Secondary haemostasis-Fourth Year March 2018

Secondary HaemostasisSecondary Haemostasis
Dr.Ibrahim Khider Ibrahim
Al-Neelain University -FMLS
Haematology Department
4th
year March 2018
4th Year LEctures-FMLs-Neelain

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.

Overview
 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
factors. 4th Year LEctures-FMLs-Neelain

Haemostatic Plug Formation
Thrombin
AGGREGATION
Fibrin
Hemostatic
clot
ClottingPlatelet Aggregation
0 min 10 min5 min
SECONDARY
PRIMARY
COAGULATION

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.

Factor Nomenclature
 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.

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

Physical Groupings

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

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

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)
 Purpose: activate the intrinsic pathway & fibrinolytic
system 4th Year LEctures-FMLs-Neelain

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

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.

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

Intrinsic Pathway
 The intrinsic pathway triggered
when the blood comes in contact
with any negatively charged non-
endothelial surface.

Intrinsic Pathways
 Following endothelial injury:
 the contact factors are adsorbed to
the sub endothelium
 activated by the negatively charged
connective tissue fibers such as
collagen fibers.

Extrinsic Pathway
 The extrinsic pathway is triggered
by tissue factor (F III) which is
released from damaged tissues.

Common pathway
 Both intrinsic and extrinsic
pathways are lead to common
pathway.

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.

Naturally occurring Inhibitors

Antithrombin III (AT III)
 AT III is a major inhibitor of thrombin.
 It is formed by the liver
 Complexes to heparin sulfate and
inactivates the serine proteases :
 Thrombin, FXIa, FXa,FIXa, FVIIa.

Antithrombin IIIAntithrombin III
Heparin
ThrombinThrombin
ThrombinThrombin

Proposed Mechanism of AT III-Heparin
System
HeparinThrombin Antithrombin
III
Lysine
sites
Serine site
Arginine
site
H
Th
H
AT III
AT III
Th

. 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.

α2-macroglobulin
 It is a large plasma protein,
 Inhibit thrombin but less effective
than ATIII
 Heparin does not enhance its
activity.
 Also inhibits Xa and kallikrein

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.

Protein C/S system
 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.

 Tissue factor pathway inhibitor(TFPI)
 Act on extrinsic pathway factors, mainly
FVIIa.
 Also it inhibits Xa.

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

Protein Z-dependent inhibitor
 Protein Z (PZ) is a 62-kDa vitamin K-
dependent plasma protein
 Serves as a cofactor for PZ-dependent
inhibitor (ZPI).
 Inhibition of FXa
 Also has an inhibitory effect on Xia.

Secondary haemostasis-Fourth Year March 2018

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