266
U N I T 3
Hematopoietic Function
The Coagulation Cascade
The coagulation cascade is the third component of the
hemostasis. It is a stepwise process resulting in the con-
version of the soluble plasma protein fibrinogen into
insoluble fibrin strands. The fibrin strands create a
meshwork that cements platelets and other blood com-
ponents together to form the clot.
The coagulation process results from the activation
of what have traditionally been designated the
intrinsic
and the
extrinsic
pathways
1,3
(Fig. 12-3). The intrinsic
pathway, which is a relatively slow process, begins in the
circulation with the activation of factor XII (Hageman
factor). The extrinsic pathway, which is a much faster
process, begins with trauma to the blood vessel or sur-
rounding tissues and the release of an adhesive lipopro-
tein called
tissue factor
(also known as thromboplastin or
factor III) from the subendothelial cells. In the presence
of calcium, factors V and VII form a complex that, in
turn, activates factor X. The terminal steps in both path-
ways are the same: the activation of factor X and the con-
version of prothrombin (II) to thrombin (IIa). Thrombin
then acts as the enzyme to convert fibrinogen (I) to fibrin
(Ia), the material that stabilizes a clot. The intrinsic sys-
tem is activated as blood comes in contact with collagen
in the injured vessel wall; the extrinsic system is activated
when blood is exposed to tissue extracts. However, this
classification is largely artificial since both systems are
needed for normal hemostasis, and many interrelations
exist between them.
8
Moreover, each system is activated
when blood leaks out of the vascular system.
Clinical laboratories assess the function of the two
limbs of the coagulation pathway through two standard
assays: the
prothrombin time
(PT) and the
partial throm-
boplastin
time (PTT). The PT assesses the function of the
extrinsic pathway (factors VII, X, V, II, and fibrinogen),
while the PTT assesses the function of the intrinsic path-
way (factors XII, XI, IX, VII, X, V, II, and fibrinogen).
3
Once initiated, the coagulation cascade must be
restricted to the local site of vascular injury to prevent
clotting from occurring in the entire vascular system.
Several natural anticoagulants function to control clot-
ting—antithrombin III, proteins C and S, and tissue
factor pathway inhibitor.
4
Antithrombin III inhibits the
activity of thrombin (IIa) and factors IXa, Xa, XIa, and
XIIa (see Fig. 12-3). It is activated by binding to hepa-
rin-like molecules on endothelial cells. Proteins C and S
are two vitamin K–dependent plasma proteins that inac-
tivate the cofactors Va and VIIIa. Tissue factor pathway
inhibitor is a protein secreted by the endothelium that
inactivates factor Xa and tissue factor VIIa complexes.
The anticoagulant drugs warfarin and heparin are
used to prevent thromboembolic disorders, such as deep
vein thrombosis and pulmonary embolism.
6
Warfarin
acts by decreasing prothrombin and other procoagula-
tion factors. It alters vitamin K in a manner that reduces
its ability to participate in the synthesis of the vitamin
K–dependent coagulation factors in the liver. Warfarin is
readily absorbed after oral administration. Its maximum
effect takes 36 to 72 hours because of the varying half-
lives of different clotting factors that remain in the circu-
lation. Heparin is naturally formed and released in small
XII
XIIa
XI
XIa
IX
IXa
Ca
++
Xa
Ca
++
Prothrombin
Fibrinogen
Thrombin
Fibrin (monomer)
Fibrin (polymer)
Extrinsic system
(tissue factor)
X
X
VIIa
VII
Intrinsic system
(blood or vessel injury)
Thrombin
VIII
VIIIa
Ca
++
Ca
++
FIGURE 12-3.
The intrinsic and extrinsic
coagulation pathways. The terminal steps in
both pathways is the same. Calcium, factor
X, and platelet phospholipids combine to
form prothrombin activator, which then
converts prothrombin (II) to thrombin (IIa).This
interaction causes conversion of fibrinogen
(I) into the fibrin (Ia) strands that create the
insoluble blood clot.
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