Hemostasis - the blood clotting cascade

The blood cloting cascade relies on pre-existing zymogens in the blood. Each activated blood clotting factor is essentially a proteolytic enzyme which activates the next zymogen in the cascade.

There are 2 main pathways (extrinsic/tissue activating, and intrinsic/contact activating) which culminates to a common pathway (whereby prothrombin is converted to thrombin, and fibrinogen is converted to the insoluble fibrin).

The extrinsic pathway - ends with the activation of Factor X (begins with tissue damage)

When tissues suffer trauma, tissue factors are released (tissue thromboplastin/Factor III). This reacts with Factor VII and Ca2+ to activate Factor X.

Factor X cannot be activated merely by this pathway, and requires activation by the intrinsic pathway as well.

The intrinsic pathway - ends with the activation of Factor X (begins with endothelial damage/exposed collagen/contact with foreign surfaces)

The intrinsic pathway requires Platelet factors (PF3) - a phospholipid.

When the blood is exposed to a foreign surface, or when there is damage to the blood vessel, Factor XII is activated.

Factor XIIa activates Factor XI.

Factor XIa activates Factor IX (with the help of Factor IV and Ca2+).

Factor IVa activates Factor X (with the help of Factor VII and Ca2+)

The common pathway - begins with activation of factor X

Factor Xa catalyses the change of prothrombin (factor II) to thrombin.

[in the presence of Factor V, Ca2+, PF3)

Thrombin has 2 roles:

• Change Fibrinogen (Factor I) to Fibrin
• Activates Factor XIII which stabilises the fibrin meshwork to form a stable clot.

The common pathway ends with a clot formation.

Several cofactors which are important are as follows:

1. Vitamin K - Required to activate the precursor zymogens as it helps in the formation of Ca2+ binding site. [ 'glu' components of glutamyl to 'gla' components of g-carboxyglutamyl]
2. Calcium + phospholipid - required for the binding of Factor Xa and prothrombin. Platelet phospholipids have negative charges which attracts Ca2+ to bind. 'Gla' components of Factor Xa are attracted to these Ca2+, and concentration of Xa builds up. At the same time, concentration of prothrombin (also has 'gla' components) also builds up. Factor Xa and prothrombin are brought to close proximity, starting the common pathway.

Fibrinolysis follows....which is the dissolution of blood clots by plasmin (which is formed from plasminogen whihc is already present normally in blood). Products of the dissolved blood clot is removed by phagocytic WBC.

[ plasminogen (from liver) is converted to plasmin with the help of tPA (tissue plasminogen activator)]