Plasmin-mediated proteolysis of vascular endothelial cell heparin releasable tissue factor pathway inhibitor.
BACKGROUND
Fibrinolytic therapy represents a widely available and effective treatment modality for ST segment elevation myocardial infarction (MI). Its overall benefit is attenuated by a high incidence of coronary arterial reocclusion.


RESULTS
Human umbilical vein endothelial cells (HUVEC) were incubated with unfractionated heparin (1.5 U/ml) (to provoke tissue factor pathway inhibitor [TFPI] release) followed by the addition of varying concentrations of alteplase (recombinant tissue plasminogen activator), plasminogen, their combination or plasmin alone. In the presence of 20% TFPI-depleted human plasma, there was a concentration-dependent decrease in TFPI levels following incubation with alteplase (28% reduction at 200 ng/ml; P < 0.01); 37% reduction at 1000 ng/ml (P < 0.001). Similar effects were observed for alteplase combined with plasminogen (P < 0.001), plasmin alone (P < 0.001) and with HUVEC incubated with low concentrations of plasmin (10 ng/ml) prior to heparin exposure.


CONCLUSIONS
Plasmin, a non-specific protease, degrades vascular endothelial cell (constitutive) TFPI and heparin-releasable TFPI, attenuating an important pathway of vascular surface thromboresistance and potentially contributing to coronary arterial reocclusion after fibrinolytic therapy.
Cardiovascular Thrombosis Research Center, Laboratory for Vascular Biology Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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Li
Frederick A
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Spencer
Richard C
RC
Becker
D003324:Coronary Artery Disease / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005341:Fibrinolysin / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000187:drug effects* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D012008:Recurrence; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014471:Umbilical Veins
D005343:Fibrinolytic Agents; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D006493:Heparin; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin