COAGULATION,PROCESS OF COGULATION COGULATION FACTOR AND THAIR USE

COAGULATION

Haemostasis involves a series of related and overlapping events. It results in coagulation of blood to prevent blood loss from an injured or ruptured vessel. The entire process of haemostasis is initiated by a vessel injury involving the platelets, the endothelium and the surrounding tissues leading to the formation of a clot.

Coagulation of blood occurs by conversion of a soluble protein, fibrinogen, into cross-linked fibrin strands. by the action of the enzyme, thrombin. This transformation occurs in a cascade of enzymatic reactions by 'activated clotting factors along with other non-enzymatic cofactors. If any of these factors and cofactors are deficient, severe trauma from an injury can result in the collapse of the coagulation mechanism, leading to severe hemorrhage.

 Thus, coagulation is a delicately controlled process which continues the maintenance of blood circulation and responds to injury when necessary. In a series of biochemical reactions, inactive proenzymes are converted into active enzyme forms. These, in turn, activate other proenzymes. 

The coagulation process is thus a cascade of factor activities, initiated by: 

(i) Interaction of certain clotting factors with the collagen fibres beneath the endothelium (intrinsic pathway),or

(ii) Release of a lipoprotein tissue factor (extrinsic pathway). Both the pathways ultimately activate factor X on the surface of the platelets and finally lead to the formation of fibrin strands.

Coagulation factor
Factor		name
I.		Fibrinogen
II.		Prothromibin
III.		Tissue thromboplastin
IV.		Calcium
V.		proaccelerin
VI.		6th  factor is unknown  factor  which is not mention in the list remember it during learning the table
VII.		proconvertin
VIII.		Ant hemophilic factor(HIF)
IX.		Plasma thromboplastin component (PIC)
X.		Stuart- power factor
XI.		Plasma thromoboplatin antecedent (PTA)
XII.		Hagemen factor
XIII.		Fibrinase Prekallikrein (PK) High-molecular –waight kininogen (HMWK)
REMEMBER THE TABLE

COAGULATION FACTORS

With the exception of calcium and the phospholipid in platelets, all the coagulation factors are proteinin nature which become active enzymes after some changes in their structure. In order to standardise the complex nomenclature, twelve coagulation factors are designated by Roman numerals I to XIII (there is no factor VI). In addition to the Roman numerals, the other substances which participate in the coagulation process are the phospholipoprotein of platelets (PF3); prekallikrein (the active form of kallikrein); kininogen and protein C When factors have been activated, they have 'a' added after the numeral, e.g., Xa

Factor 1 (Fibrinogen)

Fibrinogen or factor I is a plasma protein having a molecular weight of 340,000 daltons. It is synthesised in the liver, but does not depend on vitamin K for its production. Fibrinogen is precipitated at 56°C, and the half life is 3-4 days.

By the action of the enzyme thrombin, fibrinogen is converted into a monomer of fibrin, which then polymerises and aggregates to form polymers (fibrin strands). The normal range of plasma fibrinogen is 200-400 mg/dl.

Factor II (Prothrombin)

Prothrombin is a protein with a molecular weight of about 69,000 daltons. It is synthesised in the

liver through the action of vitamin K. Prothrombin is heat stable and the half-life is of 3-5 days.

Prothrombin is a precursor of thrombin. It is converted to thrombin in the presence of calcium ions by some enzymes which act on fibrinogen to produce fibrin. Concentration of prothrombin is about 10 mg/dl. It is consumed in the process of coagulation.

Factor III (Tissue Thromboplastin)

Tissue thromboplastin is a high molecular weight lipoprotein that is found in almost all body tissues, but is present in higher concentrations in the lungs and the brain. Its molecular weight depends on its source and ranges from 45,000 to 1 million daltons.

Thromboplastin can bring about conversion of prothrombin to thrombin. All injured tissues posses a potential thromboplastic activity.

Factor IV (Calcium)

The term factor IV is used for calcium in its ionic state when it participates in the process of coagulation. It appears to function as a bridge between the platelets and other clotting factors.

Because coagulation cannot occur without calcium the substances that bind calcium can be used as anticoagulants. For example, ethylene diamine tetra acetic acid (EDTA).

Factor V (Proaccelerin)

Factor V is a globulin with a molecular weight of about 330,000 daltons. It is synthesised in the liver. It is labile, and deteriorates rapidly in oxalated plasma, even when it is frozen. It is the most unstable of the coagulation factors, and therefore, is called labile factor. It does not require vitamin K for its synthesis.

Factor V is essential for the prompt conversion of prothrombin to thrombin in both the intrinsic and extrinsic pathways. It is fully consumed in coagulation. The half-life is 12-36 hours.

Factor VII (Proconvertin)

It is a beta-globulin with a molecular weight of 48,000 daltons. It is synthesized in the liver and is dependent on vitamin K. It is neither consumed nor destroyed in the process of coagulation. It has a very short half-life of about 4-6 hours. In contrast to its short half-life in vivo, factor VII is stable in citrated plasma for up to 2 weeks at 4°C. It takes part in the extrinsic pathway of coagulation by activating the tissue thromboplastin.

Factor VII converts factor X to factor Xa.

Factor VIII (Antihaemophilic Factor)

It is a high molecular weight (1.2 million daltons) beta globulin. The site of its synthesis is not yet clearly identified, but it is not dependant on vitamin K. It has a short half-life of 6-10 hours. In circulation, factor VIII has two functional sub units:

(i) Factor VIII: C is a coagulation factor. The term Haemophilia A indicates a hereditary disease with a deficiency of factor VIII: C subunit. Haemophilia is a sex-linked inherited coagulation disorder, also called 'bieeder's disease

(ii) Factor VIII: vWF (von Willebrand's Factor) is not necessary for the coagulation mechanism, but facilitates adhesion of platelets to the sub-endothelial surfaces. This subunit forms the larger part of the whole factor VIII, and is strongly antigenic in nature.

Factor IX (Plasma Thromboplastin Component)

It is a beta-globulin with a molecular weight of about 57,000 daltons. It is synthesised in the liver and requires vitamin K for its production. It is not consumed during clotting. It is stable at 4°C for upto 2 weeks. The half-life is about 20 hours.

Factor IX is required in the intrinsic thromboplastic generation system. It helps in the conversion of factor X to Xa. Its deficiency may result in a sex-linked hereditary bleeding disorder called haemophilia B. The clinical symptoms are similar to those of haemophilia A.

Factor X (Stuart-Prower Factor)

It is an alpha globulin having a molecular weight of 59,000 daltons. It is synthesised in the liver and is dependent on vitamin K. It is a stable factor which can remain unaltered for about 2 months at 4°C. It has a half-life of 24 to 65 hours.

Factor X is partially consumed in the process of coagulation. It is activated by both the intrinsic and the extrinsic pathways to form the final common pathway.

Factor XI (Plasma Thromboplastin Antecedent)

It is a beta globulin with a molecular weight of about 160,000 to 200,000 daltons. Its synthesis in the liver is independent of vitamin K. Factor XI has a half life of 60 hours and is stable at room temperature.

Factor XI is necessary for the thromboplastin generating mechanism. It circulates as a complex with another protein called kininogen or HMWK. Only a small fraction of factor XI is used in coagulation.

Factor XII (Hageman Factor)

It is a gamma globulin with a molecular weight of about 80,000 Daltons. It is synthesized in the liver and does not depend on vitamin K. Factor XII can resist heating at 60°C for 30 minutes. It can be stored at 4°C for about three months in oxalated plasma.

Factor XII takes part in the initial phase of the intrinsic pathway. This factor is activated when it comes in contact with glass. Platelets or injured endothelium can also activate it. It is not consumed during the coagulation process. Factor XIII (Fibrinase)

It is a high molecular weight alpha-globulin. The site of its synthesis is not definitely known. Factor XIII circulates in the blood as two pairs of subunits of dissociable complexes (a,b). It is an enzyme which, when activated by thrombin, catalyses polymerisation of fibrin. Most of factor XIII is used up in this process. It also helps in tissue growth and repair. Factor XIII is inhibited by EDTA.

Prekallikrein (PK, Flatcher Factor)

Prekallikrein is synthesised in the liver and is not dependent on vitamin K. Prekallikrein activates plasminogen, and is also a precursor for kallikrein, the chemotactic factor for phagocytes. PK is present in the plasma with HMWK.

High-molecular-weight kininogen (HMWK, Fitzgerald Factor)

HMWK is produced in the liver and does not depend on vitamin K for its synthesis. It is a cofactor in the activation of factor VII.

summarizes the properties of coagulation factors.

Properties of coagulation factors

Fibrinogen Group: Factors I, V, VIII, XIII Thrombin interacts with them all Activity lost in coagulation process (not present in serum) Increase during inflammation, in pregnancy and women on oral contraceptives V and VIII lose activity in stored plasma

Prothrombin Group: Factors II, VII, IX, X Dependent on vitamin K for synthesis, require Ca** for activation  All except prothrombin (II) are not consumed during coagulation (present in serum) Stable, well preserved in stored plasma

Contact group: Factors XI, XII, prekallikrein Not dependent on vitamin K for synthesis, not calcium dependent, stable, well preserved in stored plasma

PATHWAYS FOR THE COAGULATION PROCESS

The final product in the coagulation process is the fibrin clot formed by activation of prothrombin to form thrombin, which in turn converts fibrinogen to fibrin. There are two pathways leading to the activation of prothrombin, the intrinsic pathway and the extrinsic pathway. Both lead to a common pathway. The various factors, their precursors and other reacting substances respond in an orderly, controlled process called the coagulation cascade.

Intrinsic Pathway

In this pathway, all the necessary components are found within the circulating blood. When blood comes in contact with a foreign surface, for example exposed collagen fibres in the wall of the blood vessel or a glass surface, a series of reactions, mediated by enzymes, start. On contact with a foreign surface, prekallikrein and HMWK participate in the activation of factor XII to XIIa. XIIa in turn activates factor XI to form XIa. This process continues further involving factors IX, VIII and X. Factor X is converted to Xaby the action of calcium ions and phospholipid on the platelets..

Extrinsic Pathway

The extrinsic system is initiated when there is tissue damage together with an injured blood vessel. The damaged tissue releases thromboplastin which is not normally present in the blood. This thromboplastin, along with factor VII in the presence of calcium, activates factor X to produce Xa. The extrinsic pathway is much shorter and quicker than the intrinsic pathway .

Common Pathway

The common pathway involves the activation of factor X to Xa via the extrinsic or intrinsic pathway. Factor Xa, in the presence of calcium ions, platelet factor 3 and factor V, converts factor II (prothrombin) to the active enzyme thromb

Thrombin acts on factor I (fibrinogen) to convert it to fibrin. Factor XIII helps in the formation of stabilised, stronger clot. shows the relationship between the extrinsic, intrinsic and common pathways.

Control of Coagulation

In health there is a balance between the clot inhibiting and clot promoting activities of the coagulation system so that harmful intravascular clotting is prevented. Endothelial cells play a major role and has both clot promoting and clot inhibiting functions.

There are three mechanisms by which coagulation is controlled.

 (i) Physical control The continuous flow of cir culating blood in the blood vessel is maintained by dilution of activated products.

(ii) Physiological control Physiological inhibitors of coagulation act on the activated coagulation factors and inhibit their action, thus bringing the coagulation process to a halt. Antithrombin III and Oly-macroglobulin are the two major inhibitors. Antithrombin III reacts mainly with factor Xa and thrombin. It also inhibits other factors such as IXa, Xla, Xlla and VII. Oly-macroglobulin is particularly active against thrombin, kallikrein and plasmin. Other inhibitors of coagulation include 0-antitrypsin.. -antiplasmin, protein C and Sinhibitors. 

(iii) Cellular control Haemostasis is partially regulated by the removal of active materials by the reticulo-endothelial (RE) system. The RE system and the liver actively clear away fibrinogen and fibrin degradation products.