State-of-the-Art-Review : Statins Induce Hypothrombotic States?

Statins inhibit 3-hydroxy-3-methyl-glutaryl coenzyme A (HMGCoA) reductase, which synthesizes mevalonic acid in the isoprenoid pathways. These pathways lead to squalene and subsequently to cholesterol and related products (e.g., steroids, vitamin D, bile salts, lipopro teins) and have major branches producing cell regulatory substances (e.g., farnesyl- and geranylgeranyl conjugated proteins) (1,2). Although cholesterol reduc tion in blood has been widely believed to be beneficial (e.g., less available for accumulation by foam cells in atherosclerotic plaques), the ability of cholesterol reduc tion to mitigate the incidence and severity of cardiovas cular diseases has recently been questioned. Like others (3-10), we (11) believe that statins and other substances, for example, plant isoprenoids in the diet (12), have ben eficial antithrombotic properties arising through the in hibition of an isoprenoid product other than cholesterol. However, unlike others, we also believe that this isopren oid product has cell regulatory functions upregulated by thrombin stimulation. Moreover, through such cellular pathways, thrombin should upregulate its own genera tion, and statins and dietary isoprenoids should induce hypothrombotic states by downregulating thrombin gen eration (Fig. 1).