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The hemostatic mechanism is a dynamic
system that maintains the fluidity of blood, while allowing for
the formation of blood clots to prevent bleeding subsequent to blood vessel
injury. These interrelated components consist of vessel walls (including
endothelial cells), platelets, coagulation factors, inhibitors,
and the fibrinolytic mechanism. Perturbation of any of these systems
can lead to disease states that are thrombotic or hemorrhagic in
nature. This chapter discusses the normal and abnormal hemostatic
system in children, with emphasis on disorders involving the endothelium,
platelets, and defects in coagulation and fibrinolysis.
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Role of the
Endothelium
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The endothelium is comprised of a single layer of endothelial
cells lining the inner lumen of the vascular wall and the underlying basement
membrane matrix that provides structural and functional support
to the entire vascular network. The primary role of the endothelial
cells is to act as a selective barrier between the circulating blood
and the underlying tissues, ensuring vascular patency by providing
a nonthrombogenic surface for circulating blood under normal, physiologic conditions.
In addition, the endothelium interacts with the underlying matrix
by directing the passage of molecules, nutrients, solutes, and hormones
from the blood. Blood flow within the vasculature can be altered
by the endothelial cells that work in conjunction with pericytes
(specialized smooth muscle cells) and basement membrane (BM) matrix.1,2 This
is accomplished by modulating vascular tone through contraction3-5 or
relaxation6-8 of the smooth muscle cells by releasing
vasoactive substances into the adjacent milieu, ultimately influencing
blood flow and pressure and permeability. Intact endothelial cells
inhibit platelet adhesion by production of nitric oxide (NO) and
prostaglandin I2 (PGI2), which also has a vasodilatory
effect. Weibel-Palade bodies in endothelial cells are important
for storage and sequestration of the largest multimers of von Willebrand
factor (vWF).9,10 Endothelial cells also produce
tissue factors and tissue factor pathway inhibitor (TFPI), tissue plasminogen
activator (t-PA), prostacyclin, antithrombin (AT), and thrombomodulin,
as well as the surface protein for activation of protein C (PC).
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The multifunctionality of the endothelium also includes metabolic processes
that release substances into the bloodstream, influencing conditions
both locally and systemically in the blood, and basal lamina, to
sustain and direct BM matrix composition and function. BMs have
unique composition dependent on the specific environment of the
vasculature (tissue specific).11-13 In constant
contact with cells, BM plays a vital role by providing structural
support, compartmentalization of tissues, and regulation of cell
behavior, such as cell attachment, migration, differentiation, and
growth.11,14-17 The thrombogenic subendothelial layer
is composed of collagen, elastin, and fibronectin. The main component
of the BM is collagen (mainly, type IV), comprising ~50% of
its protein.12,13,18 Endothelial cells are capable
of altering the surrounding basement membrane matrix by secreting
collagenases.19-21 Preserving the integrity of
the endothelium in an ever-changing environment is essential because disruption
to any of these systems that alter the ...