1. CASCADE THEORY
of Coagulation
By: Raissa T. Guldam
BSMT - IV

2. Overview of Hemostasis
• Hemostasis is a dynamic process whereby blood coagulation
is initiated and terminated in a rapid and tightly regulated
fashion (Nathan, Orkin, Ginsburg, & Look, 2003).
• Hemostasis is regulated by 3 basic components—namely, the
vascular wall, platelets, and the coagulation cascade.
• Primary hemostasis – constriction of the damaged blood
vessels and formation of platelet plug
• Secondary hemostasis – coagulation factors present in the
blood interact, forming a fibrin meshwork (clot)

3. Overview of Blood Coagulation
V aso co n-
strictio n
P latelet P latelet
A ctivatio n P lu g
V essel P latelet
C lot
A gg reg ation
In ju ry
T hro m bin
T issu e
F acto r
C o agu latio n
C ascad e

4. Coagulation Mechanism
• Most of the substances necessary for coagulation are
present in an INERT form and must be converted to
an ACTIVATED state.
• As one ENZYME is formed, it then becomes available
to convert the next ZYMOGEN to its activated
enzyme.
• The activated form of a factor is indicated by the
letter “a” to the right of the Roman Numeral
(activated factor X = Xa).

5. Coagulation Cascade
• The classic theory of coagulation was described by
Paul Morawitz in 1905.
• This model described each clotting factor as a
proenzyme that could be converted to an active
enzyme.
• The “cascade” and “waterfall” models suggested
that the clotting sequences were divided into 2
pathways.

6. • Coagulation could be initiated via an “intrinsic
pathway,” so named because all the components
were present in blood, or by an “extrinsic pathway,”
in which the subendothelial cell membrane protein,
tissue factor (TF), was required in addition to
circulating components.
• The initiation of either pathway resulted in activation
of FX and the eventual generation of a fibrin clot
through a common pathway.

7. The “Cascade” Theory
• Blood coagulation is a series of biochemical
reactions.
• Transforms circulating substances into
insoluble gel.
• Converts soluble fibrinogen into fibrin.
• Process requires plasma
proteins, phospholipids and calcium.
• A fibrin clot is the end product of coagulation.

8. Coagulation Cascade
Intrinsic pathway
XII
XI
Extrinsic pathway
IX
APTT VII
VIII X
PT
Prothrombin thrombin
V, Ca, P/L
(II)
fibrinogen fibrin
XIII
STABILIZED FIBRIN

9. • It is thought of as occurring in 4 phases:
1. Contact phase
2. Activation of Factor X
3. Conversion of Prothrombin to Thrombin
4. Formation of a Fibrin Clot

10. A. Contact Phase
1. Small amounts of factor XII automatically activate
when coming in contact with negatively charged
surfaces (collagen)
Negatively charged
XII XIIa (small amounts)
surface
2. Prekallikrein is converted to kallikrein by small
amount of XIIa
XIIa
Prekallikrein Kallikrein
CLICK

11. 3. The kallikrein formed, together with HMWK,
activates more factor XII.
Kallikrein
XII XIIa (larger amounts)
HMWK
4. Factor XI is activated by factor XIIa.
XIIa
XI XIa

13. B.1. Activation of Factor X via
the Intrinsic Pathway
5. Factor IX is activated by factor XIa in the presence of
calcium ions.
XIa
IX IXa
Ca++
6. Conversion of factor X to factor Xa most probably
takes place on the surface of the platelet and is
catalyzed by a complex composed of factor IXa,
factor VIII, calcium ions and phospholipid (from
platelet).

14. IXa - VIII
X Xa
Pl – Ca++
* Factor VIII acts as a cofactor

16. B.2. Activation of Factor X via
the Extrinsic System
• Tissue factor is released and act as a cofactor in
initiating coagulation (since all cells have this except
those in the blood)
1. Factor VII binds to tissue factor and to calcium ions
to activate factor X.
VII – Tissue factor
X Xa
Pl – Ca++

18. 2. This complex (factor VII, tissue factor, and calcium
ions) is also capable of activating small amounts of
factor IX.
VII – Tissue factor
IX IXa (small amounts)
Pl – Ca++
*As factor Xa is formed, it in turn will activate factor VII.
*Factor IXa will also activate factor VII but not as
efficiently as factor Xa.
* Factor VIIa is much more active and will speed up the
activation of factor X.

20. Summary
• The INTRINSIC coagulation mechanism requires a
contact phase.
• This is followed by the activation of factors IX and X.
• The EXTRINSIC mechanism’s primary action is the
activation of factor X.
• From this point on, the two systems combine into
what is termed the COMMON PATHWAY.

21. C. Conversion of Prothrombin
to Thrombin
• This is the beginning of the COMMON PATHWAY.
1. Calcium ions are bound to prothrombin, which
adheres to platelet surfaces along with factor Xa and
factor V (cofactor). This complex attacks the
prothrombin molecule, forming fragment 2 and
fragment 1.2.
Xa - V Fragment 2 +
Prothrombin
Pl – Ca++ Fragment 1.2

23. 2. In the presence of this same complex, thrombin is
formed from fragment 2.
Xa - V
Fragment 2 Thrombin
Pl – Ca++
* The resultant thrombin is capable of activating factor
V, thereby increasing its activity.

24. D. Formation of the Fibrin Clot
1. Fibrin formation occurs by the action of thrombin
on fibrinogen.
Fibrinogen Thrombin Fibrinopeptide A & B +
Fibrin monomer
2. The fibrin monomer will polymerize end to end and
laterally to form fibrin polymers (fibrin strands)
which are soluble in 5 M urea.
Fibrin polymer
Fibrin monomer
(soluble in 5 M urea)

26. 3. Factor XIII, activated by thrombin and calcium
ions, converts the fibrin polymer to a covalent cross-
linked fibrin clot. This stable fibrin clot is insoluble
in 5 M urea.
Fibrin polymer XIIIa Stable fibrin clot
Ca++ (insoluble in 5 M urea)
4. In the presence of activated platelets the formed
clot will retract.
Activated
Stable fibrin clot platelets
Retracted clot

28. Intrinsic Pathway
XII XIIa
PTT
XI XIa Partial Thromboplastin Time
IX IXa
VIIIa+Ca+Pl
X Xa
Va+Ca+Pl
II IIa
Fibrinogen Fibrin

29. Extrin sic
p a th w a y
In ju red = C alciu m & P L co m p lex
C ells
V II
* = activ e serin e p ro tease
unk. T F
X
* V IIa
*X a
Va V fib rin o g en
p ro th ro m b in * th ro m b in
F ib rin m o n o m er
X III X IIIa
Com m on
p a th w a y
CLOT F ib rin p o ly m er

30. Intrinsic Vs. Extrinsic
Intrinsic Pathway Extrinsic Pathway
Contact Activation Pathway Tissue factor pathway
Begins with the exposure of a Starts when blood is in contact
foreign surface like collagen as with tissue factor (TF)
a result of endothelium
damage
XII, Prekallikrein, HMWK, XI, IX, TF and VII
and cofactor VIII
Both pathways lead to the COMMON PATHWAY which consists of factor X,
cofactor V, Pf3, Ca++, prothrombin and fibrinogen.
The final product of coagulation is cross-linked fibrin, produced in
response to factor XIII, Ca++ and thrombin.

31. • The Prothrombin Time or PT is a laboratory screening test
used to detect coagulation disorders.
• It measures the activity factors of the EXTRINSIC PATHWAY
including factors II, V, VII, X and I (fibrinogen).
• The extrinsic factors not measured in the PT test are Factors
III (Thromboplastin) and IV (Calcium).
• The PT is also used into monitor oral anticoagulant therapy
such as warfarin.

32. Feedback Mechanisms
• Fibrin formation at the site of small wounds takes
place in minutes.
• Feedback mechanisms increase the velocity of the
cascade reactions.
• Positive feedback loop – increases the reaction rate
• Negative feedback loop – dampens the reaction rate