Recombinant plasminogen activator inhibitor-1 protects platelets against the inhibitory effects of plasmin.
Plasmin-induced degradation of platelet glycoprotein Ib (GPIb), the von Willebrand factor (vWF) receptor, has been implicated as a mechanism contributing to the development of platelet dysfunction following cardiopulmonary bypass (CPB). The goal of this study was to assess whether biologically active recombinant plasminogen activator inhibitor-1 (rPAI-1), could antagonize the inhibitory effects of plasmin on GPIb. GPIb function, as evaluated by measuring vWF-dependent, ristocetin-induced platelet agglutination in human platelet rich plasma (PRP) was significantly impaired following incubation with plasmin (60 +/- 14% inhibition, p < 0.01). Inclusion of rPAI-1 (10 micrograms/ml) in the PRP antagonized this plasmin effect, restoring agglutination to 92 +/- 8% of the control value (p < 0.01). The effect of rPAI-1 on the enzymatic activity of plasmin was further evaluated in an amidolytic assay with the plasmin substrate S2251 where an apparent second order rate constant of plasmin inhibition by rPAI-1 of 9.4 x 10(4) M-1 S-1 was determined. Our results suggest that rPAI-1, by inhibiting both tissue plasminogen activator-induced plasmin generation and plasmin activity directly, may have clinical value for improving platelet function during and after CPB.
Reilly
T M
TM
Du Pont Merck Pharmaceutical Company, Cardiovascular Diseases Research, Wilmington, Delaware 19880-0400.
Forsythe
M S
MS
Racanelli
A L
AL
Spitz
S M
SM
Walton
H L
HL
Mousa
S A
SA
D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology
D017395:Plasminogen Activator Inhibitor 1; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D005341:Fibrinolysin