C h a p t e r 1 2
Disorders of Hemostasis
267
amounts by mast cells in connective tissue surrounding
capillaries. Heparin binds to antithrombin III, causing
a conformational change that increases the ability of
antithrombin III to inactivate thrombin (IIa), factor Xa,
and other clotting factors. By promoting the inactiva-
tion of clotting factors, heparin ultimately suppresses the
formation of fibrin and therefore inhibits coagulation.
Pharmacologic preparations of heparin are extracted from
animal tissues. Heparin is unable to cross the membranes
of the gastrointestinal tract and must be given by injec-
tion, usually by intravenous infusion. Low–molecular-
weight heparins have been developed that inhibit activa-
tion of factor X, but have little effect on thrombin and
other coagulation factors. The low–molecular-weight
heparins are given by subcutaneous injection and require
less-frequent administration and monitoring compared
with the standard (unfractionated) heparin.
Clot Retraction
Clot retraction normally occurs within 20 to 60 min-
utes after a clot has formed, contributing to hemostasis
by squeezing serum from the clot and joining the edges
of the broken vessel. Platelets, through the action of
their actin and myosin filaments, also contribute to clot
retraction. Clot retraction therefore requires large num-
bers of platelets, and failure of clot retraction is indica-
tive of a low platelet count.
Clot Dissolution
The dissolution of a blood clot begins shortly after its
formation; this allows blood flow to be reestablished
and permanent tissue repair to take place.
1
The process
in which the strands of the clot are dissolved is called
fibrinolysis.
As with clot formation, clot dissolution
requires a sequence of steps controlled by activators and
inhibitors. Plasminogen, the proenzyme for the fibri-
nolytic process, normally is present in the blood in its
inactive form. It is converted to its active form, plasmin,
by plasminogen activators (PAs) formed in the vascular
endothelium, liver, and kidneys. The plasmin formed
from plasminogen digests the fibrin strands of the clot
and certain clotting factors, such as fibrinogen (I), fac-
tor V, factor VIII, prothrombin (II), and factor XII. The
most important of the plasminogen activators is
tissue-
type plasminogen activator
(tPA), which is synthesized
principally by endothelial cells and is most active when
attached to fibrin. The affinity of tPA for fibrin makes
it a useful therapeutic agent, since it largely confines
its activity to sites of recent thrombosis.
3
Another plas-
minogen activator called
urokinase-type plasminogen
activator
(uPA) is present in the tissues and can activate
plasminogen in the fluid phase.
As with other potent physiologic systems, the activity
of plasmin is tightly controlled. Excess circulating plas-
min is rapidly inactivated by
α
2
-antiplasmin, which lim-
its the fibrinolytic process to the local clot rather than
allowing it to spread throughout the entire circulation.
3
Endothelial cells further modulate the coagulation/anti-
coagulation process by releasing PA inhibitors, which
block fibrinolysis and confer an overall procoagulation
effect. The PA inhibitors are increased by certain cyto-
kines and probably play a role in the intravascular
thrombosis accompanying severe inflammation.
Hypercoagulability States
Hypercoagulability represents an exaggerated form of
hemostasis that predisposes to thrombosis and blood
vessel occlusion. There are two general forms of hyperco-
agulability states: conditions that create increased plate-
let function and conditions that cause accelerated activity
of the coagulation system. Chart 12-1 summarizes con-
ditions commonly associated with hypercoagulability
states. Arterial thrombi are usually due to turbulence and
composed largely of platelet aggregates, whereas venous
thrombi are usually due to stasis of flow and composed
largely of platelet aggregates and fibrin complexes that
result from activation of the coagulation cascade.
Increased Platelet Function
Increased platelet function predisposes to platelet adhe-
sion, formation of platelet clots, and the disruption of
blood flow. The causes of increased platelet function
SUMMARY CONCEPTS
■■
Hemostasis is an orderly multistep physiological
process that preserves vascular integrity by
balancing the processes that maintain blood
in a fluid state and prevent excessive bleeding
following injury.
■■
Hemostasis involves platelets, plasma clotting
factors, naturally occurring anticoagulants, and
the endothelial cells that line blood vessels, in
order to transform blood into a semisolid clot
with erythrocytes trapped in its fibrin meshwork.
■■
The process of hemostasis begins when a loss of
endothelial integrity causes platelet activation.
Upon activation, platelets undergo adhesion,
granule release, and aggregation to form a
primary platelet plug.
■■
The formation of the secondary hemostatic plug
cements the platelet plug, forming an insoluble
hemostatic clot.To occur, the formation of the
definitive clot requires activation of the coagulation
cascade, which terminates with thrombin
converting fibrinogen into insoluble fibrin.
■■
The final step of the process involves fibrinolysis
or clot dissolution, which involves the action of
plasmin to dissolve the clot and allow blood flow to
be reestablished and tissue healing to take place.
