Cardiovascular Physiology
437
reduces both platelet aggregation and the ensuing coagula-
tion. Importantly, low doses of aspirin cause a steady-state
decrease in
platelet
cyclooxygenase (COX) activity but not
endothelial-cell
cyclooxygenase, and so the formation of pros-
tacyclin—the prostaglandin that opposes platelet aggrega-
tion—is not impaired. (There is a reason for this difference
between the responses of platelet and endothelial-cell cyclo-
oxygenase to drugs: Platelets, once formed and released from
megakaryocytes, have lost their ability to synthesize proteins,
so that when their COX is blocked—the effect on any given
COX molecule is irreversible—thromboxane A
2
synthesis is
gone for that platelet’s lifetime. In contrast, the endothelial
cells produce new COX molecules to replace the ones blocked
by the drug.) Aspirin appears to be highly effective at prevent-
ing heart attacks. In addition, the administration of aspirin
following a heart attack signifi cantly reduces the incidence of
sudden death and a recurrent heart attack.
A variety of new drugs that interfere with platelet func-
tion by mechanisms different from those of aspirin also have
great promise in the treatment or prevention of heart attacks.
In particular, certain drugs block the binding of fi brinogen to
platelets and thus interfere with platelet aggregation.
Drugs that interfere with the action of vitamin K, which
is required for the synthesis of clotting factors by the liver, are
collectively termed
oral anticoagulants
.
Heparin, the naturally occurring endothelial cell cofac-
tor for antithrombin III, can also be administered as a drug,
which then binds to endothelial cells. In addition to its role in
facilitating the action of antithrombin III, heparin also inhib-
its platelet function.
In contrast to aspirin, the fi brinogen blockers, the oral
anticoagulants, and heparin, all of which prevent clotting, the
fi fth type of drug—plasminogen activators—dissolves a clot
after it is formed. The use of such drugs is termed
thrombo-
lytic therapy
.
Intravenous administration of
recombinant
t-PA
or a proteolytic drug called
streptokinase
within three
hours after myocardial infarction signifi cantly reduces myocar-
dial damage and mortality. Recombinant t-PA has also been
effective in reducing brain damage following a stroke caused
by blood vessel occlusion. In addition, exciting new clinical
studies suggest that a plasminogen activator found in vampire
bat saliva may be even more effective than t-PA at protecting
the brain after an ischemic stroke. Its name includes the genus
and species of the animal—
Desmodus rotundus salivary
plasminogen activator
(
DSPA
).
SECTION F SUMMARY
Plasma
I. Plasma is the liquid component of blood; it contains proteins,
(albumins, globulins, and fi brinogen), nutrients, metabolic end
products, hormones, and inorganic electrolytes.
II. Plasma proteins, synthesized by the liver, play many roles
within the bloodstream, such as exerting osmotic pressure for
absorption of interstitial fl uid and participating in the clotting
reaction.
The Blood Cells
I. The blood cells, which are suspended in plasma, include
erythrocytes, leukocytes, and platelets.
II. Erythrocytes, which make up more than 99 percent of blood
cells, contain hemoglobin, an oxygen-binding protein. Oxygen
binds to the iron in hemoglobin.
a. Erythrocytes are produced in the bone marrow and
destroyed in the spleen and liver.
b. Iron, folic acid, and vitamin B
12
are essential for erythrocyte
formation.
c. The hormone erythropoietin, which is produced by the
kidneys in response to low oxygen supply, stimulates
erythrocyte differentiation and production by the bone
marrow.
Table 12–15
Anticlotting Roles of Endothelial Cells
Action
Result
Normally provide an intact barrier between the blood and
subendothelial connective tissue
Platelet aggregation and the formation of tissue factor-factor VIIa
complexes are not triggered.
Synthesize and release PGI
2
and nitric oxide
These inhibit platelet activation and aggregation.
Secrete tissue factor pathway inhibitor
This inhibits the ability of tissue factor-factor VIIa complexes to
generate factor Xa.
Bind thrombin (via thrombomodulin), which then activates
protein C
Active protein C inactivates clotting factors VIIIa and Va.
Display heparin molecules on the surfaces of their plasma
membranes
Heparin binds antithrombin III, and this molecule then inactivates
thrombin and several other clotting factors.
Secrete tissue plasminogen activator
Tissue plasminogen activator catalyzes the formation of plasmin,
which dissolves clots.
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