EFFECT OF CHOLESTEROL-LOWERING ON INTRAVASCULAR POOLS OF TFPI AND ITSANTICOAGULANT POTENTIAL IN TYPE-II HYPERLIPOPROTEINEMIA

Tissue factor pathway inhibitor (TFPI) inhibits the extrinsic coagulat ion system. A major pool of TFPI is associated with the vascular endot helium and can be mobilized into the circulation by heparin. In circul ating blood, TFPI is mainly associated with LDL (80%), whereas 10% to 20% is carrier free. In this study, heparin administration caused a 2. 2-fold and a 7.5-fold increase in TFPI activity and TFPI antigen, resp ectively, in 25 patients with phenotypes IIa and IIb hyperbetalipoprot einemia. Because the antigen determination of TFPI almost exclusively measures carrier-free TFPI, more than 90% of the heparin-induced incre ase in TFPI activity was caused by mobilization of carrier-free TFPI f rom the vascular endothelium. Therapeutic lowering of total cholestero l (a decrease of 31.1+/-11.6%, P<.001) by 40 mg/d lovastatin in 17 pat ients with hyperbetalipoproteinemia was accompanied by a parallel decr ease in TFPI activity (of 27.7+/-24.2%, P<.001) because of a reduction in LDL-TFPI complexes. However, drug intervention did not affect carr ier-free TFPI or the magnitude of the vascular pool of TFPI that could be mobilized into the circulation by heparin. Moreover, this reductio n of LDL-TFPI complexes did not reduce the anticoagulant potency of TF PI in plasma or of the vascular endothelial pool. The results of this study may imply that the anticoagulant potency of TFPI is associated w ith its carrier-free form in plasma or on the endothelium and that dow nregulation of LDL affects neither the size nor the anticoagulant pote ncy of the endothelial pool of TFPI.