Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis.
Despite its affinity for fibrin, tissue plasminogen activator (t-PA) administration causes systemic fibrinogenolysis. To investigate the mechanism, t-PA was incubated with plasma in the presence or absence of a fibrin clot, and the extent of fibrinogenolysis was determined by measuring B beta 1-42. In the presence of fibrin, there is a 21-fold increase in B beta 1-42 levels. The potentiation of fibrinogenolysis in the presence of fibrin is mediated by soluble fibrin degradation products because (a) the extent of t-PA induced fibrinogenolysis and clot lysis are directly related, (b) once clot lysis has been initiated, fibrinogenolysis continues even after the clot is removed, and (c) lysates of cross-linked fibrin clots potentiate t-PA-mediated fibrinogenolysis. Fibrin degradation products stimulate fibrinogenolysis by binding t-PA and plasminogen because approximately 70% of the labeled material in the clot lysates binds to both t-PA- and plasminogen-Sepharose, and only the bound fractions have potentiating activity. The binding site for t-PA and plasminogen is on the E domain because characterization of the potentiating fragments using gel filtration followed by PAGE and immunoblotting indicates that the major species is (DD)E complex, whereas minor components include high-molecular weight derivatives containing the (DD)E complex and fragment E. In contrast, D-dimer is the predominant species found in the fractions that do not bind to the adsorbants, and it has no potentiating activity. Thus, soluble products of t-PA-induced lysis of cross-linked fibrin potentiate t-PA-mediated fibrinogenolysis by providing a surface for t-PA and plasminogen binding thereby promoting plasmin generation. The occurrence of this phenomenon after therapeutic thrombolysis may explain the limited clot selectivity of t-PA.
Weitz
J I
JI
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Leslie
B
B
Ginsberg
J
J
D004789:Enzyme Activation; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism*; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry / Q000378:metabolism*; D005340:Fibrinogen / Q000378:metabolism*; D005342:Fibrinolysis; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D010958:Plasminogen / Q000378:metabolism; D011994:Recombinant Proteins; D012995:Solubility; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D005338:Fibrin Fibrinogen Degradation Products; D011994:Recombinant Proteins; D005337:Fibrin; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator