Most of the clotting factors are proteins in the form of enzymes. Normally, all the factors are present in the form of inactive proenzyme. These proenzymes must be activated into enzymes to enforce clot formation. It is carried out by a series of proenzyme-enzyme conversion reactions. First one of the series is converted into an active enzyme that activates the second one, which activates the third one; this continues till the final active enzyme thrombin is formed. Enzyme cascade theory explains how various reactions, involved in the conversion of proenzymes to active enzymes take place in the form of a cascade. Cascade refers to a process that occurs through a series of steps, each step initiating the next, until the final step is reached.

Stages of Blood Clotting

In general, blood clotting occurs in three stages:

1. Formation of prothrombin activator

2. Conversion of prothrombin into thrombin

3. Conversion of fibrinogen into fibrin.


Blood clotting commences with the formation of a substance called prothrombin activator, which converts

prothrombin into thrombin. Its formation is initiated by substances produced either within the blood or outside the blood.

Thus, formation of prothrombin activator occurs through two pathways:

i. Intrinsic pathway

ii. Extrinsic pathway.

i. Intrinsic Pathway for the Formation of Prothrombin Activator

In this pathway, the formation of prothrombin activator is initiated by platelets, which are within the blood itself.

Sequence of Events in Intrinsic pathway

i. During the injury, the blood vessel is ruptured. Endothelium is damaged and collagen beneath

the endothelium is exposed.

ii. When factor XII (Hageman factor) comes in contact with collagen, it is converted into

activated factor XII in the presence of kallikrein and high molecular weight (HMW) kinogen.

iii. The activated factor XII converts factor XI into activated factor XI in the presence of HMW


iv. The activated factor XI activates factor IX in the presence of factor IV (calcium).

v. Activated factor IX activates factor X in the presence of factor VIII and calcium.

vi. When platelet comes in contact with collagen of damaged blood vessel, it gets activated and

releases phospholipids.

vii. Now the activated factor X reacts with platelet phos pholipid and factor V to form prothrombin

activa tor. This needs the presence of calcium ions.

viii. Factor V is also activated by positive feedback effect of thrombin.

ii. Extrinsic Pathway for the Formation of Prothrombin Activator

In this pathway, the formation of prothrombin activator is initiated by the tissue thromboplastin, which is formed from the injured tissues.

Sequence of Events in Extrinsic Pathway

i. Tissues that are damaged during injury release tissue thromboplastin (factor III). Thromboplastin

contains proteins, phospholipid and glycoprotein, which act as proteolytic enzymes.

ii. Glycoprotein and phospholipid components of thromboplastin convert factor X into activated

factor X, in the presence of factor VII.

iii. Activated factor X reacts with factor V and phospholipid component of tissue thromboplastin

to form prothrombin activator. This reaction requires the presence of calcium ions.


Blood clotting is all about thrombin formation. Once thrombin is formed, it definitely leads to clot formation.

Sequence of Events in Stage 2

i. Prothrombin activator that is formed in intrinsic and extrinsic pathways converts prothrombin

into thrombin in the presence of calcium (factor IV).

ii. Once formed thrombin initiates the formation of more thrombin molecules. The initially formed

thrombin activates Factor V. Factor V in turn accelerates formation of both extrinsic and

intrinsic prothrombin activator, which converts prothrombin into thrombin. This effect of thrombin

is called positive feedback effect.


The final stage of blood clotting involves the conversion of fibrinogen into fibrin by thrombin.

Sequence of Events in Stage 3

i. Thrombin converts inactive fibrinogen into activated fibrinogen due to loss of 2 pairs of

polypeptides from each fibrinogen molecule. The activated fibrinogen is called fibrin monomer.

ii. Fibrin monomer polymerizes with other monomer molecules and form loosely arranged strands of


iii. Later these loose strands are modified into dense and tight fibrin threads by fibrin-stabilizing factor

(factor XIII) in the presence of calcium ions. All the tight fibrin threads are aggregated

to form a meshwork of stable clot

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