Hematology

Coagulation
Mechanism of Coagulation
Initiation of the coagulation
process may occur via one of
two pathways
Converge into common pathway
Outcome of this process is the
conversion
of
circulating
insoluble coagulation factors
into gelatinous fibrin clot with
entrapped blood cells, a blood
clot
Coagulation has been divided
into 2 system: the intrinsic
system, in which all substances
are necessary for clotting are
present in the blood & the
extrinsic system in which tissue
factors
is
necessary
for
coagulation
Clotting pathways
1. Intrinsic all components are in
the blood
- must have a negative surface
(glass slide)
2. Extrinsic at least one component
from tissue; injury response
- need tissue factor (TF) for
activation of VIIa
- TF & factor VIIa contact only
after injury
- TF-factor VIIa complex also activates
factor Xia

Clotting is localized by requiring

a negatively charged surface so
initially, platelets bind collagen,
& later clot formation promoted
by platelet membranes in
surfaces of clot

Extrinsic coagulation pathway

It is initiated by entry of the
tissue thromboplastin into the
circulating blood

Tissue
thromboplastin
is
derived
from
phospholipoproteins
&
organelle
membranes
from
disrupted tissue cells
Factor VII binds to these
phospholipids in the tissue cell
membranes & is activated to
factor VIIa, a potent enzyme
capable of activating factor X to
Xa in the presence of ionized
calcium

Intrinsic coagulation pathway

Involves
the
contact
activation, factors pre-K,
HMWK, factor XII & XI
These factors interact on a
surface to activate factor IX
to IXa
Factor IXa reacts with factor
VIII, PF3 & calcium to
activate factor X to Xa
In the presence of factor V,
factor
XA
activates
prothrombin (factor II) to
thrombin, which in turns
converts fibrinogen to fibrin
Final common pathway
Once factor X is activated to Xa,
the entrinsic & intrinsic pathway
enters a common pathway
Factor
II
is
activated
to
thrombin,
which
normally
circulated in the blood as an
inactive factor
Following activation of factor
Xa, it remains platelet bound &
activates factor Va on the
platelet surface is formed near
platelet
bound
factor
II
molecules

principal
inhibitor
of
fibrinolysis, inhibits plasmin.
Proteins
of
the
fibrinolysis
pathway
Plasminogen
TPA (secreted by activated
endothelium)
Urokinase
(activates
plasminogen)
PAI-1 (secreted by endothelium,
inhibits TPA)
Alpha 2 antiplasmin (inhibits
plasmin)

Step 3: Conversion of soft fibrin

clots to hard clots
involves
crosslinking
of
neighboring fibrin molecules
- catalyzed by FSF or Factor XIII
- joins C-term segments or
gamma chain by forming isopeptide
bonds between Gln on 1 gamma and a
Lys on the other
Fibrinolysis
Once the clot has served its
useful purpose, it becomes a
waste product that must be
discarded. The fibrin mesh is
too large to be phagocytized.
The fibrin mesh is systemically
degraded by plasmin
This is called the fibrin lysis
system
Activators
of
plasminogen
convert it to the active enzyme
plasmin
Plasmin, in turn, acts to split
the fibrin clot into fibrin
degradation
products.
To
balance this activity there are
inhibitors
The most important inhibitor of
plasminogen activators is PAI1, which is fast acting.
Alpha2-antiplasmin, another

Plasminogen
- produced by the liver
- single chain protein
glycosylated loops (kringles)

with

Plasminogen activators
1.
endogenous
tissue
type
plasminogen activator & urokinase
2. exogenous streptokinase & acylplasminogen
activator
complex
(APSAC)
Inhibitors
Alpha 2 antiplasmin
Tissue plasminogen
inhibitor

activator

Fibrin degradation products

X, Y, D, E and D-D (D dimer)
D dimer is specific marker for
thrombosis
Used to identify DIC & to rule
out thromboembolism
Heart attack most are caused
by blood clots that cut off blood
flow to muscles
Tissue
type
plasminogen
activator (tPA) is present in
minute
quantities
in
the
vascular endothelium
When tPA encounters a blood
clot transforms plasminogen

to plasmin then degrades the

clots fibrin meshwork
Synthetic
tPA
has
been
developed post MI & PE

Hemostasis
equilibrium

is

permanent

Normal
protective
against thrombosis

mechanism

Activities include:
the normal flow of blood
- the normal blood flow prevents
the accumulation of procoagulant
material
- these mechanism reduces the
chance of local fibrin formation
removal
of
activated
clotting
factors
&
particulate material
- removal from the blood by
hepatocytes

natural
anticoagulant
systems
1. Antithrombin III
- major inhibitor of coagulation
- alpha 2 globulin glycoprotein
that circulates in plasma
- synthesized by hepatocytes,
megakaryocytes
&
vascular
endothelium
2. Heparin factor
- produced endogenously by
mast cells & heparin like molecules
found in endothelium
3. Protein C
vit.K
dependent
plasma
protein synthesized in the liver,
represents a natural anticoagulant
formed in response to thrombin
generation
- circulated in blood as zymogen
(inactive precursor form)
- thrombin activates protein C
in the presence of endothelial cell
associated
lipoprotein
cofactor
thrombomodulin
- requires protein S to function
as anticoagulant
4. Protein S
- essential cofactor for activated
protein C to express anticoagulant
effect
cellular regulators
Cellular
proteases

plasma
proteases derived from the lysosomes
of granulocytes