Secondary Haemostasis

1. Secondary HaemostasisSecondary Haemostasis
Dr.Ibrahim Khider Ibrahim
Al-Neelain University -FMLS
Haematology Department

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

3. drmsaiem
Hemostatic Plug Formation
Thrombin
AGGREGATION
Fibrin
Hemostatic
clot
ClottingPlatelet Aggregation
0 min 10 min5 min
SECONDARY
PRIMARY
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.

9. Classification of Coagulation Factors
 Based on functional or structural properties
 Physical groupings
 Prothrombin
 Fibrinogen
 Contact
 Functional Groupings
 Substrate
 Cofactors
 Enzyme

10. Physical Groupings

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.

21. Current Concept of
coagulation

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

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.

37. Proposed Mechanism of Tissue Factor
Pathway Inhibitor (TFPI) Activity
F-Xa
Endothelium
Tissue factorF-VIIa
TFPI
F-Xa
TFPI
TFPI
F-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.

39. Thanks!!!