Hypertriglyceridemia is a common lipoprotein abnormally apparent in the general population and in the subpopulation of patients who have experienced myocardial infarction (MI). 1 MI is preceded by atherosclerotic buildup and triggered by a thrombotic event. Several studies have implicated elevated triglyceride levels with increased risk for MI and ischemic heart disease (IHD). 2-5 Moreover, evidence suggests that hypercoagulability is associated with elevated triglycerides and this may promote MI in hypertriglyceridemic subjects. For example, in 18 severely hypertriglyceridemic patients, Factor Xa was significantly elevated compared with normolipidemics. 6 Drug therapy, aimed at reducing plasma triglyceride levels, resulted in a concomitant, consistent lowering of the plasma levels of coagulation Factors VIIa and Xa. Elkeles et al7 noted a decrease in Factor VIIa, Villa, and Xa with increased fibrinolytic activity in hypertriglyceridemic subjects after a fat-modified diet that lowered triglyceride levels. Hamsten et al8 suggested that certain risk factors for MI are linked with an imbalance in fibrinolytic activity. In these patients decreased levels of tissue plasminogen activator (t-PA) activity was explained by high plasma levels of a t-PA inhibitor, which was positively and significantly correlated with serum triglyceride levels. Hulley et al9 reviewed the early studies (before 1980) concerning the role of triglyceride in premature heart disease and concluded that the evidence did not indicate that triglyceride was an independent risk factor for IHD. Carlson and Böttinger10 have criticized the conclusions of this study, noting that most studies from Scandinavia demonstrate that elevated triglyceride is an independent risk factor when appropriate end points are used. Austin, in this issue of Seminars, has discussed the particular problems of implicating triglyceride as a risk factor in many epidemiologic studies. The Hulley et al review9 also suggested that little biochemical or physiologic evidence existed to implicate triglyceride, unlike cholesterol, as a causal factor for IHD, nor were there animal studies to support such a notion. Recent basic studies have identified potential biochemical pathways in which triglyceriderich lipoproteins may be involved in the atherogenic process (Gianturco and Bradley in this issue of Seminars). Furthermore, Spady and Dietschy11 have directly implicated triglyceride, in particular saturated triglyceride, in the down-regulation of the hepatic low-density lipoprotein (LDL) receptor in the golden hamster, a phenomenon, if it occurs in humans in vivo that could result in increased LDL (and precursors of LDL) levels and increased cardiovascular risk. Thus, biochemical mechanisms and animal models now exist to provide a rational basis for the relationship of elevated triglyceride and risk for premature heart disease.

The purpose of this presentation is to address additional evidence suggesting a biochemical basis that establishes a potential relationship between increased triglyceride levels and hypercoagulability. Our studies show that coagulation zymogens can bind to the triglyceride-rich very low-density lipoproteins (VLDL), partially through a Ca2+-dependent association, can be activated, and thereby can process the apoproteins (apo) of VLDL. In terms of hypercoagulability the VLDL can serve as a localized, alternate site for activation of prothrombin or other coagulation enzymes