"Plasminogen steal" and clot lysis.
Although initially developed to reduce the risk of bleeding, second-generation (clot-selective) thrombolytic agents have been found to induce more prompt and frequent recanalization than do nonselective, first-generation agents. To determine whether they do so in part by preserving clot-associated plasminogen, human whole blood clots formed in Chandler tubes were studied. Addition of suprapharmacologic concentrations of recombinant tissue-type plasminogen activator (rt-PA) to the media bathing mature clots led to a paradoxic impairment of clot lysis and a concomitant concentration-dependent depletion of clot-associated plasminogen (Western blot analysis). In contrast, supplementation of the plasma with plasminogen (0.27 mg/ml) led to significant conservation of both plasma and clot-associated plasminogen (p less than or equal to 0.05, n = 4), and prevented the diminution of clot lysis (p less than or equal to 0.05; n = 4). Fibrinogen degradation products did not account for the attenuation of lysis with the highest concentrations of rt-PA. In concentrations equivalent to those that were induced by the highest concentrations of rt-PA evaluated, fibrinogen degradation products potentiated rather than inhibited lysis (p less than or equal to 0.05, n = 4), probably by stimulating rt-PA activity directly. When preformed clots were incubated with plasminogen-depleted plasma plus 1,000 ng/ml rt-PA, the plasminogen content in residual clot declined (9.36 +/- 0.46 versus 12.39 +/- 0.69 ng/mg clot found in nondepleted plasma; p less than or equal to 0.05; n = 6). Furthermore, clot lysis was attenuated completely.(ABSTRACT TRUNCATED AT 250 WORDS)
Torr
S R
SR
Cardiovascular Division, Washington University School of Medicine, Saint Louis, Missouri 63110.
Nachowiak
D A
DA
Fujii
S
S
Sobel
B E
BE
D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D005340:Fibrinogen / Q000187:drug effects / Q000502:physiology; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D010958:Plasminogen / Q000032:analysis / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D011994:Recombinant Proteins; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin