(Circulation. 1998;98:1824-1827.)
© 1998 American Heart Association, Inc.
Erythrocyte Promotion of Platelet Reactivity Decreases the Effectiveness of Aspirin as an Antithrombotic Therapeutic Modality
I.A. Jagroop, BSc;
; D.P. Mikhailidis, MD
Royal Free Hospital and School of Medicine,
London, UK
To the Editor:
Vallés et al1 report persistent
serotonin release from platelets prepared from patients
with vascular disease who were taking aspirin (200 to 300 mg/d). These
authors point to the potential clinical significance of their
observation because serotonin stimulates vascular smooth
muscle cell (VSMC) proliferation.
Serotonin is also a vasoconstrictor and can induce or
enhance platelet shape change (PSC) and
aggregation.2 3 4 5 PSC is an early phase of
platelet activation that is aspirin resistant and precedes
aggregation.2
A link between serotonin and platelet activity
was demonstrated in dyslipidemic patients in whom
simvastatin (an effective lipid-lowering drug) reduced
platelet hyperactivity and corrected the intraplatelet levels
of serotonin.3 Furthermore, after
PTCA, the addition of ticlopidine (a potent inhibitor of
platelet activation) to aspirin and heparin normalized
serotonin release from
platelets.4 Because some 95% of the
serotonin in the blood is stored in platelets, these
findings suggest a correctable imbalance between intraplatelet and
plasma serotonin levels.5
The circulating levels of serotonin are elevated in
patients with peripheral vascular
disease.5 It is therefore of interest that
elevated plasma serotonin levels may predict
restenosis after peripheral arterial
surgery.5
Serotonin may play a role in the pathogenesis of
restenosis (a process in which VSMC proliferation is important)
and could be a marker for mediators released by platelets despite
the administration of aspirin. We agree with Vallés et
al1 that more than aspirin-induced inhibition of
platelet thromboxane A2 synthesis
may be required in patients with vascular disease.
References
-
Vallés 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. 1998;97:350–355.
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Barradas MA, O'Donoghue S, Mikhailidis DP.
Measurement of platelet volume using a channelyzer: assessment of
the effect of agonists and antagonists. In
Vivo. 1992;6:629–634.
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Coumar A, Gill JK, Barradas MA, O'Donoghue S, Jeremy
JY, Mikhailidis DP. The effect of treatment with
simvastatin on platelet function indices in
hypercholesterolaemia. J Drug Develop. 1991;4:79–86.
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Gregorini L, Marco J, Fajadet J, Cassagneau B, Brunel
P, Bossi IM, Mannucci PM. Ticlopidine and aspirin pretreatment reduces
coagulation and platelet activation during coronary
dilation procedures. J Am Coll Cardiol. 1997;29:13–20.
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Cheshire NJW, Wolfe JHN, Barradas MA, Chambler AW,
Mikhailidis DP. Smoking and plasma fibrinogen, lipoprotein (a) and
serotonin are markers for postoperative infrainguinal graft
stenosis. Eur J Vasc Endovasc Surgery. 1996;11:479–486.
Response
Juana Vallés, PhD;
M. Teresa Santos, PhD;
Justo Aznar, MD;
Ana Osa, MD;
Aida Lago, MD;
Juan Cosin, MD;
; Elena Sanchez, MD
Research Center and Departments of Clinical Pathology,
Cardiology, and Neurology,
University Hospital La Fé,
Valencia, Spain
M. Johan Broekman, PhD;
; Aaron J. Marcus, MD
Thrombosis Research Lab,
Divisions of Hematology and Medical Oncology and Department of
Medicine,
Department of Veterans Affairs Medical Center,
Cornell University Medical College,
New York, NY
We thank Drs Jagroop and Mikhailidis for their interesting
comments on our recent publication1 dealing with
our observation that erythrocyte promotion of platelet reactivity
serves to decrease the effectiveness of aspirin as an antithrombotic
modality.1 In the research described, we used
release of serotonin as a parameter of
platelet activation. Although of great importance, we did not
directly address the functional implications of serotonin
release other than mention of the well-recognized ability of released
platelet dense granule constituents to promote cell
proliferation.2
We are in complete agreement with Drs Jagroop and Mikhailidis that a
very important function for released serotonin is the
ability of this autacoid to induce vasoconstriction at a site of
vascular injury. Increased levels of serotonin in plasma
may indeed be correlated with vascular diseases, but at the present
time it remains difficult to establish definitive cause-and-effect
relationships in specific instances.
In our report,1 we demonstrated that in a
significant number of patients with vascular disease, doses of aspirin
frequently used for antithrombotic therapy were not sufficient to
completely block the platelet reactivity that is promoted by
erythrocytes.3 4 5 This was evidenced by the
insufficient blockade of both serotonin release and
platelet recruitment by those doses of aspirin. This indicated that
platelet reactivity persisted in the setting of inhibition of
synthesis of thromboxane A2 (>94%)
in all the patients. Thus, more than thromboxane
A2 inhibition would be required to reduce
ischemic complications in this patient population.
In addition, 2 other conclusions can be derived from the data
obtained in our study.1 First, an optimal dose of
aspirin needs to be established for patients with occlusive
arterial diseases to provide adequate aspirin-mediated
inhibition of both platelet reactivity and the prothrombotic
effects of erythrocytes.1 This can be achieved in
normal volunteers with a daily low dose of aspirin interrupted biweekly
with a single larger dose.5 We also suggest
consideration of a similar approach for patients with vascular
diseases. This concept is currently under study in our laboratory.
The other observation with important therapeutic implications and
now being investigated in our laboratory is that patients under
treatment can be classified into groups on the basis of the effect of
aspirin on their platelet reactivity in the presence of
erythrocytes.1 These findings indicate that there
are individual differences in the response to aspirin in different
patients. Thus, laboratory control of platelet reactivity in whole
blood as a guide for antithrombotic therapy with aspirin is the
modality for the future for optimization of aspirin therapy in
patients.
References
-
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. 1998;97:350–355.
-
Crowley ST, Dempsey EC, Horwitz KB, Horwitz LD.
Platelet-induced vascular smooth muscle cell proliferation is
modulated by the growth amplification factors serotonin and
adenosine diphosphate. Circulation. 1994;90:1908–1918.
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Santos MT, Valles J, Marcus AJ, Safier LB, Broekman
MJ, Islam N, Ullman HL, Eiroa AM, Aznar J. Enhancement of platelet
reactivity and modulation of eicosanoid production by intact
erythrocytes. J Clin Invest. 1991;87:571–580.
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Valles J, Santos MT, Aznar J, Marcus AJ,
Martinez-Sales V, Portolés M, Broekman MJ, Safier LB .
Erythrocytes metabolically enhance collagen-induced
platelet responsiveness via increased thromboxane
production, ADP release and recruitment. Blood. 1991;78:154–162.
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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.
