The mechanism by which heparin promotes the inhibition of coagulation factor XIa by protease nexin-2.
Previous kinetic studies have shown that protease nexin-2 is a potent, reversible, and competitive inhibitor of factor XIa. Here we show that high molecular weight heparin potentiates the ability of protease nexin-2 to inhibit factor XIa with a parabolic concentration dependence, predominantly because of an increase of the association rate constant with little perturbation of the dissociation rate constant. No effect on factor XIa inhibition by protease nexin-2 was observed with heparin preparations of 6-22 saccharide units (0.1 nM-10 microM), whereas heparin preparations with 32-64 saccharide units potentiated factor XIa inhibition by protease nexin-2 in a size- and concentration-dependent manner. We propose a model wherein heparin exerts this effect by providing a template for the assembly of factor XIa-protease nexin-2 complexes, and only heparin polymers consisting of greater than 32 saccharide units (Mr approximately 10,000) are sufficiently long to provide a template to which factor XIa and protease nexin-2 molecules can bind simultaneously. Heparin-mediated enhancement of factor XIa inhibition by protease nexin-2 was partially abrogated by high molecular weight kininogen, suggesting that high molecular weight kininogen may play a role in regulating factor XIa activity.
Zhang
Y
Y
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Scandura
J M
JM
Van Nostrand
W E
WE
Walsh
P N
PN
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins / Q000378:metabolism*; D015945:Factor XIa / Q000037:antagonists & inhibitors*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008970:Molecular Weight; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D015032:Zinc / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D006493:Heparin; D015945:Factor XIa; D015032:Zinc