Daily 50 mg or 500 mg Aspirin Does Not Affect the Cooperation of Arachidonic Acid and ADP on Platelet Aggregation
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.
- Copyright © 1998 by American Heart Association
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.
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.
Rocca B, FitzGerald GA. Simply read: erythrocytes modulate platelet function: should we rethink the way we give aspirin? Circulation.. 1997;95:11-13.
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.
Altman R, Scazziota A. Why aspirin cannot prevent arterial thrombosis. Circulation.. 1996;94:3002-3003. Letter.
We thank Dr Altman and his colleagues for their interesting and provocative comments concerning the results presented in our recent publication in CirculationR1 and the associated Editorial.R2 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,R3 R4 erythrocytes,R1 R5 R6 R7 R8 R9 and neutrophils.R10 R11
Our studies of the effects of aspirin on platelet-erythrocyteR1 R7 R8 and platelet-neutrophil interactionsR10 have demonstrated that aspirin directly reduces the prothrombotic effect of erythrocytesR1 and enhances the inhibitory effects of neutrophils on platelet reactivity in vitro.R10 This indicates that cell-cell interactions modulate effects of aspirin on platelets.
The conclusion of our articleR1 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 systemR5 R6 R7 R8 R9 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,R12 in which pairs of platelet agonists are directly added to platelet preparations.
The synergistic action of different pairs of agonists as studied by Dr AltmanR12 reduces the inhibitory effect of aspirin on platelet reactivity. This effect is unrelated to TXA2 synthesis.R12 In our report,R1 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 EditorialR2 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.R13 The overall goal in these studies is to optimize the clinical use of aspirin as an antithrombotic agent.
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.
Rocca B, FitzGerald GA. Simply read: erythrocytes modulate platelet function: should we rethink the way we give aspirin? Circulation. 1997;95:11–13.
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.
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.
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.
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.
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.
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.
Altman R, Scazziota A, Cordero-Funes J. Why single daily dose of aspirin may not prevent platelet aggregation. Thromb Res. 1988;51:259–266.
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.