Erythrocyte Promotion of Platelet Reactivity Decreases the Effectiveness of Aspirin as an Antithrombotic Therapeutic Modality
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.
- Copyright © 1998 by American Heart Association
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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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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We thank Drs Jagroop and Mikhailidis for their interesting comments on our recent publicationR1 dealing with our observation that erythrocyte promotion of platelet reactivity serves to decrease the effectiveness of aspirin as an antithrombotic modality.R1 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.R2
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,R1 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.R3 R4 R5 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.R1 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.R1 This can be achieved in normal volunteers with a daily low dose of aspirin interrupted biweekly with a single larger dose.R5 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.R1 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.
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.
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.
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.
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.