SEQUENCE OF CLOTTING MECHANISM
ENZYME CASCADE THEORY
Most of the clotting factors are proteins in the form of enzymes. Normally, all the factors are present in the form of inactive proenzyme. These proenzymes must be activated into enzymes to enforce clot formation. It is carried out by a series of proenzyme-enzyme conversion reactions. First one of the series is converted into an active enzyme that activates the second one, which activates the third one; this continues till the final active enzyme thrombin is formed. Enzyme cascade theory explains how various reactions, involved in the conversion of proenzymes to active enzymes take place in the form of a cascade. Cascade refers to a process that occurs through a series of steps, each step initiating the next, until the final step is reached.
Stages of Blood
Clotting
In general, blood
clotting occurs in three stages:
1. Formation of
prothrombin activator
2. Conversion of
prothrombin into thrombin
3. Conversion of
fibrinogen into fibrin.
STAGE 1: FORMATION OF
PROTHROMBIN ACTIVATOR
Blood clotting commences
with the formation of a substance called prothrombin activator, which converts
prothrombin into
thrombin. Its formation is initiated by substances produced either within the
blood or outside the blood.
Thus, formation of
prothrombin activator occurs through two pathways:
i. Intrinsic pathway
ii. Extrinsic pathway.
i. Intrinsic
Pathway for the Formation of Prothrombin Activator
In this pathway, the
formation of prothrombin activator is initiated by platelets, which are within
the blood itself.
Sequence of Events in
Intrinsic pathway
i. During the injury,
the blood vessel is ruptured. Endothelium is damaged and collagen beneath
the endothelium is
exposed.
ii. When factor XII
(Hageman factor) comes in contact with collagen, it is converted into
activated factor XII
in the presence of kallikrein
and high molecular weight (HMW) kinogen.
iii. The activated factor
XII converts factor XI into activated factor XI in the presence of HMW
kinogen.
iv. The activated
factor XI activates factor IX in the presence of factor IV (calcium).
v. Activated factor IX
activates factor X in the presence of factor VIII and calcium.
vi. When platelet
comes in contact with collagen of damaged blood vessel, it gets activated and
releases
phospholipids.
vii. Now the activated
factor X reacts with platelet phos pholipid and factor V to form prothrombin
activa tor. This needs
the presence of calcium ions.
viii. Factor V is also
activated by positive feedback effect of thrombin.
ii. Extrinsic
Pathway for the Formation of Prothrombin Activator
In this pathway, the
formation of prothrombin activator is initiated by the tissue thromboplastin,
which is formed from the injured tissues.
Sequence of Events in
Extrinsic Pathway
i. Tissues that are
damaged during injury release tissue thromboplastin (factor III).
Thromboplastin
contains proteins,
phospholipid and glycoprotein, which act as proteolytic enzymes.
ii. Glycoprotein and
phospholipid components of thromboplastin convert factor X into activated
factor X, in the
presence of factor VII.
iii. Activated factor
X reacts with factor V and phospholipid component of tissue thromboplastin
to form prothrombin
activator. This reaction requires the presence of calcium ions.
STAGE 2: CONVERSION
OF PROTHROMBIN INTO THROMBIN
Blood clotting is all
about thrombin formation. Once thrombin is formed, it definitely leads to clot
formation.
Sequence of Events in
Stage 2
i. Prothrombin activator
that is formed in intrinsic and extrinsic pathways converts prothrombin
into thrombin in the
presence of calcium (factor IV).
ii. Once formed
thrombin initiates the formation of more thrombin molecules. The initially
formed
thrombin activates
Factor V. Factor V in turn accelerates formation of both extrinsic and
intrinsic prothrombin
activator, which converts prothrombin into thrombin. This effect of thrombin
is called positive feedback effect.
STAGE 3: CONVERSION
OF FIBRINOGEN INTO FIBRIN
The final stage of
blood clotting involves the conversion of fibrinogen into fibrin by thrombin.
Sequence of Events in
Stage 3
i. Thrombin converts
inactive fibrinogen into activated fibrinogen due to loss of 2 pairs of
polypeptides from each
fibrinogen molecule. The activated fibrinogen is called fibrin
monomer.
ii. Fibrin monomer
polymerizes with other monomer molecules and form loosely arranged strands of
fibrin.
iii. Later these loose
strands are modified into dense and tight fibrin threads by fibrin-stabilizing
factor
(factor XIII) in the
presence of calcium ions. All the tight fibrin threads are aggregated
to form a meshwork of stable clot
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