(Circulation. 1998;97:118-119.)
© 1998 American Heart Association, Inc.
Daily 50 mg or 500 mg Aspirin Does Not Affect the Cooperation of Arachidonic Acid and ADP on Platelet Aggregation
Raul Altman, MD, PhD;
Alejandra Scazziota, PhD;
; Jorge Rouvier, MD
Buenos Aires Thrombosis Center,
Buenos Aires, Argentina
To the Editor:
Some years ago, Dr Valles and colleagues1
provided interesting information about the role of erythrocytes on
platelet reactivity. This synergistic activity between red cells
and platelets could facilitate thrombus formation. The same group
also indicated, in an article that appeared in
Circulation,2 that low-dose aspirin did not
prevent this cooperative effect but that a higher dose (500 mg) did. As
pointed out by Rocca and FitzGerald in their Editorial in the same
issue of Circulation,3 the fact that red cells
might modulate platelet function attracted the attention of some
workers many years ago, and the possibility that ADP was involved in
this activity was also postulated. Conversely, Maalej and
Folts4 showed that platelet activation was also
enhanced by increasing the shear stress and, in these circumstances,
the antithrombotic effect of aspirin was also overcome. We
postulated5 that red cells, leukocytes, and products
released after endothelial cell damage could also be
involved in platelet activation under the experimental conditions
referred to in the Folts model.4
The article by Santos et al2 confirmed our previous
finding from ex vivo experiments. In 1988, we suggested6
that the behavior of aspirinated platelets varied with dose and
time elapsed between aspirin ingestion and blood collection when
platelet-rich plasma was stirred with arachidonic
acid plus ADP, with platelet-activating factor, or with collagen:
independently of time elapsed since blood collection, a complete
synergistic aggregation was obtained after a single or a daily repeated
low dose (50 mg) of aspirin, an effect that is independent of
thromboxane A2 formation. When 500 mg aspirin
was administered, the response was related to time: 2.5 hours after
aspirin intake, synergism was abolished, but full irreversible
aggregation was restored in the 24-hour blood samples. This effect was
also independent of thromboxane A2, whose
concentration in serum was 2% to 8% of the preaspirin values. Nor did
a daily repeated 500-mg aspirin produce a cumulative effect: synergism
was obtained after aspirin intake for 7 to 10 days.
This fact, together with the various origins of ADP in addition to
erythrocytes (endothelial cells, platelets), makes
the point of cooperation between different cells very complex. On the
basis of our published studies, it does not seem to us that the aspirin
regimen proposed by Valles et al will be able to modify the response of
platelets in the presence of damage to the
endothelium, in which many agonists from different
cells are released.
Why low-dose aspirin prevented thrombosis and thromboembolism in
different clinical trials (secondary myocardial infarction, stroke, and
thromboembolic events in patients with cardiac valve prostheses), as
higher-dose aspirin did, is an open question that is difficult to
answer at present.
References
1.
Valles J, Santos T, Aznar J, Marcus AJ,
Martinez-Sales V, Portoles M, Broekman MJ, Safier LB.
Erythrocytes metabolically enhance collagen-induced
platelet responsiveness via increasing thromboxane
production, adenosine diphosphate release, and
recruitment. Blood.. 1991;78:154-162.[Abstract/Free Full Text]
2.
Santos MT, Valles J, Aznar J, Marcus AJ, Broekman MJ,
Safier LB. Prothrombotic effects of erythrocytes on platelet
reactivity: reduction by aspirin. Circulation.. 1997;95:63-68.[Abstract/Free Full Text]
3.
Rocca B, FitzGerald GA. Simply read: erythrocytes
modulate platelet function: should we rethink the way we give
aspirin? Circulation.. 1997;95:11-13.[Free Full Text]
4.
Maalej N, Folts JD. Increased shear stress
overcomes the antithrombotic platelet inhibitory effect
of aspirin in stenosed dog coronary arteries.
Circulation.. 1996;93:1201-1205.[Abstract/Free Full Text]
5.
Altman R, Scazziota A. Why aspirin cannot prevent
arterial thrombosis. Circulation.. 1996;94:3002-3003. Letter.
6.
Altman R, Scazziota A, Cordero Funes J. Why
single daily dose of aspirin may not prevent platelet
aggregation. Thromb Res.. 1988;51:259-266.[Medline]
[Order article via Infotrieve]
Response
M. Teresa Santos, PhD;
Juana Valles, PhD;
; Justo Aznar, MD
Research Center University Hospital La Fe,
46009 Valencia,
Spain
Aaron J. Marcus, MD;
; M. Johan Broekman, PhD
Thrombosis Research Laboratory,
Department of Veterans Affairs Medical Center,
New York, NY
We thank Dr Altman and his colleagues for their
interesting and provocative comments concerning the results
presented in our recent publication in
Circulation1 and the associated
Editorial.2 We agree with Dr Altman that
different cell types are involved in the pathogenesis of
cardiovascular diseases. Our experimental work was
specifically oriented to demonstrate that thrombosis is a multicellular
process, and we have conducted an extensive series of in vitro studies
on platelet responsiveness as modulated by
endothelial cells,3 4
erythrocytes,1 5 6 7 8 9 and
neutrophils.10 11
Our studies of the effects of aspirin on
platelet-erythrocyte1 7 8 and
platelet-neutrophil interactions10 have
demonstrated that aspirin directly reduces the prothrombotic effect of
erythrocytes1 and enhances the
inhibitory effects of neutrophils on platelet
reactivity in vitro.10 This indicates that
cell-cell interactions modulate effects of aspirin on
platelets.
The conclusion of our article1 was that
daily low-dose aspirin administration required intermittent
supplementation with a high dose to overcome the prothrombotic effect
of erythrocytes, which otherwise negates the protective effects of
low-dose aspirin. Our conclusions derive from an experimental
system5 6 7 8 9 devised to more closely approximate
participation of multiple cell types in the thrombotic process.
Moreover, this system separately measures platelet activation
(release reaction) and recruitment (proaggregatory effect of cell-free
releasates from combined suspensions of activated platelets
and other cells) at an early time point during platelet-erythrocyte
interactions. This allows better characterization of the erythrocyte
response to aspirin ex vivo. This premise differs from Dr Altman's
approach,12 in which pairs of platelet
agonists are directly added to platelet preparations.
The synergistic action of different pairs of agonists as studied
by Dr Altman12 reduces the inhibitory
effect of aspirin on platelet reactivity. This effect is unrelated
to TXA2 synthesis.12 In our
report,1 we found that aspirin was ineffective in
blocking platelet reactivity in the presence of erythrocytes
originating from donors who had not ingested aspirin or from donors who
had taken a low dose of aspirin, despite blockade of platelet
TXA2 formation. In contrast, when erythrocytes
were treated with an adequate dose of aspirin, their prothrombotic
activity was inhibited in normal donors. This has led us to propose the
following clinical regimen: A 500-mg dose should be dispensed after
each 2 weeks of low-dose aspirin. Under these conditions, the daily low
dose continuously inhibits platelet TXA2
formation, and the intermittent high dose blocks the prothrombotic
activity of erythrocytes, as demonstrated in our system.
Thus, although we agree with Dr Altman about the limited protection
provided by aspirin due to TXA2-independent
mechanisms of platelet activation, blockade of erythrocyte
prothrombotic potential with an adequate dose of aspirin may improve
the clinical effectiveness of this medication.
The comments of Drs Rocca and FitzGerald in their
Editorial2 concerning the appropriateness of
additional clinical studies related to the effects of aspirin on
erythrocyte prothrombotic activity were of importance. In fact, such an
investigation was completed and is in press.13 The overall
goal in these studies is to optimize the clinical use of aspirin as an
antithrombotic agent.
References
1.
Santos MT, Valles J, Aznar J, Marcus AJ, Broekman
MJ, Safier LB. Prothrombotic effects of erythrocytes on platelet
reactivity: reduction by aspirin. Circulation. 1997;95:63–68.
2.
Rocca B, FitzGerald GA. Simply read: erythrocytes
modulate platelet function: should we rethink the way we give
aspirin? Circulation. 1997;95:11–13.
3.
Marcus AJ, Weksler BB, Jaffe EA, Broekman MJ.
Synthesis of prostacyclin from platelet-derived
endoperoxides by cultured human
endothelial cells. J Clin Invest. 1980;66:979–986.
4.
Marcus AJ, Broekman MJ, Drosopoulos JHF, et al. The
endothelial cell ecto-ADP-ase responsible for
inhibition of platelet function is CD39. J Clin
Invest. 1997;99:1351–1360.[Medline]
[Order article via Infotrieve]
5.
Perez-Requejo JL, Aznar J, Santos MT, Valles J. Early
platelet-collagen interactions in whole blood and their
modifications by aspirin and dipyridamole evaluated by
a new method (basic wave). Thromb Haemost. 1985;54:799–803.[Medline]
[Order article via Infotrieve]
6.
Santos MT, Valles J, Aznar J, Perez-Requejo JL. Role
of red blood cells in the early stage of platelet activation by
collagen. Thromb Haemost. 1986;56:376–381.[Medline]
[Order article via Infotrieve]
7.
Santos MT, Valles J, Marcus AJ, et al. Enhancement of
platelet reactivity and modulation of eicosanoid production
by intact erythrocytes. J Clin Invest. 1991;87:571–580.
8.
Valles J, Santos MT, Aznar J, et al. Erythrocytes
metabolically enhance collagen-induced platelet
responsiveness via increased thromboxane
production, ADP release, and recruitment. Blood. 1991;78:154–162.
9.
Valles J, Santos MT, Aznar J, Velert M, Barberá
G, Carmena R. Modulatory effect of erythrocytes on the platelet
reactivity to collagen in IDDM patients. Diabetes. In press.
10.
Valles J, Santos MT, Marcus AJ, et al. Downregulation
of human platelet reactivity by neutrophils: participation of
lipoxygenase derivatives and adhesive proteins.
J Clin Invest. 1993;92:1357–1365.
11.
Marcus AJ, Safier LB, Ullman HL, et al.
Platelet-neutrophil interactions
(12S)-hydroxyeicosatetraen-1,20-dioic acid: a new eicosanoid
synthesized by unstimulated neutrophils from
(12S)-20-dihydroxyeicosatetraenoic
acid. J Biol Chem. 1988;263:2223–2229.[Abstract/Free Full Text]
12.
Altman R, Scazziota A, Cordero-Funes J. Why single
daily dose of aspirin may not prevent platelet aggregation.
Thromb Res. 1988;51:259–266.
13.
Valles J, Santos MT, Aznar J, Osa A, Lago A, Cosin J,
Sanchez E, Broekman MJ, Marcus AJ. Erythrocyte promotion of platelet
reactivity decreases the effectiveness of aspirin as an antithrombotic
therapeutic modality: the effect of low-dose aspirin is less than
optimal in patients with vascular disease due to prothrombotic effects
of erythrocytes on platelet reactivity. Circulation. In
press.
