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CLINICAL RESEARCH: ASPIRIN RESISTANCE

Resistance in vitro to low-dose aspirin is associated with platelet Pl^A1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T kozak (GP Ib) polymorphisms

Laurent Macchi, MD, PhD^*,*, Luc Christiaens, MD, Severine Brabant, MD^*, Nathalie Sorel, PhD^*, Stephanie Ragot, PhD, Joseph Allal, MD, Gérard Mauco, MD, PhD and André Brizard, MD, PhD^*

^* Laboratoire d'Hématologie et des maladies du sang, CHU de Poitiers Hôpital La Miletrie, Poitiers, France
Département de cardiologie, CHU de Poitiers Hôpital La Miletrie, Poitiers, France
Centre de recherche clinique, CHU de Poitiers Hôpital La Miletrie, Poitiers, France
Inserm ERM324, Faculté de Médecine et Pharmacie, CHU de Poitiers Hôpital La Miletrie, Poitiers, France

Manuscript received January 10, 2003; revised manuscript received May 20, 2003, accepted May 30, 2003.

^* Reprint requests and correspondence: Dr. Laurent Macchi, Laboratoire d'Hématologie et des maladies du sang, CHU de Poitiers, Hôpital La Milétrie, 86 000 Poitiers, France.
l.macchi{at}chu-poitiers.fr

OBJECTIVES: We investigated whether three platelet gene polymorphisms, Pl^A1/A2, C807T, and C-5T Kozak (encoding, respectively, for platelet membrane glycoproteins (GP) IIIa, GP Ia/IIa, GP Ib), could contribute to the resistance to a low dose of aspirin (160 mg/day).

BACKGROUND: Aspirin antiplatelet effect is not uniform in all patients, and the mechanism by which some patients are in vitro resistant to aspirin remains to be determined. However, it has been suggested that polymorphisms of platelet membrane glycoproteins might contribute to aspirin resistance.

METHODS: Ninety-eight patients on aspirin (160 mg/day) for at least one month were enrolled. Aspirin resistance was measured by the platelet function analyzer (PFA)-100 analyzer; genotyping of the three polymorphisms was performed using a polymerase chain reaction-based restriction fragment-length polymorphism analysis.

RESULTS: Using a collagen/epinephrine–coated cartridge on the PFA-100, the prevalence of aspirin resistance was 29.6% (n = 29). Aspirin-resistant patients were significantly more often Pl^A1/A1 (86.2%; n = 25) than sensitive patients (59.4%; n = 41; p = 0.01). Of the 29 patients, 25 were reevaluated after having taken 300 mg/day aspirin for at least one month. Only 11 patients still have nonprolonged collagen epinephrine closure time, and these were all Pl^A1/A1. No relation was found between resistance status and C-5T Kozak or C807T genotypes.

CONCLUSIONS: Platelets homozygous for the Pl^A1 allele appear to be less sensitive to inhibitory action of low-dose aspirin. This differential sensitivity to aspirin may have potential clinical implications whereby specific antiplatelet therapy may be best tailored according to the patient's Pl^A genotype.

Abbreviations and Acronyms   ADP   adenosine diphosphate   CADP   collagen adenosine diphosphate   CEPI   collagen epinephrine   CI   confidence interval   CT   closure time   GP   glycoprotein   MI   myocardial infarction   PFA   platelet function analyzer   TXA2   thromboxane A2

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