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Active Site Inhibited Factor VIIa (DEGR VIIa) Attenuates the
Coagulant and Interleukin-6 and -8, but not Tumor Necrosis Factor,
Responses of the Baboon to LD100 Escherichia
coli
F.B. Taylor Jr,
A.C.K. Chang,
G. Peer,
A. Li,
M. Ezban, and
U. Hedner
From the Oklahoma Medical Research Foundation, Oklahoma City; the
University of Oklahoma Health Sciences Center, Oklahoma City; and Novo
Nordisk, Gentofte, Denmark.
Antitissue factor antibody attenuated the coagulopathic and lethal
responses to LD100 Escherichia coli, whereas active
site inhibited factor Xa inhibited only the coagulopathic response. In
this study, we wished to determine: (1) whether active site inhibited
factor VIIa blocks the coagulopathic and/or attenuates the
lethal effects of LD100 E coli and (2) whether
these effects are accompanied by attenuation of the inflammatory
cytokine response to LD100 E coli. Eight baboons
infused for 2 hours with LD100 E coli also were
given five bolus infusions of DEGR VIIa of 280 µg/kg at
T =  10 minutes, +2, 4, 6, and 8 hours and observed for changes in
vital signs, and the concentrations of hemostatic components (fibrinogen, platelets, fibrin degradation products) and inflammatory mediators (tumor necrosis factor [TNF], interleukin-6 [IL-6], IL-8)
at T = 0, 1, 2, 4, 6, and 8 hours. Eight control baboons were also
infused with LD100 E coli alone and followed as
described above. Four of the eight baboons treated with DEGR VIIa were
permanent 7-day survivors versus none in the control group. The mean
survival times for the treated and control groups were 116 ± 22 and
26 ± 8 hours, respectively. These values differed significantly from each other, (P = .0008). The decrease in platelet and
fibrinogen concentrations and the increase in fibrin degradation
products observed in the control group were significantly attenuated in the treated group, as was thrombosis of renal glomerular capillaries. Treatment with DEGR VIIa showed no effect on the peak TNF response to
LD100 E coli at T = 2 hours (170 ± 32 v
120 ± 35 ng/mL). DEGR VIIa, however, did attenuate the IL-6 and IL-8
responses at T = 8 hours (ie, the IL-6 concentrations were 81 ± 10 for treated and 1,256 ± 236 for the control groups and the IL-8
concentrations were 28 ± 3.9 for the treated and 60 ± 8.2 for the
control group). These values for IL-6 and IL-8 differed significantly
from each other between the treated and control groups (P = .0001 and .0074, respectively). It should be noted that the initial
responses of IL-6 and IL-8 up to T = 4 hours were not attenuated. We
concluded that DEGR VIIa treatment attenuates inflammatory, as well as
hemostatic system responses to LD100 E coli. We
hypothesize that this occurs through interference with the assembly
and/or interactions of tissue factor/VIIa complexes.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1609-1615
© 1998 by The American Society of Hematology.
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