Aspirin Resistance

Aspirin is an effective drug for prevention of myocardial infarctions, strokes, and peripheral arterial occlusions (72). However, in vitro tests indicate only partial or no inhibition of platelet function in some patients taking aspirin (73), and aspirin resistance has been associated with arterial thrombotic complications (74). Although there may be many potential factors involved in aspirin treatment failures, a genetic resistance to the antith-rombotic action of aspirin would appear plausible.

Aspirin irreversibly inhibits platelet synthesis of thromboxane A2 (TxA2), by acet-ylating cyclooxygenase-1 (COX-1) enzyme (75). TxA2 activates platelets through a specific platelet membrane receptor, although the downstream steps are unknown at this time. Inactivation of COX-1 enzyme does diminish platelet activation by weak agonists, such as ADP and epinephrine, and low concentrations of collagen but does not prevent activation by such stronger agonists as thrombin.

Presently, there is no standard laboratory criterion for aspirin resistance. Typically, resistance has been defined as in vitro platelet aggregation in response to arachadonic acid (the substrate for COX-1), epinephrine, or adenosine diphosphate (ADP) that exceeds an arbitrary threshold (73,76). In most studies, documentation of aspirin ingestion in patients labeled as aspirin-resistant has been limited to patient reporting without salicylate level confirmation to assess for poor compliance. Using these laboratory criteria, reported prevalences for aspirin resistance range from 8% to 45% (77).

Possible mechanisms for platelet resistance to aspirin include alternative sources of the product of COX-1 metabolism, prostaglandin H2, from monocytes or endothelial cells through COX-2, or replenished COX-1 enzyme activity (76). Alternatively, COX-1 mutations could make the enzyme less vulnerable to acetylation. To date, no likely polymorphisms have been identified in this gene.

However, considerable attention has been focused on a common polymorphism in the beta integrin b3 that combines with the alpha integrin aIIb to form the platelet fibrinogen receptor glycoprotein IIbIIIa. The nucleotide substitution T1565C encodes for amino acid change leucine to proline at position 33 (78). This is one of the eight SNPs in the GPIIIa protein that can cause platelet alloimmunization during pregnancy or following platelet transfusion. In platelet serology nomenclature, the wild-type allele is Pl or HPA-1a, and the polymorphic one is PLA2 or HPA-1b. The allelic frequency of HPA-1b is approximately 15% among the Caucasians, and 1-2% are homozygous. In 1996, Weiss et al. (79) reported that HPA-1b was a risk factor for myocardial infarction based on a retrospective case-control study involving 71 subjects. Subsequent studies reported conflicting findings (80,81), including the Physicians Health study (81), which showed no increased risk for myocardial infarction (MI), stroke, or DVT associated with the HPA-1b phenotype. HPA-1b has been associated with an increased risk for reocclusions following percutaneous coronary artery stenting in some (82,83), but not all, studies (84). At present, the evidence for a link between glycoprotein IIIa HPA-1b polymorphism and atherosclerotic complications is inconclusive.

Meanwhile, the search for a biological mechanism whereby HPA-1b could affect a prothrombotic phenotype has lead to divergent findings. Feng et al. (85) reported increased platelet aggregability in response to epinephrine in HPL-1b compared with HPA-1a subjects among 1336 participants in the Framingham Offspring Study. However, Bray et al. (86,87), reported similar in vitro platelet aggregation responses to epinephrine and ADP for HPA-1a homozygous, HPA-1b heterozygous, and HPA-1b homozygous subjects. When exposed to aspirin, HPA-1b heterozygous platelets were significantly more sensitive to inhibition of epinephrine-induced platelet aggregation than HPA-1a or HPA-1b homozygous platelets, which do not support clinical aspirin resistance due to HPA-lb polymorphism (87). Undas (88) indirectly monitored aspirin inhibition of platelet activation by measuring thrombin generation in blood shed from a bleeding time wound. Baseline thrombin generation rates were similar for HPA-1a homozygotes (wild-type), and HPA-1b heterozygotes. After aspirin ingestion, thrombin generation was reduced in both groups but significantly less so in HPA-1b carriers. The results of a subsequent study by these investigators, measuring additional markers of thrombin activity in shed blood, showed that prior to aspirin ingestion, HPA-1b carriers had enhanced prothrombin activation compared with the HPA-1a subjects and that suppression of thrombin generation by aspirin was impaired in the HPA-1b group (89).

Given the complexities of the molecular mechanisms involved in platelet function, it is possible that the HPA-1b polymorphism could both increase platelet aggregation and decrease aspirin suppression of activated platelet generation of thrombin. However, no conclusions can be drawn from these in vitro data regarding the physiologic consequences of the PLA- 1b polymorphism in terms of atherosclerotic disease progression and choice of antithrombotic therapy.

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