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Blood, 15 November 2001, Vol. 98, No. 10, pp. 2980-2987
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Lipoprotein (a) binds and inactivates tissue factor pathway
inhibitor: a novel link between lipoproteins and
thrombosis
Noel M. Caplice,
Carmelo Panetta,
Timothy E. Peterson,
Laurel S. Kleppe,
Cheryl S. Mueske,
Gert M. Kostner,
George J. Broze Jr, and
Robert D. Simari
From the Department of Internal Medicine and
Cardiovascular Diseases and Biochemistry and Molecular Biology,
Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, MN;
Department of Internal Medicine, Washington University, St Louis, MO;
and Medical Biochemistry, University of Graz, Graz,
Austria.
Lipoprotein (a) [Lp(a)] has been associated with both
anti-fibrinolytic and atherogenic effects. However, no direct link
currently exists between this atherogenic lipoprotein and intravascular coagulation. The current study examined the binding and functional effects of Lp(a), its lipoprotein constituents, apoliprotein (a) [apo(a)] and low-density lipoprotein (LDL), and lysine-plasminogen (L-PLG), which shares significant homology with apo(a), on tissue factor pathway inhibitor (TFPI), a major regulator of tissue
factor-mediated coagulation. Results indicate that Lp(a), apo(a), and
PLG but not LDL bound recombinant TFPI (rTFPI) in vitro and that apo(a) bound to a region spanning the last 37 amino acid residues of the
c-terminus of TFPI. The apparent binding affinity for TFPI was
much higher for Lp(a) (KD ~150 nM) compared to PLG
(KD ~800 nM) and nanomolar concentrations of apo(a) (500 nM) inhibited PLG binding to TFPI. Lp(a) also inhibited in a
concentration-dependent manner rTFPI activity and endothelial cell
surface TFPI activity in vitro, whereas PLG had no such effect.
Moreover physiologic concentrations of PLG (2 µM) had no effect on
the concentration-dependent inhibition of TFPI activity induced by
Lp(a). In human atherosclerotic plaque, apo(a) and TFPI
immunostaining were shown to coexist in smooth muscle cell-rich
areas of the intima. These data suggest a novel mechanism whereby Lp(a)
through its apo(a) moiety may promote thrombosis by binding and
inactivating TFPI.
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