From the Department of Medicine, McMaster University and Hamilton Civic
Hospitals Research Centre, Hamilton, Ontario, Canada.
Correspondence to Dr Jeffrey Weitz, Hamilton Civic Hospitals Research Centre, 711 Concession St, Hamilton, Ontario, L8V 1C3. E-mail weitzj{at}fhs.mcmaster.ca
Background—Thrombolytic
therapy induces a procoagulant state characterized by elevated plasma
levels of fibrinopeptide A (FPA), but the responsible
mechanism is uncertain.
Methods and Results—Washed plasma clots were incubated in
citrated plasma in the presence or absence of tissue
plasminogen activator (t-PA), and FPA
generation was monitored as an index of unopposed thrombin activity.
FPA levels are almost twofold higher in the presence of t-PA than in
its absence. This primarily reflects the action of thrombin bound to
soluble fibrin degradation products because (a) there is
progressive FPA generation even after clots are removed from
t-PA–containing plasma, and (b) clot lysates produce
concentration-dependent FPA generation when incubated in citrated
plasma. Using thrombin-agarose affinity chromatography,
(DD)E and fragment E but not D-dimer were identified as the
thrombin-binding fibrin fragments, indicating that the thrombin-binding
site is located within the E domain. Heparin inhibits thrombin bound to
fibrin degradation products less effectively than free thrombin. In
contrast, D-Phe-Pro-ArgCH2Cl, hirudin and hirugen inhibit
free thrombin and thrombin bound to fibrin degradation products
equally well.
Conclusions—Thrombin bound to soluble fibrin degradation
products is primarily responsible for the increase in FPA levels
that occurs when a clot undergoes t-PA–induced lysis. Like clot-bound
thrombin, thrombin bound to fibrin derivatives is protected from
inhibition by heparin but susceptible to inactivation by direct
thrombin inhibitors. These findings help to explain the
superiority of direct thrombin inhibitors over heparin as
adjuncts to thrombolytic therapy.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Thrombin Binds to Soluble Fibrin Degradation Products Where it Is Protected From Inhibition by Heparin-Antithrombin but Susceptible to Inactivation by Antithrombin-Independent Inhibitors
Key Words: plasminogen activators • thrombolysis • thrombus • anticoagulants
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