Document Detail

Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors.
MedLine Citation:
PMID:  9494024     Owner:  NLM     Status:  MEDLINE    
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.
J I Weitz; B Leslie; M Hudoba
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Circulation     Volume:  97     ISSN:  0009-7322     ISO Abbreviation:  Circulation     Publication Date:  1998 Feb 
Date Detail:
Created Date:  1998-03-10     Completed Date:  1998-03-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  544-52     Citation Subset:  AIM; IM    
Department of Medicine, McMaster University and Hamilton Civic Hospitals Research Centre, Ontario, Canada.
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MeSH Terms
Analysis of Variance
Antithrombin III / pharmacology
Enzyme Activation
Fibrin Fibrinogen Degradation Products / chemistry,  metabolism*
Fibrinopeptide A / metabolism
Heparin / pharmacology
Thrombin / antagonists & inhibitors,  metabolism*
Thrombolytic Therapy
Tissue Plasminogen Activator / pharmacology
Reg. No./Substance:
0/Fibrin Fibrinogen Degradation Products; 25422-31-5/Fibrinopeptide A; 9000-94-6/Antithrombin III; 9005-49-6/Heparin; EC; EC Plasminogen Activator

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