Bucher and colleagues' meta-analysis [1] suggests that treating hyperlipidemic patients with HMGcoA reductase inhibitors reduces the incidence of first stroke. These inhibitors seem to reduce the incidence of stroke to a greater degree than other antilipidemic interventions, and the authors will report similar findings for the end point of death from coronary artery disease. They speculate that the mechanism responsible is the cholesterol-lowering effect of the HMGcoA reductase inhibitors, which is a more potent effect than that of other lipid-lowering agents. We postulate a possible additional mechanism in light of emerging knowledge of the role of the procoagulant molecule, tissue factor, in the pathogenesis of atherosclerosis [2, 3] and recent studies showing that HMGcoA reductase inhibitors reduce monocyte and macrophage tissue factor expression [4, 5]. Tissue factor is a membrane-bound glycoprotein that initiates the extrinsic pathway of coagulation through the formation of a complex with the coagulation factor VIIa and subsequent activation of factor X. In normal arteries, tissue factor is present only in the adventitia, but it is abundant in the macrophages and smooth-muscle cells of lipid-rich atherosclerotic plaques. Spontaneous plaque rupture exposes tissue factor in the lipid core to circulating coagulation factors, triggering thrombosis and acute coronary syndromes. Tissue factor probably also plays a role in thrombotic stroke.

Recently, Allessandri and colleagues [4] reported significantly elevated monocyte procoagulant activity and tissue factor levels in patients with type IIa hyperlipidemia compared with normal controls, and this elevation correlated directly with serum cholesterol levels. The investigators randomly assigned 12 hyperlipidemic patients to receive simvastatin plus a low-fat diet or a low-fat diet alone. The patients receiving simvastatin plus dietary treatment had significant reductions in both monocyte procoagulant activity and tissue factor antigen compared with patients who received dietary intervention alone. Colli and coworkers [5] have shown that fluvastatin inhibits tissue factor expression in human macrophages cultured from peripheral blood monocytes in a dose-dependent fashion.

The provocative results of these studies suggest that reduction of monocyte and macrophage tissue factor expression may be one mechanism by which the HMGcoA reductase inhibitors prevent thrombotic events in hyperlipidemic patients. Confirmation of these findings in additional investigations would provide a rationale for studying these drugs in patients with other thrombotic states in which tissue factor plays a role, such as the antiphospholipid antibody syndrome, where they may augment or even replace traditional anticoagulant therapy.