c h a p t e r 36
Biochemistry of Hemostasis
(A lso see color figure.) C ontem porary m odel for the procoagulant
subsystem . This m odel recognizes that the transform ations o f proteinase
precursors to active proteinases are organized on the surfaces to w hich the
proteins bind. The binding o f the freely circulating coagulation proteins to
these surfaces localizes the reactions that m akeup the hem ostatic response,
as well as increases the rates of the reactions. U nlike the other coagulation
factors, tissue factor does not circulate freely. It is an integral m em brane
protein that is exposed as a result of exposure o f the subendothelium . In the
color version o f this figure, each stage of the sequence a proteinase
precursor (shown in orange), a proteinase from the preceding com plex
(shown in dark green), and an activated cofactor protein (shown in
yellow -green) form a noncovalent com plex on the m em brane surface
(shown as is distinguished a blue “island”). D issociation of the proteinase
form ed in one com plex (the product proteinase) perm its that proteinase to
diffuse to the next com plex and catalyze the transform ation of a different
precursor protein into an active proteinase. Throm bin is the only proteinase
that does not bind to the surface o f the m em brane; it dissociates and
diffuses so that it can convert the soluble fibrinogen into the insoluble
fibrin clot. Vitamin K -dependent proteins are prothrom bin and factors VII,
IX, and X. Two vitam in K -dependent proteins are not shown, protein C and
protein S. The
u n a c tiv a ted
cofactor proteins, tissue factor, and factors V
and VIII are shown in yellow.
components become functionally active as the result of an
initiating event, the formation of the fibrin itself. Through
association of the plasminogen, and plasminogen activa-
tors with the fibrin, the processes responsible for the for-
mation of plasmin are localized to the fibrin. Fibrinolysis
is responsible for the temporary
of the fibrin clot.
thrombus. Rather, a combination of defects in more than
one component appears to be required. Each defect can
increase the risk of thrombosis at some time during an
individual’s lifetime. The cumulative increased risk re-
duces the age at which a thrombotic event may occur. De-
ficiencies or defects in the inhibitors of the procoagulant
proteinases, an increased concentration of fibrinogen, an-
tibodies to lipid-bound proteins, and hyperhomocysteine-
mia are examples of situations that create an increased
risk of thrombosis. Hyperhomocysteinemia results from a
decrease in methylene tetrahydrofolate reductase activity.
This may be caused by a defect in this enzyme, by other
enzymes in the pathway, and/or by a decrease in vitamin
Bn (Chapter 17).
Estrogen therapy has been linked to changes in the
concentrations of several components of the hemostatic
system. However, there are no changes in components of
the procoagulant, anticoagulant, or fibrinolytic system that
can be clearly linked to an increase in risk of thromboem-
bolic disease sometimes associated with estrogen therapy.
36.3 Functional Properties and Structures of the
Hemostatic System Factors (Proteins)
Although there are approximately 20 plasma proteins or
plasma clotting factors that participate in the reactions of
blood clotting, these proteins can be divided into four cate-
gories based on their principal functions. Grouping in this
way simplifies and facilitates our understanding of how
and what these proteins do in the clotting process. The
four categories are as follows:
1. Proteinase precursors,
2. Cofactor proteins,
3. Proteinase inhibitors, and
4. Other proteins not included in the first three
categories. This fourth group contains one enzyme, a
transglutaminase, one adhesion and carrier protein,
and fibrinogen, the structural protein of the fibrin clot.
Thrombosis: A Dark Side of Hemostatic
System Function
Formation of a hemostatic plug or a red thrombosis (fibrin
and entrapped red blood cells) at a site at which there is
no injury produces occlusion. Death to the surrounding
tissues can occur (infarction), or pieces of the thrombus
may be “tom” away and moved to the lungs, producing
pulmonary embolism. Such dysfunction of the hemostatic
system is generally not attributable to a single cause. For
example, heterozygous individuals with half of the nor-
mal amount of protein C do not necessarily present with
Proteinase Precursors
Proteinase precursors, also called zymogens or proen-
zymes, become catalytically active enzymes upon specific
proteolytic cleavage. The precursor molecules circulate as
inactive forms that do not exhibit enzymatic activity. The
activation processes are irreversible. Extensive structural
similarities are found among all proteinase precursors. The
regions of the molecules that express proteinase activity
after activation are found in the C-terminal one-half to
one-third of each molecule. The portion of each precursor
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