Blood Clotting Mechanism

By: Mujahid Hussain

DVM 3rd Semester

Coagulation prevents further blood loss from damaged tissue,blood vessels or organs.It seals the wound and prevents the entry of microbes.Coagulation is a property of plasma; RBCs & WBCs do not directly take part in clotting process but get caught up in the meshes of the clot.

Coagulation is complicated process with a cellular system comprised of cells called platelets that circulate in the blood and serve to form a platelet plug over damaged vessels and a second system based upon the actions of multiple proteins (called clotting factors) that act in concert to produce a fibrin clot.these two systems work in concert to form a clot;Disorders in either system can cause either too much clotting or too little clotting.

Platelets serve three primary functions:1) Platelet Adherence: Sticking to the injured blood vessel2) Platelet Aggregation: Attaching to other platelets to enlarge the forming plug3) Support: Provide support for the processes of the coagulation cascade

Platelet Adherence:When a break in a blood vessel occurs,substances are exposed that normally are not in direct contact with the blood flow.These substances (Primary collagen & von Willebrand factor) allow the platelets to adhere to the broken surface.Platelets get active and cause vasoconstriction to minimize blood loss.

Platelet Aggregation:Once a platelet adheres to the surface,it releases chemicals that attract additional platelets to the damaged area,referred to as platelet aggregation.Support:The support is provided to the coagulation cascade by one of the components of the outside of a platelet,called phospholipids which are required for many of the reactions in the clotting cascade.

When the blood is shed,it loses its liquid property in 3-6 minutes and sets as a semi solid jelly.This phenomenon is called as Blood Clotting (Blood Coagulation or Haemostasis)

Coagulation cascade serves to stabilize the clot that has formed and further seal up the wound.The goal of the cascade is to form fibrin which will form a mesh within the platelet aggregate to stabilize the clot.

There are major 13 factors which are involved in the coagulation cascade.All these factors are blood proteins or their derivatives.Even if one of the factor is defective,the whole clotting process is impaired leading to haemorrhage.These factors are F-I to F-XIII.

Names & functions of these factors are given below:

Factor Common Name FunctionF-I Fibrinogen Forms clot (fibrin)F-II Prothrombin Its active form (IIa) activates

I,V,VII,VIII,XI,XIII,protein C,platelets

F-III Tissue Factor (TF) or Thromboplastin or Platelet Phosholipids

Co-factor of VII

F-IV Calcium (Ca++) Required for coagulation factors to bind to phospholipid

F-V Proaccelerin Co-factor of X with which it forms prothrombinase complex

F-VI Old name of factor Va UnassignedF-VII Proconvertin Activates IX,XF-VIII Anti-hemophilic Factor A Co-factor of IX with which it

forms the tenase complexF-IX Anti-hemophilic Factor B or

Christmas FactorActivates X which forms tenase complex with VIII

F-X Stuart-Prower Factor Activates II which forms prothrombinase complex with V

F-XI Anti-hemophilic Factor C or Plasma Thromboplastin Antecedent (PTA)

Activates IX

F-XII Hageman Factor Activates XI,VII & prekallikreinF-XIII Fibrin Stabilizing Factor Crosslinks Fibrin

Coagulation Cascade

There are some other factors which also take part in coagulation & help the above mentioned factors in regulating their function.Their names & functions are give below:

Name Of Factor Functionvon Willebrand Factor Binds to VIII,mediates platelet adhesionPrekallikrein (Fletcher Factor) Activates XII,kallikrein and cleaves HMWKHigh Molecular Weight Kininogen (HMWK) (Fitzgerald Factor)

Supports reciprocal activation of XII,XI,prekallikrein

Fibronectin Mediates cell adhesionAnti-thrombin III Inhibits IIa,Xa and other proteasesHeparin Co-factor II Inhibits IIa ; co-factor for heparinVitamin K Synthesis of II,VII,IX,X from hepatic cells of liverProtein C Inactivates Va,VIIIaProtein S Co-factor for activated protein CProtein Z Mediates thrombin adhesion to phospholipids and

stimulate degradation of X by ZPIProtein Z-related Protease Inhibitor (ZPI) Degrades X (inpresence of protein Z) and XIPlasminogen Converts to plasmin,lyses fibrin and other proteinsAlpha 2-antiplasmin Inhibits plasminTissue Plasminogen Activator (tPA) Activates plasminogenUrokinase Activates plasminogenPlasminogen Activator Inhibitor-1 (PAI-1) Inactivates tPA & urokinase (Endothelial PAI)Plasminogen Activator Inhibitor-2 (PAI-2) Inactivates tPA & urokinase (Placental PAI)Cancer Procoagulant Pathological X activator linked to thrombosis in

cancer

There are 3 major stages in the coagulation cascade:

Stage 1: Formation of Prothrombinase Complex (Prothrombin Activator)

Prothrombinase is formed in two ways1) Extrinsic Pathway (also known as Tissue Factor Pathway)2) Intrinsic Pathway (also known as Contact Activation Pathway)

Stage 2: Conversion of Prothrombin into Thrombin

Stage 3: Conversion of Fibrinogen into Fibrin

Stage 2 & Stage 3 is collectively called as Final Common Pathway

Extrinsic Pathway:In this pathway,the formation of prothrombinase complex is initiated by the tissue thromboplastin

Factors III,V,VII,X are involved in this pathwayMechanism:

It begins with trauma to blood vessel or tissues outside the blood vessel.It releases F-VII and tissue phosholipids.F-VII comes in contact with F-III (TF or Thromboplastin) expressed on TF-bearing cells (stromal fibroblasts & leukocytes) forming an activated complex (TF-VIIa)

TF-VIIa activates F-IX,F-X in presence of Ca++ and tissue phosholipids Activation of F-X by TF-VIIa is almost immediately inhibited by TFPI

F-Xa acts on F-V and activates it F-Xa complexes with tissue phospholipids,F-Va,Ca++ and forms a complex called prothrombinase

complex or prothrombin activator

Stage 1

Intrinsic Pathway:In this pathway,the formation of prothrombinase complex is initiated by platelets which are within the blood itself

Factors F-III,F-V,F-VIII,F-IX,F-X,F-XI,F-XII are involved in this pathwayMechanism:

Begins with the formation of the primary complex on collagen by HMWK,prekallikrein and F-XII Prekallikrein is converted to kallikrein and F-XII gets activated.

Damaged platelets adhere to the wet surface of blood vessel and release platelet phospholipids i.e. F-III

F-XIIa acts enzymatically on F-XI (Plasma Thromboplastin Antecedent) and activates it F-XIa acts enzymatically on F-IX and activates it in presence of Ca++

F-IXa activates F-VIII (Anti Haemophilic Factor) F-IIIa,F-VIIIa and F-IXa activate F-X F-Xa acts enzymatically on F-V (Proaccelerin) and activates it in presence of Ca++

F-Va,F-Xa,F-IIIa and Ca++ form a complex called prothrombin complex

In the presence of prothrombin activator or prothrombinase complex and Ca++,prothrombin is converted to thrombin

Thrombin itself increases its own rate of formation (+ive feedback mechanism) Thrombin then activates other components of the coagulation cascade, including F-V

and F-VIII (which activates F-XI,which in turn activates F-IX)and activates and releases F-VIII from being bound to vWF

F-VIIIa is the co-factor of F-IXa, and together they form the "tenase" complex, which activates F-X and so the cycle continues.("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes)

Thrombin converts fibrinogen (plasma protein produced by the liver) to fibrin Thrombin also activates F-XIII (Fibrin Stabilizing Factor) which in presence of Ca++ stabilizes

the fibrin polymer through covalent bonding of fibrin monomers

Stage 2

Stage 3

Fibrin Polymerization:

Fibrinogen is an abundant plasma protein that is a dimer of the Aα,Bβ and ϒ chains connected by disulphide bonds.The fibrinogen dimer is composed of two flanking D globular domains with a central E domain.Fibrinogen forms the main structure of the fibrin clot after cleavage of fibrinopeptides A (FpA) and B (FpB) by thrombin.The fibrin monomer assembles in a half-staggered overlap with adjoining fibrin monomers and is then covalently cross-linked into a fibrin polymer by the transmidase F-XIIIa.

New Model Of Coagulation Pathway:

Overview Of Coagulation Cascade

For the sake of clarity,Ca++ and phospholipids have been omitted from figure.These two co-factors are necessary for all of the reactions listed in figure that result in the activation of prothrombin to thombin