Blood coagulation involves a biological Blood coagulation involves a biological amplification system in which relatively amplification system in which relatively few initiation substances sequentially few initiation substances sequentially activate by proteolysis a cascade of activate by proteolysis a cascade of circulating precursors proteins (the circulating precursors proteins (the coagulation factor enzymes) which coagulation factor enzymes) which culminate in the generation of thrombin, culminate in the generation of thrombin, this in turn, converts soluble plasma this in turn, converts soluble plasma fibrinogen into fibrin. fibrinogen into fibrin.

Fibrin catches or traps the platelets Fibrin catches or traps the platelets aggregation at the side of the injury and aggregation at the side of the injury and converts the unstable primary platelet converts the unstable primary platelet plug to firm and solid, definite and staple plug to firm and solid, definite and staple haemostatic plug.haemostatic plug.

Factor Factor number.number.

Descriptive name.Descriptive name.Active form.Active form.

IIFibrinogen Fibrinogen Fibrin subunitFibrin subunit

IIIIProthrombin Prothrombin Serine proteaseSerine protease

IIIIIITissue factorTissue factorReceptor/ Cofactor.Receptor/ Cofactor.

VVLabile factorLabile factorCofactor Cofactor

VIIVIIProconvertin Proconvertin Serine proteaseSerine protease

VIIIVIIIAntihaemophilic factorAntihaemophilic factorCofactor Cofactor

IXIXChristmas factorChristmas factorSerine proteaseSerine protease

XXStuart-Prower factor.Stuart-Prower factor.Serine proteaseSerine protease

XIXIPlasma thromboplastin antecedentPlasma thromboplastin antecedentSerine proteaseSerine protease

XIIXIIHageman (contact factor)Hageman (contact factor)Serine proteaseSerine protease

XIIIXIIIFibrin stabilizing factor.Fibrin stabilizing factor.Transglutaminase Transglutaminase

--Prekallikrein ( Fletcher factor)Prekallikrein ( Fletcher factor)Serine proteaseSerine protease

--High Molecular Weight Kininogen (HMWK).High Molecular Weight Kininogen (HMWK).cofactorcofactor

Factor VIII is pound in plasma to VWF. It is Factor VIII is pound in plasma to VWF. It is synthesized in the liver may be by the synthesized in the liver may be by the hepatocytes.hepatocytes.

The factors I, V, VIII, XI and XII increase in The factors I, V, VIII, XI and XII increase in inflammation, pregnancy and oral inflammation, pregnancy and oral contraceptives. Thrombin interacts with contraceptives. Thrombin interacts with them.them.

Vitamiin-K-dependent coagulation proteinsVitamiin-K-dependent coagulation proteins: : Clotting factors II, VII, IX and X Clotting factors II, VII, IX and X (Procoagulant), also PC and PS (Procoagulant), also PC and PS (anticoagulants) are called also the (anticoagulants) are called also the Prothrombin group, vitamin K needed for Prothrombin group, vitamin K needed for synthesis, required Ca 2+ for activation and synthesis, required Ca 2+ for activation and are stable factors, all synthesized by the are stable factors, all synthesized by the liver. liver.

Contact factorContact factor are XII, Prekallikrein are XII, Prekallikrein and High Molecular Weight Kininogen and High Molecular Weight Kininogen (HMWK). They produce by the liver. (HMWK). They produce by the liver. XII can be non-enzymatically XII can be non-enzymatically activated by contact with collagen activated by contact with collagen fibers and other negatively charged fibers and other negatively charged surfaces.surfaces.

Thrombin-sensitive coagulation Thrombin-sensitive coagulation proteins:proteins: these are fibrinogen, XIII, V these are fibrinogen, XIII, V and VIII protein complex. and VIII protein complex.

The operation of these enzyme cascade The operation of these enzyme cascade requires local concentration of circulating requires local concentration of circulating coagulation Factors At the site of the injury.coagulation Factors At the site of the injury.

Surface-mediated reactions occur on Surface-mediated reactions occur on exposed collagen, platelet phospholipids exposed collagen, platelet phospholipids and tissue factor. and tissue factor.

Although it has been traditional (and useful Although it has been traditional (and useful for in vitro laboratory testing) to divide the for in vitro laboratory testing) to divide the coagulation system into intrinsic and coagulation system into intrinsic and extrinsic pathways, such a division does not extrinsic pathways, such a division does not occur in vivo because tissue factor- factor occur in vivo because tissue factor- factor VIIa complex is a potent activator of both VIIa complex is a potent activator of both factor IX and factor X.factor IX and factor X.

Coagulation begins when tissue Coagulation begins when tissue factor activated on the surface of factor activated on the surface of injured cells binds and activates injured cells binds and activates factor VII: the complex activates factor VII: the complex activates factor IX which, with cofactor VIII. factor IX which, with cofactor VIII. Activates factor X to Xa.Activates factor X to Xa.

Platelets accelerate the Platelets accelerate the coagulation process by providing coagulation process by providing membrane phospholipid.membrane phospholipid.

The complex of Xa and Va, activated The complex of Xa and Va, activated from cofactor V acts on prothrombin from cofactor V acts on prothrombin (factor II) to generate thrombin.(factor II) to generate thrombin.

Thrombin then converts fibrinogen Thrombin then converts fibrinogen into fibrin monomers, which are able into fibrin monomers, which are able to polymerize non-enzymatically and to polymerize non-enzymatically and become a gel.become a gel.

This early fibrin clot is relatively This early fibrin clot is relatively solubilized and digested by the solubilized and digested by the fibrinolytic system. A tough insoluble fibrinolytic system. A tough insoluble fibrin colt is formed after interaction fibrin colt is formed after interaction with factor XIII.with factor XIII.

Factor VIII protein complex Factor VIII protein complex (factor VIII:C) consists of two (factor VIII:C) consists of two proteins: factor VIII proteins: factor VIII procoagulant protein and vWF.procoagulant protein and vWF.

Factor VIII:C and vWF (the last Factor VIII:C and vWF (the last makes up over 99% of the makes up over 99% of the complex) circulate in plasma as complex) circulate in plasma as a complex and probably a complex and probably stabilize and protect each stabilize and protect each other.other.

Coagulation cascade:Coagulation cascade:11-2-2 Injury initiates release of tissue factor Injury initiates release of tissue factor

(TF).which binds and activates factor VII. (TF).which binds and activates factor VII. Tie TF VIIa complex activates factors X and Tie TF VIIa complex activates factors X and

IX.IX. The activity of the TF VIIa complex is The activity of the TF VIIa complex is

inhibited by T F pathway inhibitor (T FPI ). inhibited by T F pathway inhibitor (T FPI ). The VIIIa-IXa complex amplifies Xa The VIIIa-IXa complex amplifies Xa

production from X. production from X. Thrombin is generated from prothrombin Thrombin is generated from prothrombin

by the action of Xa-Va complex leads to by the action of Xa-Va complex leads to fibrin clot formation. fibrin clot formation.

Thrombin also: Thrombin also: Activates XI leading to increased Activates XI leading to increased

IXa production. IXa production. Cleaves VIII from its carrier protein Cleaves VIII from its carrier protein

vWF activating VIII. vWF activating VIII. Activates V to Va.Activates V to Va. Activates XIII to XIIIa, which Activates XIII to XIIIa, which

stabilizes the fibrin clot.stabilizes the fibrin clot.

Note that:Note that: TFPI inhibits TF/VIIa, and Xa.TFPI inhibits TF/VIIa, and Xa.

Activated PC and PS will inhibit Va and Activated PC and PS will inhibit Va and VIII.VIII.

Antihrombin inhibits thrombin, Xa, IXa. Antihrombin inhibits thrombin, Xa, IXa. Extrinsic pathway: Factor VII.Extrinsic pathway: Factor VII. Intrinsic pathway: Factors XI, IX, VIII.Intrinsic pathway: Factors XI, IX, VIII. Common pathway: Factors X, V, II and Common pathway: Factors X, V, II and

fibrinogen. fibrinogen. Factor XIII crosslink the polymer to form Factor XIII crosslink the polymer to form

a more stable clot.a more stable clot.

Thrombin has a number of key Thrombin has a number of key rules in the coagulation process:rules in the coagulation process:

It converts plasma fibrinogen into It converts plasma fibrinogen into fibrin.fibrin.

It amplifies coagulation by: It amplifies coagulation by: Activating factor XI which Activating factor XI which

increases IXa production. increases IXa production. Cleaving factor VIII from its carrier Cleaving factor VIII from its carrier

molecule vWF to activate it and molecule vWF to activate it and augment Xa pro duction.augment Xa pro duction.

Activating factor V to factor Va.Activating factor V to factor Va. It activates factor XIII to factor XIII It activates factor XIII to factor XIII

in. which stabilizes the fibrin clot.in. which stabilizes the fibrin clot. It potentates platelet aggregation.It potentates platelet aggregation. It hinds to thrombomodulin on the It hinds to thrombomodulin on the

endothelial cell surface to form a endothelial cell surface to form a complex which activates protein complex which activates protein C, which is involved in regulating C, which is involved in regulating coagulation.coagulation.