From the Research Center (J.V., M.T.S., J.C.) and Departments of Clinical
Pathology (J.A.), Cardiology (A.O., E.S.), and Neurology (A.L.), University
Hospital La Fe, Valencia, Spain; and the Divisions of Hematology and Medical
Oncology and Departments of Medicine, Veterans Affairs Medical Center and
Cornell University Medical College, New York, NY (M.J.B., A.J.M.).
Correspondence to Dr Juana Valles, Research Center, University Hospital La Fe, Avda. Campanar 21, 46009 Valencia, Spain. E-mail mteresas{at}san.gva.es
Background—Aspirin
(acetylsalicylic acid, ASA) is widely used for
secondary prevention of ischemic vascular events, although its
protection only occurs in 25% of patients. We previously demonstrated
that platelet reactivity is enhanced by a prothrombotic effect of
erythrocytes in a thromboxane-independent manner. This
diminishes the antithrombotic therapeutic potential of ASA. Recent data
from our laboratory indicate that the prothrombotic effect of
erythrocytes also contains an ASA-sensitive component. In accordance
with this observation, intermittent treatment with high-dose ASA
reduced the prothrombotic effects of erythrocytes ex vivo in healthy
volunteers. In the present study, the effects of
platelet-erythrocyte interactions were evaluated ex vivo in 82
patients with vascular disease: 62 patients with ischemic heart
disease treated with 200 mg ASA/d and 20 patients with ischemic
stroke treated with 300 mg ASA/d.
Methods and Results—Platelet activation (release reaction)
and platelet recruitment (fluid-phase proaggregatory activity of
cell-free releasates from activated platelets) were
assessed after collagen stimulation (1 µg/mL) of platelets,
platelet-erythrocyte mixtures, or whole blood. Platelet
thromboxane A2 synthesis was inhibited by
>94% by ASA administration in all patients. Importantly, platelet
recruitment followed one of three distinct patterns. In group A (n=32;
39%), platelet recruitment was blocked by ASA both in the presence
and absence of erythrocytes. In group B (n=37; 45%), recruitment was
abolished when platelets were evaluated alone but continued in the
presence of erythrocytes, indicating a suboptimal effect of ASA on
erythrocytes of this patient group. In group C (n=13; 16%), detectable
recruitment in stimulated platelets alone persisted and was
markedly enhanced by the presence of erythrocytes.
Conclusions—In two thirds of a group of patients with vascular
disease, 200 to 300 mg ASA was insufficient to block platelet
reactivity in the presence of erythrocytes despite abolishing
thromboxane A2 synthesis. Platelet
activation in the presence of erythrocytes can induce the release
reaction and generate biologically active products that recruit
additional platelets into a developing thrombus. Insufficient
blockade of this proaggregatory property of erythrocytes can lead to
development of additional ischemic complications.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
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
Key Words: aspirin • blood cells • platelets • cardiovascular diseases • cerebrovascular disorders
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