Although the control of
thrombin in the microvasculature at the endothelial cell surface is crucial to prevent
atherothrombosis, the role of
antithrombin in arterial
thrombosis is unclear. It is widely considered that
antithrombin deficiency is unlikely to contribute to arterial
thrombosis, but no convincing epidemiological study has been performed because of the low frequency of this deficiency. In this study we evaluated the role in
myocardial infarction (MI) of a relatively common mutation affecting
antithrombin gene (A384S:
Antithrombin Cambridge II) that has functional features that may impair the right control of thrombogenic events caused by injury to the vascular wall. Moreover, this deficiency, which is not detected using common methods to diagnose
antithrombin deficiency, also increases the risk of
venous thrombosis. We included 1,224 patients with MI (691 consecutive patients and 533 survivors of a premature event), and 1,649 controls. The mutation was identified in 0.3% of controls, but 0.8% of MI patients. After adjusting for sex and other cardiovascular risk factors, the
antithrombin Cambridge II significantly increased 5.66-fold the risk of MI (95% CI: 1.53-20.88; p = 0.009). Interestingly, young patients had the highest risk of MI associated with the mutation (OR: 9.98; 95%CI: 1.60-62.24; p = 0.009). This is the first epidemiological study that supports a role for
antithrombin deficiency in arterial
thrombosis. These results suggest that deficiency of
antithrombin may be an independent risk factor for MI that has been underestimated, but larger studies are needed to confirm the relevance of inhibitors of
thrombin in arterial
thrombosis.