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Coagulation-dependent inhibition of fibrinolysis: role of
carboxypeptidase-U and the premature lysis of clots from hemophilic plasma
GJ Broze and DA Higuchi
Division of Hematology, Jewish Hospital, Washington University Medical
Center, St Louis, MO 63110, USA.
Coagulation is initiated by the binding of factor VIIa to tissue factor,
with resultant limited factor IX and X activation and thrombin production.
Owing to the feedback inhibition of the factor VIIa/tissue factor complex
by tissue factor pathway inhibitor (TFPI), additional factor X activation
and thrombin generation must proceed through a pathway involving factors
VIII, IX, and XI. Experiments designed to elucidate the requirement for
amplified factor Xa and thrombin generation in normal hemostasis show that
the resistance of plasma clots to tissue plasminogen activator (tPA)- and
urokinase-induced fibrinolysis is related to the extent of thrombin
generation. Inhibition of fibrinolysis is mediated in part by plasma
carboxypeptidase-U ([CPU] carboxypeptidase-R, procarboxypeptidase-B,
thrombin-activatable fibrinolysis inhibitor), a proenzyme that is
proteolytically activated by thrombin in a process enhanced dramatically by
the cofactor thrombomodulin. A clot induced in factor IX-deficient plasma
with limited amounts of tissue factor in the presence of urokinase (100
U/mL) lyses prematurely, and this defect is corrected by supplementation of
the deficient plasma with factor IX (5 micrograms/mL) or thrombomodulin (20
ng/mL). These additions enhance the rate and extent of CPU activation: in
the case of factor IX, presumably by permitting amplified generation of
factor Xa and thrombin, and in the case of thrombomodulin, presumably by
increasing the degree of CPU activation produced by the low levels of
thrombin generated in the absence of factor IX. Pretreatment of the factor
IX- deficient plasma with specific anti-CPU antibodies prevents the
increased resistance to fibrinolysis produced by addition of factor IX and
thrombomodulin. Likewise, when coagulation is induced by thrombin (2 U/mL)
in the presence of tPA (60 U/mL), clots formed from plasmas deficient in
factors VIII, IX, X, or XI lyse prematurely unless the missing factor is
replaced or thrombomodulin (20 ng/mL) is added.
Volume 88,
Issue 10,
pp. 3815-3823,
11/15/1996
Copyright © 1996 by The American Society of Hematology
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