Hematology-Immunology Module
07 August 2009
Nina Rosario L. Rojas, PhD
COAGULATION CASCADE
OUTLINE
I.
II.
III.
IV.
A.
B.
V.
VI.
VII.
VIII.
IX.
Blood Components
Clotting Factors
Steps in Hemostasis
Hemostatic Plug Formation
Primary: Plate Aggregation
Secondary: Coagulation
Coagulation Cascade
Important Cofactors
Clot Removal
Tests for Activity
Hemophilia
C.
D.
E.
I.
BLOOD COMPONENTS
 Fibrinogen stimulates platelet clumping by
binding to exposed collagen
Activation
 Platelets release ADP and Thromboxane A2 (an
eicosanoid) to activate more platelets
 Platelets secrete serotonin, phospholipids,
lipoproteins and other cascade proteins
Aggregation
 Secondary hemostasis occurs, where cascade
forms fibrin mesh or a clot forms to trap
platelet ply in place
White thrombus (only platelets) or Red
Thrombus (with RBCs)
Dissolution
 Plasmin is the key enzyme which dissolves clot
to resume blood flow after repair
Blood Clotting – Anti-platelet effect of Aspirin is due to platelet
cyclooxygenase-1 inhibition.
IV.
II.
CLOTTING FACTORS
 Immunoglobulins
 Major Histocompatibility Complexes and Tcell Receptors
 Cell Surface Markers
o Blood Types
o HLA Types
A. Hemostasis
 The cessation of blood loss from a damaged
blood vessel
 Blood clotting begins when an injury to the
endothelial layer of a blood vessel reveals the
collagen in the endothelium
Disorders lead to hemorrhage
(excessive bleeding) or thrombosis
(unnecessary clotting)
III.
A.
B.
Group 10
STEPS IN HEMOSTASIS
Vascular Constriction
 Limits blood flow
Adhesion
 Primary hemostasis by platelet plug
formation
GONZALES. LENON. MENDOZA. PAREJA. SAMSON.
HEMOSTATIC PLUG FORMATION
A.
Primary: Plate Aggregation
 Plate Aggregation  Clotting
 Collagen-Platelet Interaction
Direct: collagen-specific glycoprotein Ia or
IIa receptors
Indirect: platelets adhere to collagen via
the Von Willebrand factors

The vWF-platelet interaction is due
to glycoproteins Ib, IX and V on the
membrane of platelets

GP IIIa and IIb also interact with vWF

Platelets then release their granule
content and form aggregates

Von
Will
ebra
nd
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BATCH 2014  COAGULATION CASCADE
D
i
s
e
a
s
e
bleeding
-
Common
hereditary
disorder
Autosomal dominant or autosomal
recessive
 Platelets release their Granule Contents
ADP, serotonin, platelet-activating
factor (PAF), vWF, platelet factor IV
and Thromboxane A2 instigate a Gprotein linked receptor cascade

Ca2+ concentration in the
cytosol
increases,
which
activates PKC

Phospholipase A2 is activated
which modifies GP IIb/IIIa

Activated platelets change
shape from spherical to stellate

Clots are formed when
fibrinogen cross-links with GP
IIb/IIIa
-
B.
-

 The blood clotting cascade is regulated by
positive feedback, or by inhibitors such as antithrombin III (forms an irreversible complex with
thrombin) and heparin (enhances antithrombin
activity)
 Plasma concentration of different factors in the
plasma that is required for hemostasis may vary
to some degree
Secondary: Coagulation
VI.
 Coagulation  Thrombin  Fibrin
V.
Group 10
COAGULATION CASCADE
 The conversion of fibrinogen to fibrin via
proteolytic cleavage
GONZALES. LENON. MENDOZA. PAREJA. SAMSON.
Traditionally classified as extrinsic (tissue
factors),
intrinsic
(zymogens
and
proteases) and common pathways
 Factors in the blood are synthesized
in the liver
 Numbers refer to order in which
factors were discovered, not in order
of reaction
Cascade is facilitated by proteolytic
activation (serine proteases)
 Fibrinogen is activated to fibrin by IIa
(thrombin) which causes fibrin
polymerization
 Thrombin results from activation of II
(prothrombin) by Xa
The intrinsic pathway seems to be less
important, since patients with severe
deficiencies of its factors (i.e. FXII do not
have a bleeding disorder)
IMPORTANT COFACTORS
A. Calcium
B. Vitamin K
 Cofactor to hepatic γ-glutamyl carboxylase,
which converts carboxyl groups to glutamic acid
residues on factors II, VII, IX and X and proteins
S, C and Z
 Activates the said factors and proteins through
the oxidation of Vitamin K
 Regenerated by Vitamin K Epoxide Reductase
(VKORC), which reduces it back to its active
form
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BATCH 2014  COAGULATION CASCADE
VII.
REMOVING THE CLOT
 Plasmin, a serine protease, whose inactive
precursor is plasminogen, has a high
affinity for fibrin clots
 Removal is catalyzed by tissue-type
plasminogen activator (TPA), a 72-kd
protein that has a domain structure closely
related to that of prothrombin
VIII.
A.
B.
IX.
-
Factor VII recently introduced as
NovoSeven to control hemorrhage at site
of injury (works with tissue factor)
TESTS FOR ACTIVITY
Contact Factor (Intrinsic) Pathway
 “contact factors” of plasma
 Activated partial thromboplastin time test
(aPTT)
Tissue Factor (Extrinsic) Pathway
 Tissue factor (specific cellular lipoprotein)
 Prothrombin time test (PTT)
 PTT results are often reported as ration to
monitor dosing of oral anticoagulants such
as warfarin
Hemophilia
Hemophilia A
 Factor VIII deficiency
 X-linked recessive
 Transfusions are required; however,
sometimes Factor VIII is recognized as
foreign by the immune system after the
process
 Due to the risk of blood-borne disease,
recombinant Factor VIII is now used
instead
B. Hemophilia B
 Factor IX deficiency
 X-linked recessive
 Called the Christmas disease after the first
reported case
 Transfusions are also used
C. Hemophilia C
 Factor XI deficiency
 Autosomal recessive
 Mild bleeding tendencies, such as nose
bleeds
 Recombinant Factor XI or plasma is used
NEW THERAPIES
A.
Group 10
GONZALES. LENON. MENDOZA. PAREJA. SAMSON.
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BATCH 2014  COAGULATION CASCADE
Group 10
GONZALES. LENON. MENDOZA. PAREJA. SAMSON.
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