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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3049-3055
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Characterization of the protein Z-dependent protease
inhibitor
Xin Han,
Ryan Fiehler, and
George J. Broze Jr
From the Division of Hematology, Barnes-Jewish Hospital
at Washington University Medical Center, St Louis, MO.
Protein Z-dependent protease inhibitor (ZPI) is a 72-kd
member of the serpin superfamily of proteinase inhibitors that produces rapid inhibition of factor Xa in the presence of protein Z (PZ), procoagulant phospholipids, and Ca++ (t1/2 less
than 10 seconds). The rate of factor Xa inhibition by ZPI is reduced
more than 1000-fold in the absence of PZ. The factor Xa-ZPI complex is
not stable to sodium dodecyl sulfate-polyacrylamide gel
electrophoresis, but is detectable by alkaline-polyacrylamide gel
electrophoresis. The combination of PZ and ZPI dramatically delays the
initiation and reduces the ultimate rate of thrombin generation in
mixtures containing prothrombin, factor V, phospholipids, and
Ca++. In similar mixtures containing factor Va, however, PZ
and ZPI do not inhibit thrombin generation. Thus, the major effect of PZ and ZPI is to dampen the coagulation response prior to the formation
of the prothrombinase complex. Besides factor Xa, ZPI also inhibits
factor XIa in the absence of PZ, phospholipids, and Ca++.
Heparin (0.2 U/mL) enhances the rate (t1/2 = 25 seconds
vs 50 seconds) and the extent (99% vs 93% at 30 minutes) of
factor XIa inhibition by ZPI. During its inhibitory interaction with
factor Xa and factor XIa, ZPI is proteolytically cleaved with
the release of a 4.2-kd peptide. The N-terminal amino acid
sequence of this peptide (SMPPVIKVDRPF) establishes Y387 as the
P1 residue at the reactive center of ZPI. ZPI activity is
consumed during the in vitro coagulation of plasma through a
proteolytic process that involves the actions of factor Xa with PZ
and factor XIa.
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