The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists

Abstract

Genetic variants are risk factors for coronary disease, but their role in recurrent events and in response to treatment is less clear. We genotyped genetic variants implicated in primary coronary disease in 924 Caucasians with acute coronary syndromes participating in the OPUS-TIMI16 trial of the GPIIb/IIIa antagonist orbofiban. These were the platelet glycoprotein (GP) receptors GPIIIa, GPIa, GPIb␣; platelet ligands ␤-fibrinogen and von Willebrand Factor (vWF); interleukins (IL) IL-1RN, and IL-6; adhesion proteins E-selectin and Pselectin; and metalloproteinase MMP-9. Cox modelling of all genetic variants demonstrated no significant impact on the composite endpoint (P ϭ 0.88), which included myocardial infarction (MI), death, recurrent ischemia, urgent revascularisation and stroke, but a significant impact on recurrent myocardial infarction alone ( 2 ϭ 20.4, 10 df, P = 0.04). There was a significant interaction of the polymorphisms with orbofiban treatment influencing bleeding outcomes (P ϭ 0.004). Thus, genetic polymorphisms may be associated with subsequent myocardial infarction, and may also be associated with treatment-associated bleeding among coronary patients.

Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic Brain Disease

“…Likewise, polymorphisms have been shown to affect the variability of response to oral GPIIb/IIIa receptor antagonists as observed in patients with unstable coronary syndromes [37]. However, polymorphisms may also be the cause for the occurrence of treatment-related bleeding [38,39].…”

Aspirin and Clopidogrel Resistance

“…2 Platelets adhere to areas of injury through engagement of adhesion receptors (including glycoproteins VI, IB/V/IX, α IIb β 3 ) with adhesive proteins (collagen, von Willebrand factor, and fibrinogen, respectively), triggering activation and shape change. Secondary platelet activation is triggered by soluble agonists released or generated as a consequence of platelet activation, including thromboxane (TXA 2 ) and adenosine diphosphate (ADP) or the formation of thrombin locally.…”

Platelet genomics and proteomics in human health and disease

“…Atherothrombosis and CAD are the outcome of a complex interaction between genes and the environment, but it is clear that variations in platelet activity modulate thrombus formation. For example, large-scale clinical trials of oral "antiplatelet" drugs demonstrate that minor variations in platelet function can dramatically increase the risk of myocardial infarction (3). Evidence suggests that single nucleotide polymorphisms are associated with changes in platelet function (4,5); however, conflicting results have been obtained when these polymorphisms are tested for disease association (6).…”