BLOOD COAGULATION

THE CLOTTING CASCADES:

1. The intrinsic cascade is initiated when contact is made between blood and exposed negatively charged
surfaces.
2. The extrinsic pathway is initiated upon vascular injury which leads to exposure of tissue factor, TF (factor III),
a subendothelial cell-surface glycoprotein that binds phospholipid.
3. The two pathways converge at the activation of factor X to Xa.
4. Factor Xa has a role in the further activation of factor VII to VIIa.
5. Active factor Xa hydrolyzes and activates prothrombin to thrombin.
6. Thrombin can then activate factors XI, VIII and V furthering the cascade.
7. Ultimately the role of thrombin is to convert fibrinogen to fibrin and to activate factor XIII to XIIIa.
8. Factor XIIIa (also termed transglutaminase) cross-links fibrin polymers solidifying the clot.

Written by Norrifhan Akmal Ismail MBBS student of University Malaya 2010-2015

INTRINSIC PATHWAY

Intrinsic Pathway - Is initiated by the blood coming in contact with exposed collagen in the blood vessel wall,
i.e., material within the blood or blood vessel wall. This process is considerably slower (5 to 10 minutes) but
results in the formation of larger amounts of thrombin. This allows the formation of larger clots.

1. Factor XII is activated by making contact with exposed collagen underlying the endothelium in the blood
vessel wall.

2. Factor XIIa activates Factor XI.

3. Factors XIa activates Factor IX.

4. Factor IXa together with Factor VIII activate factor X.

5. Factor VIII together with Calcium ions and Factor III from platelets (Platelet Thromboplastin) activate
Factor X - Prothrombin Activator. Since Factor III is released from activated platelets, the completion of the
Intrinsic Pathway depends on there being an adequate number of platelets in circulation.

It should be noted that both pathways lead to the same reaction, namely, the activation of Factor X -
Prothrombin Activator. From this point on, both pathways follow the same course to Fibrin formation. For
this reason the steps from Factor X activation to Fibrin formation are referred to as the Common Pathway

EXTRINSIC PATHWAY

1. The trauma releases tissue factor (factor III) and together with factor VII activate factor X.

2. At this point the intrinsic and extrinsic pathways converge and the subsequent steps are the same

COMMON PATHWAY

1. Factor Xa engages in a series of reactions with Factor V, Calcium ions and phospholipids derived from
platelets.  This composite of clotting factors and their reactions is referred to as the Factor V Complex or
Prothrombin Activator.

2. Factor V Complex initiates the conversion of Prothrombin to active form of the enzyme Thrombin.

3. Thrombin accelerates the formation of Fibrin threads from Fibrinogen (Factor I).

ACTIVATION OF PROTHROMBIN TO THROMBIN

1. Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by Factor Xa.
2. The activity of factor Xa is greatly enhanced by binding to Factor Va, termed the prothrombinase complex.

Written by Norrifhan Akmal Ismail MBBS student of University Malaya 2010-2015

 3. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction
that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla).
4. In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers.
5. Factor V and factor Xa also bind to the same membrane phospholipids
6. The binding of prothrombin, factor V and factor Xa on the membrane allows activation to occur

7. Activation of prothrombin is done by hydrolysis of peptide bonds by the factor Xa releasing the N-terminal
that rich in Gla and the activated protein.
8. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-
carboxyglutamic acid residues.

9. Deficient in Vitamin K also will lead to formation of abnormal prothrombin

10. Abnormal prothrombin has low affinity towards Ca 2+

11. Thus thrombin is unable to be produced.

ACTIVATION OF FIBRINOGEN TO FIBRIN

1. Protease thrombin cleaves peptide bonds, releasing 4 negatively charged fibrinopeptides, and fibrin
monomer

2. Aggregation of fibrin monomer forms soft fibrin clots

3. The fibrin clots is stabilised by the formation of cross-links between Gln and Lys

4. Fibrin forms long strands that bind the platelets together to form a dense web.

5. Thrombin also activates factor XIII, which helps fibrin strands cohere to one another.

6. The result is a clot.

INHERITED CLOTTING DISORDERS

1. Hemophilia A (classic hemophilia) - leads to the production of a defective Factor VIII. This is the most
common form of hemophilia and is due to a X chromosome-linked recessive gene.  It is most common in
males.

2. Hemophilia B (Christmas disease) - leads to the production of a defective Factor IX.  Hemophilia B is due to
a defective gene linked to the X chromosome and is most commonly found in males.

3. Von Willebrand's Disease - the result of a lack of effective von Willebrand's Factor. It is due to an
autosomal dominant gene and occurs equally in males and females.

PHASES OF HEMOSTASIS

1. Constriction of the injured vessels to diminish blood flow distal to the injury

Written by Norrifhan Akmal Ismail MBBS student of University Malaya 2010-2015

 2. Formation of a loose and temporary platelet plug at the site of injury

3. Formation of fibrin mesh or white or red thrombus

4. Dissolution of blood clot

DISSOLUTION OF BLOOD CLOT

1. tPA is activated by binding to the fibrin

2. activated tPA activated plasminogen within the clot to generate plasmin

3. Plasmin ingests the fibrin, dissolving the clot

4. The plasmin is then inactivated by α 2-antiplasmin

5. Urokinase and streptokinase can also be used in activating plasminogen

BLOOD COAGULATION EFFECTS FROM PIT VIPER VENOM POISONING

1. Fibrinogen cannot be activated because the protease thrombin just cleave 2 peptides bond instead of 4.

2. Thrombocytopenia, low platelet count that will lead to prolonged bleeding

3. Defibrination syndrome, a pathological process in the body where the blood starts to coagulate throughout
the whole body. This depletes the body of its platelets and coagulation factors, and there is an increased the
risk of hemorrhage.
4. hemorrhage.

FACTOR      NAME         SOURCE     PATHWAY

I     Fibrinogen      Liver     Common
II        Prothrombin (enzyme)   Liver *        Common
III            
Thromboplastin Released by damaged cells Extrinsic
III      Thromboplastin Released by platelets Intrinsic
IV    Calcium ions          Bone and gut Entire process
Proaccererin    
V          Liver and Platelets    Extrinsic and Intrinsic
(heat labile cofactor)
VII       Proconvertin (enzyme)   Liver *       Extrinsic
VIII   Anti-hemolytic factor(cofactor)  Platelets and endothelium Intrinsic
Christmas factor(plasma
IX Liver * Intrinsic
thromboplastin component)    
X  Stuart Prower factor (enzyme)   Liver *         Extrinsic and Intrinsic
XI    Plasma thromboplastin antecedent Liver      Intrinsic
Written by Norrifhan Akmal Ismail MBBS student of University Malaya 2010-2015
 (enzyme)
Intrinsic; also activates
XII              Hageman factor Liver   
plasmin
XIII          Fibrin stabilizing factor           Liver         Retards fibrinolysis

Written by Norrifhan Akmal Ismail MBBS student of University Malaya 2010-2015