2. Overview
Vasoconstriction and PLT plug formation are
early, important steps in haemostasis.
Further maintenance of haemostasis,
however, requires the formation of fibrin
clots via blood coagulation.
The clots, insoluble networks of fibrin, serve
to solidify the PLT plug.
Blood coagulation is the end result of
complex sequential reactions involving
trace plasma proteins called coagulation
4. Factor Nomenclature
Each factor was assigned a Roman numerical letter
by International Committee in Nomenclature of
Blood Coagulation Factors in the order of its
discovery, not its place in the reaction sequence.
They are percent as inactive forms and numerated
as I-XIII.
5. In case of the active forms (a) is added as a
suffix to the numerical roman letter(VIII
VIIIa.
Zymogene
They are usually inactive precursors of an
enzyme Inactive factors (Except:V,VIIIand
XIII).
Serine protease
They are enzymes that cleave peptide
bonds in proteins, in which serine serves as
the active site.
6.
7.
8.
9. Classification of Coagulation Factors
Based on functional or structural properties
Physical groupings
Prothrombin
Fibrinogen
Contact
Functional Groupings
Substrate
Cofactors
Enzyme
11. Prothrombin Group
II, VII, IX, X
Protein C, Protein S, Protein Z
Vitamin K dependent
Synthesized in liver
Small mw (50,000-100,000)
Contain a domain that is critical for calcium
binding
Heat stable
Inhibited by warfarin
12. Fibrinogen group
I, V, VIII, XIII
Thrombin acts on all these factors
Synthesized in liver
Exception: VIII:vWF which is produced by endothelial
cells and megakaryocytes
Large mw (250,000)
ALL are consumed in the clotting process, since
they are NOT enzymes
13. Contact Group
XI, XII, HMWK(HK), PK
Produced in liver
Activated upon contact with a negatively charged
surface
Collagen in vivo
Glass, Kaolin in vitro
Large mw (80,000-173,000)
Not consumed in coagulation, found in serum
Purpose: activate the intrinsic pathway & fibrinolytic
system
14. Functional Groupings
Substrates: substance upon which enzymes act
Factor I:fibrinogen
Cofactors: speed up the activities of enzymes
(i.e) Factor V: Proaccelerin
Enzymes
Transglutaminase
Factor XIIIa only
Serine protease
Inactive until converted to enzymes
Once activated, assist in reaction, but are not
consumed or used up
15. What’s so Special About Vitamin K?
Where does it come from?
Green leafy vegetables, fish and liver
Gram-negative intestinal bacteria
What does it do?
Vitamin K is necessary for the carboxylation
of glutamic acid. Carboxylation is essential
for binding coagulation factors to negatively-
charged phospholipid surfaces via Ca++
bridges.
Carboxylation reactions also reduce vitamin K
to be recycled.
16. What’s so Special About Vitamin K?
Why do we care?
Vitamin K antagonist drugs such as
warfin/coumadin inhibit the activity of
the recycling of Vitamin K, so the
reduced form can not be made
Deficiencies of Vitamin K result in the
production of non-functional factors
which can not participate in coagulation
reactions
17. The intrinsic pathway triggered when the blood
comes in contact with any negatively charged
non-endothelial surface.
Following endothelial injury, the contact factors
are adsorbed to the sub endothelium and
activated by the negatively charged connective
tissue fibers such as collagen fibers.
The extrinsic pathway is triggered by tissue
factor (F III) which is released from damaged
tissues.
Both intrinsic and extrinsic pathways are lead to
common pathway.
29. Regulation of coagulation
In the absence of strict regulatory
mechanism, the coagulation mechanism once
activated would continue until all the
fibrinogen in the plasma converted to fibrin.
Human blood contains many agents that
inhibit the activity of activated clotting
factors.
30. Naturally occurring Inhibitors
Antithrombin III (AT III):
AT III is a major inhibitor of thrombin.
It is formed by the liver and complexed to
heparin sulfate and inactivates the serine
proteases – Thrombin, FXIa, FXa,FIXa,
FVIIa.
31. Proposed Mechanism of AT III-Heparin
System
HeparinThrombin Antithrombin
III
Lysine
sites
Serine site
Arginine
site
H
Th
H
AT III
AT III
Th
32. 2. Heparin cofactor II (HCII):
It is a plasma protein that selectively inhibit
thrombin.
Like AT III, the activity of HCII is stimulated
markedly in the presence of heparin.
3. α2-macroglobulin:
It is a large plasma protein, inhibit thrombin but less
effective than ATIII and heparin does not enhance
its activity.
Also inhibits Xa and kallikrein
33. 4. Protein C/S system:
Protein C and protein S are vitamin-k dependent
proteins, synthesized by the liver.
Rapid activation of protein C occurs on the
surface of endothelial cells where the thrombin-
thrombomodulin complex is formed.
Once activated APC forms a complex with
protein S on the surface of either PLTs or
endothelium
This complex selectively degrades factor Va and
factor VIIIa.
34. Proposed Mechanism of Thrombomodulin, Protein C and
Protein S (TM-PC-PS) System
Thrombin
Prothrombin
Protein C
Thrombomodulin
Thrombin
F-Xa
Activated
platelet
PS
F-Va
x
Ca++
Ca++
Activated
Protein C
35.
36. α1-antitrypsin
It is a plasma protein which is a potent inhibitor
for factor XIa and weak inhibitor for thrombin .
C1 inactivator
The primary target of this serpin is the activated
form of the first component of complement, but it
also contributes in a minor way to neutralization
of FXIa and plasmin.
Tissue factorpathway inhibitor(TFPI)
Act on extrinsic pathway factors, mainly FVIIa.
Also it inhibits Xa.
38. Protein Z and protein Z-dependent inhibitor
Protein Z (PZ) is a 62-kDa vitamin K-
dependent plasma protein that serves as a
cofactor for the inhibition of FXa by PZ-
dependent protease inhibitor (ZPI).
Also has an inhibitory effect on Xia.