1. Blood Clotting Mechanism
By: Mujahid Hussain
DVM 3rd Semester

2. 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 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 vessel
2) Platelet Aggregation: Attaching to other platelets to enlarge the forming plug
3) 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.

3. Coagulation Cascade
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 Function
F-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 Co-factor of VII
Thromboplastin or Platelet
Phosholipids
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 Unassigned
F-VII Proconvertin Activates IX,X
F-VIII Anti-hemophilic Factor A Co-factor of IX with which it
forms the tenase complex
F-IX Anti-hemophilic Factor B or Activates X which forms tenase
Christmas Factor complex with VIII
F-X Stuart-Prower Factor Activates II which forms
prothrombinase complex with V
F-XI Anti-hemophilic Factor C or Activates IX
Plasma Thromboplastin
Antecedent (PTA)
F-XII Hageman Factor Activates XI,VII & prekallikrein
F-XIII Fibrin Stabilizing Factor Crosslinks Fibrin

4. 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 Function
von Willebrand Factor Binds to VIII,mediates platelet adhesion
Prekallikrein (Fletcher Factor) Activates XII,kallikrein and cleaves HMWK
High Molecular Weight Kininogen (HMWK) Supports reciprocal activation of
(Fitzgerald Factor) XII,XI,prekallikrein
Fibronectin Mediates cell adhesion
Anti-thrombin III Inhibits IIa,Xa and other proteases
Heparin Co-factor II Inhibits IIa ; co-factor for heparin
Vitamin K Synthesis of II,VII,IX,X from hepatic cells of liver
Protein C Inactivates Va,VIIIa
Protein S Co-factor for activated protein C
Protein Z Mediates thrombin adhesion to phospholipids and
stimulate degradation of X by ZPI
Protein Z-related Protease Inhibitor (ZPI) Degrades X (inpresence of protein Z) and XI
Plasminogen Converts to plasmin,lyses fibrin and other proteins
Alpha 2-antiplasmin Inhibits plasmin
Tissue Plasminogen Activator (tPA) Activates plasminogen
Urokinase Activates plasminogen
Plasminogen 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 ways
1) 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

5. Stage 1
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 pathway
Mechanism:
 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

6. 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 pathway
Mechanism:
 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

7. Stage 2
 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)
Stage 3
 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

8. 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.

9. Overview Of Coagulation Cascade
New Model Of Coagulation Pathway:
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