Increased thrombin generation and complement activation in patients with type IIa hyperlipoproteinemia: Effects of simvastatin treatment

The aim of this study was to demonstrate the existence of increased thrombin generation and complement activation in patients with type IIa primary hyperlipoproteinemia, but no signs of atherosclerotic vascular disease and to assess the effects of simvastatin treatment in these patients. We studied 40 patients with type IIa primary hyperlipoproteinemia and 40 healthy subjects matched for sex, age, body mass index, and smoking status. The study was divided into two phases. In the first phase, a cross-sectional comparison of lipid and hemostatic patterns was performed between patients and controls. In the second phase, we assessed the effect of a persistent reduction in cholesterol synthesis induced by simvastatin in patients with hypercholesterolemia. The lipid pattern in patients with hypercholesterolemia was consistent with the characteristic features of this form of hyperlipoproteinemia. Moreover, factor VII, fibrinogen, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), fibronectin, and the c fraction of the third component of the complement system (C3c) levels were significantly higher, and antithrombin III was significantly lower in patients than in controls. Regarding the fibrinolytic pattern, in patients there mere no significant differences in tissue plasminogen activator antigen before and after venous occlusion (VO), plasminogen activator inhibitor type 1 activity before and after VO, plasminogen, and alpha(2)-antiplasmin plasma levels compared with control subjects. Factor VII, fibrinogen, F1+2, TAT, fibronectin, and C3c were significantly correlated with total and low-density lipoprotein (LDL) cholesterol levels, whereas no significant correlation with high-density lipoprotein (HDL) cholesterol and triglyceride levels was found. In addition to the well-established lipid-lowering effect, simvastatin (20 mg/d for 8 weeks) significantly reduced factor VII, fibrinogen, F1+2, TAT, fibronectin, and C3c levels in patients with hypercholesterolemia, but the observed reductions were not significantly correlated with total and LDL cholesterol levels. Our results show that type IIa hyperlipoproteinemia is characterized by increased in vivo thrombin generation and complement activation with no abnormalities of fibrinolysis. This thrombophilic state, which is associated with a high incidence of atherosclerosis and thrombotic complications, can be decreased with simvastatin via cholesterol lowering, but the relationship between these events remains to be investigated.