area. Types of anticlottings 1.Coagulation automatically initiates fibrinolysis. 2. Circulating blood Contain biochemical inhibitors called anticoagulants that prevent coagulation or clotting.

5. II-Process of fibrinolysis: Blood contains proteolytic enzymes known as the “fibrinolytic system” which dissolve the fibrin .The major protein of the fibrinolytic system is plasminogen which is also known as fibrinolysin.
When a clot is formed, the injured tissues and vascular endothelium, very slowly release a powerful activator called tissue plasminogen activator (T-PA) that converts plasminogen into plasmin.
The fibrinolytic & coagulation systems are interrelated under normal conditions. In rare conditions if the fibrinolytic system is activated without the activation of the coagulation system. This may result in severe bleeding problems. On the other hand if clotting mechanism is activated without activation of fibrinolytic system this may result in clotting disorders or thrombosis.

7. III- Anticoagulants: Substances that prevent coagulation or clotting mechanism i.e. prevent coagulation factors from initiating clot formation. Types:
1. Intravascular anticoagulants (i.e. prevention of blood clotting in the normal vascular system). Examples:
a. Antithrombin III: is a plasma protein produced by the liver & inactivates thrombin.85-90% of thrombin adsorb to fibrin, the remaining combine with antithrombin III which block & inactivate thrombin action.
b. Heparin: produced by basophiles, mast cells & endothelial cells. Increases the effectiveness of antithrombin & inactivate thrombin. It is widely used in medical practice to prevent intravascular clotting.
c. Prostacylin: is a prostaglandin derivative produced by endothelial cells. is a vasodilator & inhibit the release of clotting factor from platelets inhibits their aggregation.
e. Plasma Ca++ in vivo, a low plasma Ca++ level is enough it does not interfere with blood clotting.

8. Anticoagulants used outside the body: a-Heparin
b-EDTA (ethylenediamine Tetra acetic prevents clot formation by binding to Ca making inaccessible for clotting reactions.
c-Citrate e.g. sodium citrate have the. Same action of EDTA .Citrate is not toxic to the body.
d-Oxalate ion: which precipitate Ca ions Oxalate combine with Ca and form insoluble salt. Oxalate is toxic to the body.
e-Blood bank anticoagulants. Examples: a. acid-citrate dextrose. b.citrate – phosphate dextrose

9. 3. Anticoagulant for clinical use
a. Heparin b. Cumarins such as warfarin
Heparins and cumarins are anticoagulants used for the treatment of venous thrombosis (formation of clots inside blood vessels).
Abnormalities of haemostasis (Pathophysiology of haemostasis)
Defect in the haemostatic mechanism:
1. Bleeding disorder: lead to prolonged bleeding. 2. Clotting disorder lead to clot formations.
A. Bleeding disorders: Excessive bleeding can result from deficiency of any one the following factors.1.deficiency of clotting factors. For example in Hemophilia.

10. Hemophilia A: due to lack of antihaemophilic factor A (i. e
Hemophilia A: due to lack of antihaemophilic factor A (i.e. factor VIII). Comprises about 85% of all cases of hemophilia.
This type of hemophilia is also called classic hemophilic.
Severe bleeding is common in males.
Treatment: includes replacement therapy with factor VIII.
Hemophilia B: Occurs a result of a deficiency of factor IX. It is also known as “Christmas disease” and accounts for approximately 12% of all hemophilia's.

11. Hemophilia C: The least common of three major types of hemophilia
Hemophilia C: The least common of three major types of hemophilia. Caused by deficiency of factor XI & accounts less than 3% of all hemophilia. It is inherited disease. Hemophilia C is also known as "Rosenthal syndrome.“
In all types of hemophilia bleeding usually does not occur except after trauma. Bleeding can last for weeks after extraction of a tooth. Bleeding may occur into the muscles & may result into hematomas. Bleeding in hemophilia is usually from larger vessels.
In all types of hemophilias and Vit K deficiency OR if there is abnormality and/or deficiency of any of the clotting factors the CLOTTING TIME is PROLONGED.
While the BLEEDING TIME is NORMAL

12. 3- Vitamin K deficiency: This is required for synthesis of clotting factors in the liver II ,VII,IX & X.
Laboratory diagnosis of bleeding disorders:
1. Bleeding time test.
2. Capillary fragility test.
3. Platelet count. 4. platelets functions Test.
Coagulation Screening Tests:
1. Clotting Time.
2.Thrombin Time (TT) .
3.Prothrombin Time (PT).
4.Partial Thromboplastin Time. (PTT).
5.Secreening of each of the clotting factors alone.

14. 2. Thrombocytopenia: Thrombocytopenia: means the presence of a very low quantity of platelets in the circulatory system, resulting in chronic bleeding through small capillaries & venules. Bleeding does not occur until the number of platelets in the blood falls below 50,000/ml. Levels as low as 10,000/ml is lethal. The skin of such a person displays many small, purplish blotches, giving the disease the name “Thrombocytopenic purpura”. Purpura means multiple red spots larger than petechia (multiple small red spots on the skin which result from RBC’s leaving the small blood vessel. In thrombocytopenic purpura bleeding time is greater than normal value.In Thrombasthenic purpura the function of the platelets is abnormal.BLEEDING TIME is PROLONGED in both types But CLOTTING TIME iS NORMAL.

15. Clotting Disorders:
Inappropriate of clotting mechanisms in intact blood vessels results in fibrin clot formation, a phenomenon known as intravascular thrombosis. Thrombosis may be due to activation of clotting factors or due to lack of inhibitory factors (anticoagulants) to neutralize activated clotting factors. Once a thrombus (clot) has developed, it break away from its attachment to flow along with the blood such freely flowing clots are known as emboli.

16. Thus, emboli that originate in large arteries or in the left side of the heart plug either smaller systemic arteries or arterioles in the brain, kidneys. Emboli that originate in the venous system and in the right side of the heart flow into the vessels of the lung to cause pulmonary arterial embolism. thrombosis is more common in veins(venous thrombosis) than in arteries (arterial thrombosis) because blood flow more slowly through veins than arteries.
The most serious complication of venous thrombosis is pulmonary embolism, which occurs when a clot from the legs moves via the heart to the lungs, where it obstructs the pulmonary circulation. Arterial thrombosis is rather rare & is associated with large blood vessel damage. The consequences of arterial clots are more severe than venous thrombi. They may lead to myocardial infarction (heart attack); cerebral infarction (stroke), or limb infarction, which may result in gangrene.

17. microcirculatory thrombosis leads to local ischemia & necrosis (cell death).
Laboratory Diagnosis of thrombosis
1.Venography technique: for venous thrombosis.
2.Arteriography technique: for arterial thrombosis.
3.Ultrasound for both types of thrombosis (venous & arterial).

18. Coagulation tests
Thrombin Time(TT): Exogenous thrombin is added,intrinsic& extrinsic pathways are bypassed so if fibrinogen is deficient TT is prolonged Normal value is seconds.
Prothrombin Time (PT):Assesses the Extrinsic pathway factors because factor III is added,the intrinsic factors are bypassed.Normally PT equals sec.
Partial Thromboplastin Time (PTT): Measures the competency of the intrinsic pathway Normally =35 to 45 seconds.