Coagulation Cascade
Ahmad Shihada Silmi Msc,FIBMS
IUG
Faculty of Science
Medical Technology Dept
Coagulation
A set of reactions in which blood is
transformed from a liquid to a gel
Coagulation follows intrinsic and
extrinsic pathways
The final three steps of this series of
reactions are:
Prothrombin activator is formed
Prothrombin is converted into thrombin
Thrombin catalyzes the joining of
fibrinogen into a fibrin mesh
Coagulation
Detailed Events of Coagulation
Coagulation Phase 1: Two Pathways to Prothrombin
Activator
May be initiated by either the intrinsic or
extrinsic pathway
Triggered by tissue-damaging events
Involves a series of procoagulants
Each pathway cascades toward factor X
Once factor X has been activated, it complexes
with calcium ions, PF3, and factor V to form
prothrombin activator
Coagulation Phase 2: Pathway to Thrombin
Prothrombin activator catalyzes the
transformation of prothrombin to the active
enzyme thrombin
Coagulation Phase 3: Common Pathways to the
Fibrin Mesh
Thrombin catalyzes the polymerization of
fibrinogen into fibrin
Insoluble fibrin strands form the structural
basis of a clot
Fibrin causes plasma to become a gel-like trap
Fibrin in the presence of calcium ions activates
factor XIII that:
Cross-links fibrin
Strengthens and stabilizes the clot
Fibrinogen Fibrin
Thrombin
Fibrinogen Fibrin
Prothrombin
Xa
Va
Thrombin
Fibrinogen Fibrin
Extrinsic Pathway
TF
Prothrombin
VIIa
Xa
Va
Thrombin
Fibrinogen Fibrin
Intrinsic pathway
XIIa
Extrinsic Pathway
XIa
TF
Prothrombin
IXa VIIa
VIIIa Xa
Va
Thrombin
Fibrinogen Fibrin
Intrinsic pathway
XIIa
Extrinsic Pathway
XIa
TF
Prothrombin
IXa VIIa
VIIIa Xa
Va
Soft clot
Thrombin
Fibrinogen Fibrin
XIIIa Hard clot
Fibrin
Intrinsic pathway
XIIa
Extrinsic Pathway
XIa
TF
Prothrombin
IXa VIIa
VIII VIIIa Xa
Va V
Soft clot
Thrombin
Fibrinogen Fibrin
XIIIa Hard clot
Fibrin
The intrinsic pathway begins with the contact factors,
factor XII, HMWK, and prekallikrein, which activates
factor XI.
Activated factor XI can then activate factor IX, which
then acts with its cofactor,factor VIII,to form tenase
complex on a phospholipid surface to activate factor X.
Activated factor X then combines with its cofactor,
factor V, to form the prothrombinase complex on a
phospholipid surface, converting prothrombin to
thrombin.
Extrinsic pathway
(Tissue Factor Pathway)
IX
TF
Prothrombin (II)
IXa VIIa
Xa
Thrombin (IIa)
NB: production of IXa
Interaction of intrinsic and extrinsic pathways
Tissue Factor Pathway Inhibitor
• Kunitz-type protease inhibitor (kringles)
• 34 and 41 kD forms in plasma (C-term truncation)
• Directly inhibits Xa
• Inhibits VIIa-TF complex in a [Xa]-dependent
manner
• Bound to LDL, HDL and Lp (a)
• ~10% present in platelets (endothelium also)
Tissue Factor Pathway Inhibitor
IX
TF
Prothrombin (II)
IXa VIIa
Xa
Thrombin (IIa) TFI
TFPI
NB: Inhibition of Xa and VIIa
Tissue Factor Pathway
Net result:
Production of IXa
Production of small amounts of
thrombin (IIa)
NB: no/little fibrin formed!
Tissue Factor Pathway
• VIIa forms as usual via binding of VII to TF
• VIIa activates some XXa
• Xa converts a small amt of prothrombin to thrombin;
this thrombin is used to produce small amts of VIIIa
and Va
• As the conc of TF-VIIa-Xa-thrombin increases, Tissue
Factor Pathway Inhibitor inactivates this complex
stopping further production of thrombin.
• New: VIIa also activates IXIXa (Key to new scheme)
• IXa, with VIIIa (produced as above), produces Xa;
this Xa with Va (produced as above) produces new
thrombin; this thrombin produces more VIIIa and Va
and now we get lots of thrombin and fibrin!
VIII V
Thrombin (IIa)
VIIIa Va
Tissue Factor Pathway
NB: activation of IX by VIIa
IX
TF
Prothrombin
IXa VIIa
VIII VIIIa Xa
Va V
Soft clot
Fibrinogen Thrombin Fibrin
XIIIa Hard clot
Fibrin
However, The coagulation “cascade” doesn’t
explain how blood clots in vivo.
Several evidence support that coagulation cascade
goes in different way
Cerebal matter injection led to large clot in the
heart (Dupuy experement).
Deficiency of factor X, HMWK,PK are without
haemorrhagic symptoms.
Prothrombin time reagent, this brought into
question that patient lacking factor VIII & IX
showed normal clotting time.
All these have led to
Current Concept of coagulation
Summary
This coagulation cascade suggests that there are “intrinsic” and
“extrinsic” pathways in the coagulation process, but we must modify our
definition of these pathways a little.
The “extrinsic” or tissue factor pathway consists of the FVIIa/TF complex
and the FXa/Va complex. It operates on the TF-bearing cell to initiate the
coagulation process. Its components are shown in aqua in the slide.
The “intrinsic” pathway does not include FXII or its cofactors PK and
HMWK, which do not appear to be necessary for hemostasis.
Thus, we can consider the “intrinsic” pathway to consist of FXI(a), the
FIXa/VIIIa complex, and the FXa/Va complex. It operates on the platelet
surface during the propagation phase to generate a burst of thrombin. Its
components are shown in hot pink in the slide.
Thus, both of these pathways are needed for hemostasis, because they
operate on different surfaces and play distinct roles.
This described above makes it clear what goes wrong
in Hemophilia:-
Platelet adhesion at a site of injury occurs normally in
hemophilia,as does production of FXa and small
amounts of thrombin on TF-bearing cells
during the initiation stage of coagulation.
However, platelet surface FX activation by
FIXa/FVIIIa is abolished and, therefore, platelet
surface thrombin generation fails.
The FVIIa/TF complex cannot effectively substitute for
the FIXa/VIIIa complex,because it produces FXa on
the “wrong” surface.
Naturally Occurring Inhibitors
Ahmad Sh. Silmi Msc, FIBMS
IUG
Faculty of Science
Medical Technology Dept
Coagulation Inhibitors
The activity of coagulation system must be attenuated.
– Numerous inhibitors are found in blood.
Coagulation is controlled by three types of actions.
– Inhibition of converting enzymes (e.g., AT III, C1 esterase inhibitor, 2-
macroglobulin, 2-antiplasmin, 1-antitrypsin, HC-II).
• Act on one or more of the converting enzymes (activated factors).
• AT III-heparin pathway: major system - 80% of the thrombin inhibitory action in
plasma.
– Destruction of protein cofactors (e.g., TM-PC-PS system).
• TM-PC-PS system degrades cofactors V & VIII:C, inhibiting prothrombinase and
tenase complexes, respectively.
– Blocking receptor availability needed for complex formation (e.g., Tissue factor
pathway inhibitor (TFPI) and annexin V).
Antithrombin III (AT III)
• naturally-occuring anticoagulant
• binds to factors IXa, Xa, XIa, XIIa (slow)
• accelerated by heparin manyfold
Implication:
Heparin has almost NO anticoagulant
action without AT III
Proposed Mechanism of AT III-Heparin
System
Lysine
sites
Serine site
H
AT III
Arginine
site Th
Thrombin Heparin
Antithrombin
III
AT III
Th
Proposed Mechanism of Thrombomodulin,
Protein C and Protein S (TM-PC-PS) System
F-Xa Prothrombin
Activated
F-Va
platelet
PS Thrombin
Ca++
x
Ca++
Protein C
Activated Thrombin
Protein C
Thrombomodulin
Proposed Mechanism of Tissue Factor
Pathway Inhibitor (TFPI) Activity
F-Xa
F-Xa
TFPI
TFPI
F-Xa
TFPI
F-VIIaTissue factor
Endothelium
Anticoagulant Factors
INHIBITORS (cont.)
