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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 943-951
Proteolytic processing of human coagulation factor IX by plasmin
John A. Samis,
Gillian D. Ramsey,
John B. Walker,
Michael E. Nesheim, and
Alan R. Giles
From the Departments of Pathology, Biochemistry, and Medicine;
Queen's University, Kingston, Ontario, Canada.
Previous studies have shown that thrombin generation in vivo caused
a 92% decrease in factor IX (F.IX) activity and the appearance of a
cleavage product after immunoblotting that comigrated with activated
F.IX (F.IXa). Under these conditions, the fibrinolytic system was
clearly activated, suggesting plasmin may have altered F.IX. Thus, the
effect(s) of plasmin on human F.IX was determined in vitro. Plasmin (50 nM) decreased the 1-stage clotting activity of F.IX (4 µM) by 80%
and the activity of F.IXa (4 µM) by 50% after 30 minutes at
37°C. Plasmin hydrolysis of F.IX yields products of 45, 30, 20, and
14 kd on reducing sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) and 2 products of 52 and 14 kd under
nonreducing conditions. Plasmin-treated F.IX did not bind the active
site probe, p-aminobenzamidine, or form an SDS-stable complex with
antithrombin. It only marginally activated human factor X in the
presence of phospholipid and activated factor VIII. Although
dansyl-Glu-Gly-Arg-chloromethyl ketone inactivated-F.IXa inhibited the
clotting activity of F.IXa, plasmin-treated F.IX did not. Plasmin
cleaves F.IX after Lys43, Arg145, Arg180, Lys316, and Arg318, but F.IXa
is not appreciably generated despite cleavage at the 2 normal
activation sites (Arg145 and Arg180). Tissue plasminogen activator-catalyzed lysis of fibrin formed in human plasma results in
generation of the 45- and 30-kd fragments of F.IX and decreased F.IX
clotting activity. Collectively, the results suggest that plasmin is
able to down-regulate coagulation by inactivating F.IX.
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