SEMINARS IN THROMBOSIS AND HEMOSTASIS-VOLUME 14, NO.
2, 1988
Platelets and Atherosclerosis
JOHN C. HOAK, M.D.
The major function of the blood platelet is to
maintain the hemostatic integrity of the blood vessel
and to stop bleeding after injury. To arrest bleeding,
platelets interact with subendothelial structures, such
as collagen, that activate the platelets, causing them
to change their shape from disks to spheres, form
pseudopodia, and adhere to the collagen fibrils. The
activated platelets release substances from their stor-
age granules that cause additional platelets to form
aggregates at the injury site. This hemostatic plug is
reversible and unstable in the path of streaming blood.
In association with these events, the coagulation sys-
tem is activated to generate thrombin that produces
insoluble fibrin from fibrinogen to stabilize the hemo-
static plug to form an occlusion of the defect in the
damaged vessel wall. Several steps in the coagulation
cascade are dependent on activated platelets for opti-
mal activity.
PLATELETS AND THROMBOSIS
This same process of platelet activation is in-
volved in thrombus formation in the atherosclerotic
vessel at the site of complicated lesions, such as ulcer-
ation, plaque disruption, or subintimal hemorrhage.
The consequence is a partial or total occlusion of the
affected vessel and, depending on the location, myo-
cardial infarction, stroke, or peripheral gangrene may
result. There is no doubt that the development of
thrombosis in relation to a preexisting atherosclerotic
plaque is the most important complicating event in the
natural history of atherosclerosis and is responsible
for the great majority of its clinical manifestations.
From the Department of Medicine, University of Iowa Col-
lege of Medicine, Iowa City, Iowa.
Reprint requests: Dr. Hoak, Department of Medicine, Uni-
versity of Iowa Hospitals Clinics, Iowa City, IA 52242.
202 © 1988 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
PLATELETS AND ATHEROSCLEROSIS
It has become more and more established in recent
years that platelets play a key role in the development
of atherosclerosis. Since Virchow,1 many efforts were
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made to explain the pathogenesis of atherosclerosis.
With respect to the role of platelets in the develop-
ment of atherosclerosis, the "response to injury" hy-
pothesis has brought an important concept to our
understanding of this complex process. The main sug-
gestion of this hypothesis involves the interaction of
platelets with monocytes or macrophages after injury
to the endothelium. 2 The concept of "loss of endo-
thelial integrity" is an important one and may be a
consequence of injury to the endothelium caused by
mechanical forces at sites of flow effects, by choles-
terol deposition and foam cell infiltration into the
subendothelium, vasculitis as a consequence of toxins
or bacterial or viral infections, and immunologic in-
jury. Cines et al 3 reported recently on immune endo-
thelial cell injury in patients with heparin-associated
thrombocytopenia who developed thrombosis. We
have demonstrated immune endothelial injury in several
patients with post-transfusion purpura. 4
Another type of injury to the endothelium that
has become of particular interest is due to the effect
of oxygen radicals. Shatos et al 5 demonstrated sub-
lethal endothelial injury and enhanced platelet adher-
ence using an in vitro approach with cultured endo-
thelial cells and the xanthine-xanthine oxidase system
to generate superoxide anion radicals. When superox-
ide dismutase and catalase, scavengers of the superox-
ide radical and hydrogen peroxide, were added to
treated cells, injury and platelet adherence were pre-
vented.
Injury to the endothelium can lead to its separa-
tion from the subendothelium, exposure of the suben-
dothelial collagen to circulating blood cells, and the
accumulation of macrophages and platelets at the site
of injury. In addition to vasoactive substances, plate-
PLATELETS AND ATHEROSCLEROSIS - HOAK 203

let-derived growth factor (PDGF) is released by plate-
lets. Once secreted at the locus of injury, PDGF can
induce the proliferation and migration of smooth
muscle cells leading to the development of a prolifer-
ative atherosclerotic lesion (Fig. 1). It is likely that
alternative mechanisms may operate to induce the
proliferative atherosclerotic lesion, including stimuli
from other sources such as lymphokines and the
effects of growth factors from the endothelium and
other cells of the vessel wall.
Further evidence for involvement of the platelet
in the development of the atherosclerotic lesion was
provided by Curtiss et al,6 who demonstrated that
platelets directly enhanced macrophage cholesterol
ester accumulation. Both the rate of cholesterol ester-
ification and the accumulation of cholesterol ester
were increased within 24 hours of the coculture of
adherent macrophages with platelets.
From the practical aspect of attempting to inter-
fere with the development of the proliferative athero-
sclerotic lesion, it has been demonstrated that severe
but not moderate thrombocytopenia in rabbits dimin-

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FIG. 1. The revised response to injury hypothesis. Advanced intimal proliferative lesions of
atherosclerosis may occur by at least two pathways. The pathway shown by the long arrows
to the right has been observed in experimentally induced hypercholesterolemia. Injury to the
endothelium (A) may induce growth factor secretion (short arrow). Monocytes attach to the
endothelium (B), which may continue to secrete growth factors (short arrow). Subendothelial
migration of monocytes (C) may lead to fatty streak formation and release of growth factors,
such as PDGF (short arrow). Fatty streaks may become directly converted to fibrous plaques
(arrow C to F) through release of growth factors from macrophages or endothelial cells or
both. Macrophages may also stimulate or injure the overlying endothelium. In some cases
macrophages may lose their endothelial cover and platelet attachment may occur (D), pro-
viding three possible sources of growth factors: platelets, macrophages, and endothelium
(short arrows). Some of the smooth muscle cells in the proliferative lesion itself (F) may form
and secrete growth factors such as PDGF (short arrows). An alternative pathway for devel-
opment of advanced lesions is shown by arrows from A to E to F. The endothelium may be
injured but remain intact. Increased endothelial turnover may result in growth factor forma-
tion by endothelial cells (A). This may stimulate migration of smooth muscle cells from the
media into the intima, accompanied by endogenous production of PDGF by smooth muscle
as well as growth factor secretion from the injured endothelial cells (E). These interactions
could then lead to fibrous plaque formation and further lesion progression (F). (Reproduced
with permission from Ross. 2 )
204 SEMINARS IN THROMBOSIS AND HEMOSTASIS-VOL. 14, NO. 2, 1988

ishes the size of the proliferative lesion after mechan-

ical injury to the aorta. In addition, pigs with severe
homozygous von Willebrand's disease reportedly de-
velop less atherosclerosis of the abdominal aorta than
do normal control pigs. Significant evidence is not
currently available to indicate that impaired platelet
function can prevent the development of atheroscle-
rosis in humans. Patients with the common type I
form of von Willebrand's disease (von Willebrand's
factor levels in the 15 to 60% of normal range) are
not protected from developing severe atherosclerosis.
In his hematology text Rapaport 7 described a patient
who is relevant to the issue.
A patient that I have seen has two hereditary
disorders - a disorder of lipid metabolism leading to
hypercholesterolemia and a hereditary disorder of
platelet function limiting release of adenosine diphos-

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phate (ADP) from platelets. She developed very severe
coronary atherosclerosis secondary to hypercholester-
olemia despite lifelong impaired platelet function that
prolongs the bleeding time to more than 20 minutes.
Such an experiment of nature dampens one's enthu-
siasm for long-term administration of drugs inhibiting
platelet function as prophylaxis against progression of
atherosclerosis in humans. 7
PLATELETS AND VASCULAR SPASM
Recent studies have indicated the important role
of the vascular endothelium in mediating relaxant ac-
tivity by the underlying smooth muscle8 (Fig. 2).
ADP and thrombin were the first blood constit-
uents shown to trigger endothelium-dependent re-
sponses. It was later shown that aggregating platelets
and their release products (serotonin, platelet-activat-
ing factor) can evoke endothelium-dependent relaxa-
tion.
The fact that platelets can cause the release of en-
dothelium-derived relaxing factor explains why the
presence of the endothelium considerably reduces the
ability of aggregating platelets to evolve contraction
of isolated blood vessels. It likely contributes to the
protective role of the endothelium against intravascu-
lar platelet aggregation and thrombus formation. In
contrast, the absence of the endothelium favors the
occurrence of vasoconstriction in response to the
platelet products and thrombin. In pathologic circum-
stances, the absence or dysfunction of the endothe-
lium favors the occurrence of abnormal constriction
of blood vessels resulting in vasospasm. Recent stud-
ies suggest that at least one endothelium-dependent
relaxant factor (EDRF) is nitric oxide.9 In atheroscle-
rotic arteries, less EDRF is produced. In fact, the
atherosclerotic vessel exhibits vasoconstriction in
FIG. 2. Role of endothelial cells in prevention of vasospasm.
Aggregating platelets release adenine nucleotides (ATP and
ADP), serotonin, (5-HT), thromboxane A 2 (TBA2), platelet-
activating factor (PAF), and vasopressin (VP), as well as initiat-
ing the coagulation cascade with production of thrombin. Top:
Intact endothelium prevents platelet aggregation through pro-
duction of platelet inhibitor, prostacyclin (PGI2). PGI2 is also a
vasodilator. 5-HT is taken up by endothelial cells and degraded
by monoamine oxidase (MAO). PAF (in high concentrations),
5-HT, VP, adenine nucleotides, and thrombin can stimulate the
endothelial production of a relaxing factor or factors that have
an inhibitory effect on smooth muscle. Relaxation and vasodi-
lation would tend to flush away any developing aggregate or
thrombus. Finally, an intact endothelium and basement mem-
brane probably serve as a diffusion barrier to prevent above-
mentioned substances from reaching smooth muscle layers of
media. Bottom: if endothelium is damaged, platelet aggregation
is enhanced by contact with collagen in exposed vessel wall.
Depending on blood vessels, thrombin, VP, 5-HT, adenine
nucleotides, and TBA 2 can activate vascular smooth muscle
directly. Vasospasm may thus result in areas of endothelial
abnormality. (Reproduced with permission from Vanhoutte. 1 3 )
response to thrombin rather than the usual vasodila-
tion. 10 Similarly, the atherosclerotic coronary artery
develops vasoconstriction in response to acetylcholine,
whereas the normal coronary artery dilates. Both ex-
hibit vasodilation in response to nitroglycerin.11 In
experimental animals with atherosclerosis that have
undergone regression of lesions as a consequence of
dietary change, EDRF formation and release in re-
sponse to stimulation by thrombin is restored.12 These
mechanisms extend considerably our understanding of
the role that platelets may play in normal vascular
PLATELETS AND ATHEROSCLEROSIS - HOAK
reactivity and, more importantly, how they can influ-
ence the development of persistent occlusion in the
artery with an advanced and complicated atheroscle-
rotic lesion.
SUMMARY
This discussion has centered about the conse-
quences of the loss of endothelial integrity and how
the blood platelet behaves under these circumstances.
It is clear that the platelet can function as a partici-
pant in the development of the atherosclerotic lesion,
can be an important contribution to mechanisms that
operate to produce vascular spasm, and ultimately can
play a major role in the development of thrombosis at
the site of the complicated end-stage atherosclerotic
lesion.
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3. Cines DB, A Tomaski, S Tannenbaum: Immune endothe-
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J Med 316:581-589, 1987.
4. Hoak JC: Unpublished observations.
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