The Classic Cascade has traditionally been taught in textbooks. It
is composed of two basic parts, an intrinsic pathway and an extrinsic pathway
- the intrinsic pathway occurring by physical chemical activation and the
extrinsic pathway being activated by tissue factor released from damaged
cells. Both pathways are thought to be activated simultaneously to initiate
and sustain clot formation. At the same time, platelets are also activated.
(The interrelationship between platelets and the coagulation cascade will
be discussed later.)
The Intrinsic Pathway
This pathway begins with trauma to the blood vessel, exposure of blood
to collagen in a damaged vascular wall, or exposure of the blood to a wetable
surface such as glass. In response to these stimuli, two events occur.
First, Factor XII (aka Hageman Factor) is converted from its inactive form
(zymogen) form to an active form Factor XIIa. Second, platelets are activated
(again to be discussed later). Activated Factor XII is actually a protease
which enzymatically activates Factor XI to Factor XIa ('a' at the end of
factor name denotes an activated enzymatic factor). This reaction
requires the presence of High Molecular Weight Kininogen and Prekallekrein.
Activated Factor XI is also a protease, but its function is to convert
Factor IX to Factor IXa. Also a protease, Factor IXa then converts Factor
X to Factor Xa. This activation of Factor X is also greatly accelerated
by Factor VIIIa. Deficiencies in either Factor VIII or Factor IX lead to
bleeding diatheses known as Hemophilia A and
Hemophilia B, respectively. Activated Factor X
functions as a protease to converts the inactive molecule prothrombin
to the active thrombin. This step requires the presence of Factor Va. Thrombin
then cleaves fibrinogen to fibrin, which then polymerizes to form fibrin
strands.
The Extrinsic Pathway
In this pathway, the initial step is a traumatized vascular wall or extravascular
tissue. Non-vascular tissue cells contain an integral membrane protein
called tissue factor. Damage to the vessel wall or extravascular tissue
exposes the plasma to tissue factor. Factor VII is a circulating plasma
protein that then binds to tissue factor, creating a complex. In doing
so, Factor VII is activated to Factor VIIa. This complex, in the presence
of Ca++ and phospholipids, activates Factor X to Factor Xa. Once Factor
Xa is generated, the remainder of the cascade is similar to the intrinsic
pathway.
The Combined Pathway
Thrombin, once it is generated, is a powerful procoagulant. It catalyzes
the further conversion of Factors V and VIII to their activated forms through
a positive feedback mechanism and converts more prothrombin to thrombin.
In this manner, thrombin is able to accelerate the entire cascade once
generated, resulting in the formation of large amounts of fibrin. It is
important to understand that when the cascade is activated, the amount
of product formed in the individual reactions increase logarithmically
as one moves down the cascade.
