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Regulation by alpha 2-antiplasmin and fibrin of the activation of
plasminogen with recombinant staphylokinase in plasma
K Silence, D Collen and HR Lijnen
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
The effects of alpha 2-antiplasmin and fibrin on the activation of
plasminogen by recombinant staphylokinase (STAR) were studied in an effort
to elucidate further the molecular basis of the fibrin- specificity of this
fibrinolytic agent. In purified systems consisting of 1.5 mumol/L intact or
low-M(r) plasminogen and 3 mumol/L alpha 2- antiplasmin, at 37 degrees C
and in the absence of fibrin, STAR did not induce plasminogen activation
and plasmin-alpha 2-antiplasmin complex (PAP) formation. Addition of a
purified fibrin clot (30% vol at a concentration of 3 mg/mL) to mixtures
containing intact plasminogen caused approximately 40% plasminogen
activation within 2 hours, whereas in mixtures containing low-M(r)
plasminogen, no activation was observed. In contrast, 10 nmol/L
streptokinase (SK) induced 74% to 100% plasminogen activation within 2
hours in mixtures containing either intact or low-M(r) plasminogen, in both
the absence and the presence of fibrin. In citrated human plasma in the
absence of fibrin, 30 nmol/L STAR did not induce measurable plasminogen
activation and PAP formation (< 1.5% within 2 hours), whereas addition
of a plasma clot (12% vol) resulted in complete clot lysis and conversion
of 19% +/- 8% of the plasminogen to PAP within 2 hours. Addition of a
second plasma clot produced 23% +/- 2% additional plasminogen activation.
Equipotent concentrations for plasma clot lysis of SK (100 nmol/L) induced
54% +/- 11% plasminogen activation in the absence and 49% +/- 16% in the
presence of fibrin. Addition of 50 mmol/L 6-aminohexanoic acid (6-AHA)
abolished the effect of fibrin on plasminogen activation with STAR, but not
on activation with SK. In alpha 2-antiplasmin-depleted human plasma in the
absence of fibrin, 30 nmol/L STAR did not induce fibrinogen breakdown (>
90% residual fibrinogen after 6 hours), whereas 30 nmol/L preformed
plasmin-STAR complex induced extensive fibrinogen degradation (70% within
20 minutes). Thus, in the absence of fibrin, alpha 2- antiplasmin inhibits
the activation of plasminogen by STAR, by preventing generation of active
plasmin-STAR complex. Fibrin stimulates plasminogen activation by STAR via
mechanisms involving the lysine- binding sites of plasminogen, probably by
facilitating the generation of plasmin-STAR complex and by delaying its
inhibition at the clot surface.
Volume 82,
Issue 4,
pp. 1175-1183,
08/15/1993
Copyright © 1993 by The American Society of Hematology
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