TISSUE-FACTOR PATHWAY INHIBITOR AND LIPOPROTEINS - EVIDENCE FOR ASSOCIATION WITH AND REGULATION BY LDL IN HUMAN PLASMA

Tissue-factor pathway inhibitor (TFPI) is a potent inhibitor of extrin sic coagulation, which is mainly associated with lipoproteins in circu lating blood. Gel filtration of human plasma confirmed the presence of three peaks in which approximately 10%, 70%, and 20% of total TFPI ac tivity was retained. Precipitation of very-low-density lipoproteins an d low-density lipoproteins (LDLs) in plasma by polyethylene glycol alm ost completely abolished peaks I and II. LDL isolated by ultracentrifu gation revealed two peaks of TFPI after gel filtration that coeluted w ith peaks I and II, respectively, from gel filtration of total plasma. TFPI activity in peaks I and II was also precipitated by anti-apolipo protein B antibodies. Fourteen patients with familial hypercholesterol emia had higher plasma TFPI activity than did age- and sex-matched nor molipemic control subjects (1.45+/-0.27 U/mL versus 0.80+/-0.09 U/mL, P<.001). Plasma TFPI was correlated with LDL cholesterol (r=.73, P<.00 1) and apolipoprotein B (r=.69, P<.001). No association was found with high-density lipoprotein cholesterol or apolipoprotein A-I. In a doub le-blind, placebo-controlled trial among the familial hypercholesterol emia patients, lovastatin alone or in combination with fish oil concen trate lowered plasma TFPI in parallel with LDL cholesterol. Gel filtra tion of plasma from these patients demonstrated a specific drop in apo lipoprotein B-TFPI complexes, whereas TFPI not associated with lipopro teins was unchanged. This study demonstrated that plasma TFPI was asso ciated with and regulated by LDL in plasma from healthy subjects and p atients with familial hypercholesterolemia.