Background-It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results-We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen GϪ455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, Pϭ0.12 and OR 0.89, 95% CI 0.59 to 1.35, Pϭ0.6, respectively). Inclusion of the studies that investigated young patients (Ͻ55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, Pϭ0.02). Homozygosity for the fibrinogen Ϫ455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, Pϭ0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, Pϭ0.04). Conclusions-Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted. Key Words: myocardial infarction Ⅲ genetics Ⅲ coagulation T hrombosis, triggered by atherosclerotic plaque rupture, is generally accepted as the most common pathogenetic pathway of acute myocardial infarction. 1 In recent years, several genetic variations in coagulation and fibrinolytic proteins have been described, and numerous case-control studies have sought to correlate these genetic variations with the risk of myocardial infarction. However, clear relationships have not been established, possibly owing to lack of statistical power of the individual studies or their heterogeneity in terms of methodological design, outcome definition, or selection of cases and controls. We hypothesized that a meta-analysis could provide stronger evidence in favor of the hypothesis that genetic variations in coagulation or fibrinolytic proteins are associated with the risk of myocardial infarction. We limited our analysis to 4 genetic variations that are common and on which sufficient published data were available, ie, the factor V Leiden and prothrombin G20210A mutations and the fibrinogen ␤-chain GϪ455A and plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms. Methods Literature SearchWe identified all case-control studies correlating the factor V Leiden mutation, the prothrombin G20210A mutation, the fibrinogen ␤-chain GϪ455A polymorphism, or the PAI-1 4G/5G polymorphism with myocardial infarction. The lit...

Plaque disruption with superimposed thrombosis is the main cause of acute coronary events such as acute myocardial infarction and unstable angina. Among other factors, tissue factor seems to play an important role determining plaque thrombogenicity. Tissue factor is a potent initiator of the coagulation cascade situated within the vessel wall and is highly exposed to the blood after plaque rupture. Several mediators involved in the process of atherosclerotic plaque formation are capable of inducing tissue factor expression in cells such as monocytes, macrophages and endothelial cells, which under normal conditions do not express tissue factor or to a limited extent only. The increased expression of tissue factor is not limited to the plaque but is also found in circulating monocytes in patients with acute coronary syndromes. In addition, studies have shown an important contribution of tissue factor in the pathogenesis of thrombosis and restenosis after balloon angioplasty. Recent basic studies focus on the therapeutic inhibition of tissue factor. Specific and non-specific inhibitors of tissue factor or the tissue factor/factor VIIa complex have been developed or identified, and have been tested in experimental studies. Clinical studies are currently being initiated. In this review, we present the current knowledge on the role of tissue factor in atherosclerosis, arterial intervention and potential pharmacological approaches, with focus on acute coronary syndromes.

Background-The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. Methods and Results-In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 g/kg; nϭ8), fondaparinux and placebo (nϭ4), or placebo and rFVIIa (nϭ4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1ϩ2 (F 1ϩ2 ), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. Conclusions-rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment.The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Inhibition of the tissue factor/factor VIIa complex with rNAPc2, at doses up to 7.5 microg/kg, in combination with aspirin, clopidogrel, and unfractionated heparin appears to be a safe and effective strategy to prevent thrombin generation during coronary angioplasty.