Fibrinogen and Macfarlane, 1966). In this enzymatic

Fibrinogen protein exists in the circulating blood as such, thrombin does not, but is formed from an inactive circulating precursor, prothrombin, when the blood is shed.

The conversion of prothrombin into thrombin takes place in the liver and is dependent on the presence of Ca++ and of factors which are derived from damaged tissues, disintegrating platelets and from the plasma itself.

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The formation of prothrombin depends on the absorption of adequate amount of vitamin K.

According to recent findings all the thirteen above mentioned factors are involved in the blood clotting, apart from the blood platelets.

Most of the factors undergo transformations to become active and thus constitute enzymatic cascade (Biggs and Macfarlane, 1966).

In this enzymatic cascade, the activated form of a factor catalyzes the activation of the next factor.

Very small amounts of the initial factors are needed because of the catalytic nature of the activation process. The numerons steps yield a large amplification, assuring a rapid response to trauma (injury or wound).

Clotting involves the interplay of intrinsic and extrinsic path­ways. The intrinsic pathway involves the reactions of factor XII (hageman factor), factor XI (plasma thromboplastin antecedent), fac­tor IX (Christmas factor), factor VIII (antihaemophilic factor) and factor X (Stuart factor) of plasma.

This intrinsic pathway ends with the formation of active Factor X (active Stuart factor) which in the presence of factor V (Proaccelarin v), calcium ions sad phosphogly- ceride converts the inactive factor II (prothrombin into active factor II, i.e. thrombin. Active thrombin converts the soluble protein fibrinogen into insoluble protein.

Extrinsic pathway involves the reactions of factor VII (tissue thromboplastin), factor IV (calcium ions) and phospholipids.

These factors come from the trauma or disintegrating cells. These factors along with active factor X of intrinsic pathway take part in conversion of inactive prothrombin into active thrombin. Factor XIII on activ­ation by thrombin converts fibrin into the form of hard clot.

The various processes taking place in the clotting of blood can be summarized under the following heads:

1. Coaersittn of prothrombin to thrombin:

The conversion of prothrombin into active thrombin is carried out by the proteolytic action of active factor X. This convert is accelerated by factor V, which is not itself an enzyme.

Factor V can be regarded as a modifier protein. In addition, calcium ion and phospholipid surface promote the conversion of prothrombin into thrombin. Factor X is activated by the proteolytic enzymes of both intrinsic and extrinsic pathways.

2. Proteolysis of fibrinogen:

Fibrinogen, a highly soluble molecule in the plasma, is converted into insoluble fibrin monomers by the proteolytic action of thrombin.

Thrombin hydrolyzes four arginine glycine peptide bonds of fibrinogen, ore in each of the two chains, and one in each of the two P chains, resulting is liberation of two peptides, termed fibrinopeptides A and B.

Peptide A contains 18 amino acid residues; B has 20, including tyrosine-O-suIphate. A fibrinogen molecule devoid of these fibrinopeptides is called fibrin monomere which contains four new amino-terminal glycine residues; each of the liberated fibrinopeptides contains car boxy 1-terminal arginine.

3. Fibrin monomer aggregation (formation of soft clot):

The fibrin monomers formed from fibrinogen protein on action of thrombin, spontaneously associate to form fibrin, possibly as a consequence of electrostatic attraction or of hydrogen bonding bet­ween groups unmasked by the removal of the peptides.

The forma­tion of fibrin occurs in stages and depends on factors such as pH and ionic strength but is independent of the presence of thrombin.

In the beginning the fibrin formation occurs end-to-end with formation of primitive fibrils, followed by a side-to-side polymerization of these fibrils to form coarse fibrin strands.

The fibrinogen molecules do not undergo polymerization because of the presence of an unusual negatively charged derivative of tyrosine namely tyrosine-O-sulphate in the fibrinopeptide B.

The presence of these and other negatively charged groups in the fibrinopeptides probably keeps fibrinogen molecules apart. Their release by thrombin gives fibrin monomers a different surface-charge pattern, leading to their specific aggregation.

4. Formation of hard clot:

The ibrmation of highly insoluble fibrin clot occurs in the presence of calcium ions and an enzyme, fibrinase.

Fibrinase is derived from factor XIII which is known as fibrin stabilizing factor. This reaction wakes place in the presence of thrombin. Factor XIII is found in blood platelets as well as in plasma.

The clot produced by the spontaneous aggregation of fibrin monomer is quite fragile. It is subsequently stabilized and streng­thened by the formation of covalent cross-links between the side chains of different molecules in the fibre.

Thus formation of cross-links between ? chains of different fibrin molecules converts the fibrin into its final insoluble polymeric form or hard clot.

This cross-linking reaction is catalyzed by a transamidase enzyme and ammonia is liberated during this reaction.

In this cross-linking reaction, in fact peptide bonds are formed between specific glutamine and lysine side chains in a transamidation reaction.

The steps for the conversion of fibrinogen to fibrin may be summarized as follows :


1. Proteolysis: Fibrinogen——- >Fibrin monomer+ peptides

2 Polymerization: Fibrin monomer——– >Fibrin polymer

Factor XIII

3. Clotting: Fibrin polymer——— >Insoluble fibrin clot.

Human blood clots within 3 to 4 minutes. Heat accelerates blood clotting while cold sharply slows it down.

Anticoagulants or Anticlotting compounds:

These are com­pounds which by their combined action maintain the blood in a fluid state after neutralizing the effect -of coagulation factors. Pavlov discovered these physiological anticoagulants in the year of 1887.

The physiological anticoagulants include inhibitors of all the three main coagulation phases, i.e., antithromboplastins, antithrom- bins and fibrinolysin.

It has recently been demonstrated that there are several inhibitors for each blood coagulation factor. Heparin and fibrinolysin (plasmin) are the most thoroughly studied anticoagulants and have most practical significance.

Heparin is a very powerful anticoagulant which retards the conversion of prothrombin into thrombin. In addition, it influences phases of the formation of thromboplastin and fibrin. It is synthesized in the liver.

Hirudin is also a powerful anticoagulant. These two heparin and hirudin are the anticoagulants of animal origin.

There are some other synthetic anticoagulants such as dicumarol, peleutan, etc., which block the synthesis of prothrombin in liver and thus prevent blood clotting.