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2, 1988

Platelets and Atherosclerosis


The major function of the blood platelet is to PLATELETS AND ATHEROSCLEROSIS

maintain the hemostatic integrity of the blood vessel
and to stop bleeding after injury. To arrest bleeding, It has become more and more established in recent
platelets interact with subendothelial structures, such years that platelets play a key role in the development
as collagen, that activate the platelets, causing them of atherosclerosis. Since Virchow,1 many efforts were

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to change their shape from disks to spheres, form made to explain the pathogenesis of atherosclerosis.
pseudopodia, and adhere to the collagen fibrils. The With respect to the role of platelets in the develop-
activated platelets release substances from their stor- ment of atherosclerosis, the "response to injury" hy-
age granules that cause additional platelets to form pothesis has brought an important concept to our
aggregates at the injury site. This hemostatic plug is understanding of this complex process. The main sug-
reversible and unstable in the path of streaming blood. gestion of this hypothesis involves the interaction of
In association with these events, the coagulation sys- platelets with monocytes or macrophages after injury
tem is activated to generate thrombin that produces to the endothelium. 2 The concept of "loss of endo-
insoluble fibrin from fibrinogen to stabilize the hemo- thelial integrity" is an important one and may be a
static plug to form an occlusion of the defect in the consequence of injury to the endothelium caused by
damaged vessel wall. Several steps in the coagulation mechanical forces at sites of flow effects, by choles-
cascade are dependent on activated platelets for opti- terol deposition and foam cell infiltration into the
mal activity. 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
PLATELETS AND THROMBOSIS thrombocytopenia who developed thrombosis. We
have demonstrated immune endothelial injury in several
This same process of platelet activation is in- patients with post-transfusion purpura. 4
volved in thrombus formation in the atherosclerotic Another type of injury to the endothelium that
vessel at the site of complicated lesions, such as ulcer- has become of particular interest is due to the effect
ation, plaque disruption, or subintimal hemorrhage. of oxygen radicals. Shatos et al 5 demonstrated sub-
The consequence is a partial or total occlusion of the lethal endothelial injury and enhanced platelet adher-
affected vessel and, depending on the location, myo- ence using an in vitro approach with cultured endo-
cardial infarction, stroke, or peripheral gangrene may thelial cells and the xanthine-xanthine oxidase system
result. There is no doubt that the development of to generate superoxide anion radicals. When superox-
thrombosis in relation to a preexisting atherosclerotic ide dismutase and catalase, scavengers of the superox-
plaque is the most important complicating event in the ide radical and hydrogen peroxide, were added to
natural history of atherosclerosis and is responsible treated cells, injury and platelet adherence were pre-
for the great majority of its clinical manifestations. vented.
Injury to the endothelium can lead to its separa-
tion from the subendothelium, exposure of the suben-
From the Department of Medicine, University of Iowa Col-
lege of Medicine, Iowa City, Iowa. dothelial collagen to circulating blood cells, and the
Reprint requests: Dr. Hoak, Department of Medicine, Uni- accumulation of macrophages and platelets at the site
versity of Iowa Hospitals Clinics, Iowa City, IA 52242. of injury. In addition to vasoactive substances, plate-

202 © 1988 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.

let-derived growth factor (PDGF) is released by plate- in the development of the atherosclerotic lesion was
lets. Once secreted at the locus of injury, PDGF can provided by Curtiss et al,6 who demonstrated that
induce the proliferation and migration of smooth platelets directly enhanced macrophage cholesterol
muscle cells leading to the development of a prolifer- ester accumulation. Both the rate of cholesterol ester-
ative atherosclerotic lesion (Fig. 1). It is likely that ification and the accumulation of cholesterol ester
alternative mechanisms may operate to induce the were increased within 24 hours of the coculture of
proliferative atherosclerotic lesion, including stimuli adherent macrophages with platelets.
from other sources such as lymphokines and the From the practical aspect of attempting to inter-
effects of growth factors from the endothelium and fere with the development of the proliferative athero-
other cells of the vessel wall. sclerotic lesion, it has been demonstrated that severe
Further evidence for involvement of the platelet 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 )

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 FIG. 2. Role of endothelial cells in prevention of vasospasm.
Aggregating platelets release adenine nucleotides (ATP and
atherosclerosis in humans. 7
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:
PLATELETS AND VASCULAR SPASM 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
Recent studies have indicated the important role by monoamine oxidase (MAO). PAF (in high concentrations),
of the vascular endothelium in mediating relaxant ac- 5-HT, VP, adenine nucleotides, and thrombin can stimulate the
tivity by the underlying smooth muscle8 (Fig. 2). endothelial production of a relaxing factor or factors that have
ADP and thrombin were the first blood constit- an inhibitory effect on smooth muscle. Relaxation and vasodi-
lation would tend to flush away any developing aggregate or
uents shown to trigger endothelium-dependent re-
thrombus. Finally, an intact endothelium and basement mem-
sponses. It was later shown that aggregating platelets brane probably serve as a diffusion barrier to prevent above-
and their release products (serotonin, platelet-activat- mentioned substances from reaching smooth muscle layers of
ing factor) can evoke endothelium-dependent relaxa- media. Bottom: if endothelium is damaged, platelet aggregation
tion. is enhanced by contact with collagen in exposed vessel wall.
Depending on blood vessels, thrombin, VP, 5-HT, adenine
The fact that platelets can cause the release of en-
nucleotides, and TBA 2 can activate vascular smooth muscle
dothelium-derived relaxing factor explains why the directly. Vasospasm may thus result in areas of endothelial
presence of the endothelium considerably reduces the abnormality. (Reproduced with permission from Vanhoutte. 1 3 )
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 response to thrombin rather than the usual vasodila-
contrast, the absence of the endothelium favors the tion. 10 Similarly, the atherosclerotic coronary artery
occurrence of vasoconstriction in response to the develops vasoconstriction in response to acetylcholine,
platelet products and thrombin. In pathologic circum- whereas the normal coronary artery dilates. Both ex-
stances, the absence or dysfunction of the endothe- hibit vasodilation in response to nitroglycerin.11 In
lium favors the occurrence of abnormal constriction experimental animals with atherosclerosis that have
of blood vessels resulting in vasospasm. Recent stud- undergone regression of lesions as a consequence of
ies suggest that at least one endothelium-dependent dietary change, EDRF formation and release in re-
relaxant factor (EDRF) is nitric oxide.9 In atheroscle- sponse to stimulation by thrombin is restored.12 These
rotic arteries, less EDRF is produced. In fact, the mechanisms extend considerably our understanding of
atherosclerotic vessel exhibits vasoconstriction in the role that platelets may play in normal vascular

reactivity and, more importantly, how they can influ- lial-cell injury in heparin-associated thrombocytopenia. N Engl
ence the development of persistent occlusion in the J Med 316:581-589, 1987.
artery with an advanced and complicated atheroscle- 4. Hoak JC: Unpublished observations.
5. Shatos M, J Doherty, D Allen, J Hoak: Alterations in vascu-
rotic lesion. lar endothelial cell function by oxygen-free radicals. Thromb
Haemost 58:155, 1987.
6. Curtiss LK, AS Black, Y Takagi, EF Plow: New mechanisms
SUMMARY for foam cell generation in atherosclerotic lesions. J Clin Invest
80:367-373, 1987.
This discussion has centered about the conse- 7. Rapaport SI: Introduction to Hematology, 2nd ed. JB Lippin-
cott, Philadelphia, 1987, p 559.
quences of the loss of endothelial integrity and how 8. Furchgott RF, JV Zawadzki: The obligatory rate of endothe-
the blood platelet behaves under these circumstances. lial cells in the relaxation of arterial smooth muscle by ace-
It is clear that the platelet can function as a partici- tylcholine. Nature 288:373-376, 1980.
pant in the development of the atherosclerotic lesion, 9. Palmer RM, AG Ferrige, S Moncada: Nitric oxide release
can be an important contribution to mechanisms that accounts for the biological activity of endothelium-derived
relaxing factor. Nature 327:524-526, 1987.
operate to produce vascular spasm, and ultimately can
10. Freiman PC, GC Mitchell, DD Heistad, ML Armstrong, DG
play a major role in the development of thrombosis at Harrison: Atherosclerosis impairs endothelium-dependent vas-
the site of the complicated end-stage atherosclerotic cular relaxation to acetylcholine and thrombin in primates. Circ

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lesion. Res 58:783-789, 1986.
11. Ludmer PL, AP Selwyn, TL Shook, RR Wayne, GH Mudge,
RW Alexander, P Ganz: Paradoxical vasoconstriction induced
by acetylcholine in atherosclerotic coronary arteries. N Engl J
REFERENCES Med 315:1046-1051, 1986.
12. Harrison DG, ML Armstrong, PC Freiman, DD Heistad:
1. Virchow R: Gesammelte Abhandlungen zur wissenschaftlichen Restoration of endothelium dependent relaxation by dietary
Medizin. Frankfurt/Main, 1856, pp 458-463. treatment of atherosclerosis. J Clin Invest 80:1808-1811, 1987.
2. Ross R: The pathogenesis of atherosclerosis —an update. N 13. Vanhoutte: Could the absence on malfunction of vascular
Engl J Med 314:488-500, 1986. endothelium precipitate the occurrence of vasospasm? J Mol
3. Cines DB, A Tomaski, S Tannenbaum: Immune endothe- Cell Cardiol 18:679-689, 1986.