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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1124-1129
FOCUS ON HEMATOLOGY
Tissue factor pathway inhibitor dose-dependently inhibits
coagulation activation without influencing the fibrinolytic and
cytokine response during human endotoxemia
Evert de Jonge,
Pascale E. P. Dekkers,
Abla A. Creasey,
C. Erik Hack,
Susan K. Paulson,
Aziz Karim,
Jozef Kesecioglu,
Marcel Levi,
Sander J. H. van Deventer, and
Tom van der Poll
From the Department of Intensive Care, Laboratory of Experimental
Internal Medicine, and the Department of Vascular Medicine, Academic
Medical Center, University of Amsterdam, Central Laboratory of the Red
Cross Blood Transfusion Service, Amsterdam, The Netherlands; Searle
Research & Development, Skokie, IL; and Chiron Corporation, Emeryville,
CA.
 |
Abstract |
Inhibition of the tissue factor pathway has been shown to attenuate
the activation of coagulation and to prevent death in a gram-negative
bacteremia primate model of sepsis. It has been suggested that tissue
factor influences inflammatory cascades other than the coagulation
system. The authors sought to determine the effects of 2 different
doses of recombinant tissue factor pathway inhibitor (TFPI) on
endotoxin-induced coagulant, fibrinolytic, and cytokine responses in
healthy humans. Two groups, each consisting of 8 healthy men, were
studied in a double-blind, randomized, placebo-controlled crossover
study. Subjects were studied on 2 different occasions. They received a
bolus intravenous injection of 4 ng/kg endotoxin, which was followed by
a 6-hour continuous infusion of TFPI or placebo. Eight subjects
received 0.05 mg/kg per hour TFPI after a bolus of 0.0125 mg/kg
(low-dose group), and 8 subjects received 0.2 mg/kg per hour after a
bolus of 0.05 mg/kg (high-dose group). Endotoxin injection induced the
activation of coagulation, the activation and subsequent inhibition of
fibrinolysis, and the release of proinflammatory and antiinflammatory
cytokines. TFPI infusion induced a dose-dependent attenuation of
thrombin generation, as measured by plasma F1 + 2 and
thrombin-antithrombin complexes, with a complete blockade of
coagulation activation after high-dose TFPI. Endotoxin-induced changes
in the fibrinolytic system and cytokine levels were not altered by
either low-dose or high-dose TFPI. The authors concluded that TFPI
effectively and dose-dependently attenuates the endotoxin-induced
coagulation activation in humans without influencing the fibrinolytic
and cytokine response.
(Blood. 2000;95:1124-1129)
© 2000 by The American Society of Hematology.
| |
Introduction |
Disseminated intravascular coagulation (DIC) is a
frequent complication of severe infection and, in patients with septic
shock, a strong predictor of death.1 A pivotal
mechanism in the pathogenesis of DIC is the activation of the
(extrinsic) tissue factor/factor VIIa-dependent pathway of
coagulation.2 Under physiological conditions, tissue factor
(TF) cannot be detected on the luminal surface of the vascular
endothelium,3 and it can be detected only in low quantities
on circulating blood cells.4-6 However, during infection
and after stimulation with endotoxin or tumor necrosis factor, TF can
be induced rapidly on blood mononuclear cells4,7,8 and on
vascular endothelium.9-11
Evidence for the role of TF/factor VIIa in activation of the
coagulation system is derived from studies in primates showing that the
coagulant response during bacteremia or endotoxemia could be completely
blocked by monoclonal antibodies to TF12,13 or factor
VIIa,14 by active site-inhibited factor VIIa,15
and by infusion of the tissue factor pathway inhibitor
(TFPI).16,17 Blockade of the TF-driven pathway of
coagulation by TFPI16,17 or antibodies to TF13
not only resulted in decreased activation of the coagulation system but
also in the prevention of death. It is unlikely that inhibition of the
TF pathway reduced mortality during severe bacteremia merely by
preventing DIC.18 Indeed, in baboons, an alternative method
of blocking the generation of thrombin by the administration of
active-site blocked factor Xa did not protect against organ failure and
death after Escherichia coli-induced sepsis.19 It
has been suggested that TF may modulate the inflammatory response by a
mechanism other than the initiation of blood coagulation.20
In accordance with this hypothesis are findings that inhibiting the
activity of the TF/VIIa pathway reduced the release of interleukin 6 (IL-6) and IL-8 during severe bacteremia.15,16
TFPI is a natural anticoagulant that acts by direct factor Xa
inhibition and, in a factor Xa-dependent manner, by feedback inhibition
of the TF/VIIa complex.21 In animal sepsis models, TFPI was
able to block the coagulant response completely and to prevent death
while reducing the cytokine response.16,17,22,23 Knowledge
of the effect of TFPI in humans is limited. Therefore, in the current
study, we used the well-characterized human model of endotoxemia to
determine the effect of TFPI, given as a 6-hour infusion in 1 of 2 doses, on coagulant, fibrinolytic, and cytokine responses.
| |
Methods |
Study design
The study was performed as a randomized, double-blind,
placebo-controlled crossover experiment. Written informed consent was obtained from each subject before the start of the study, and the study
was approved by the institutional scientific and ethics committees.
Sixteen healthy men (aged 19-29 years) volunteered to participate in
the study. None had abnormalities on physical examination or routine
laboratory investigation. Results of tests for hepatitis B, hepatitis
C, and human immunodeficiency virus were negative. The subjects did not
take any medication and did not smoke or use illicit drugs. Each was
studied on two occasions 6 weeks apart. Two doses of TFPI were
administered. Eight subjects were examined after the
administration of endotoxin and low-dose TFPI/placebo, and 8 subjects
were examined after the administration of endotoxin and high-dose
TFPI/placebo. All subjects fasted overnight before endotoxin
administration. At 7 AM two intravenous cannulas were
inserted, one for endotoxin administration and blood collection and the
other for the infusion of TFPI or placebo. Endotoxin (E. coli
lipopolysaccharide, lot G; US Pharmacopeia, Rockville, MD) was administered at 9 AM as a bolus intravenous injection
at a dose of 4 ng/kg body weight. Recombinant human TFPI/SC-59 735 (Chiron, Emeryville, CA) was given immediately after the endotoxin injection as a bolus of 0.0125 mg/kg body weight. This was followed by
a continuous 6-hour infusion of 0.05 mg/kg per hour (low-dose group) or
as a bolus of 0.05 mg/kg body weight and then by a continuous 6-hour
infusion of 0.2 mg/kg per hour (high-dose group). In the control
experiments, the same solution used for diluting TFPI was given as
placebo. Oral temperature, blood pressure, heart rate, and oxygen
saturation were measured at half-hour intervals (Dinamap1846 SX;
Critikon, Tampa, FL). Clinical symptoms such as headache, shivers,
nausea, vomiting, tiredness, and malaise were recorded throughout the
study periods using a graded scale (0, absent; 1, weak; 2, moderate; 3, severe).
Blood collection
Blood was obtained from an intravenous cannula at 20 minutes before
endotoxin administration and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and
24 hours thereafter. Blood for coagulation and fibrinolysis assays was
collected in siliconized Vacutainer tubes (Becton Dickinson, Plymouth,
UK) containing 0.105 mol/L sodium citrate; the ratio of anticoagulant
to blood was 1:9 (vol/vol). Blood for cytokine assays and leukocytes
was collected in K3-EDTA-containing tubes. Leukocyte
counts and differentials were assessed by a Stekker analyzer (STKS Hematology Flow Cytometer, Beckman Coulter,
Buckinghamshire, UK). All blood samples, except those for the
determination of leukocyte counts and differentials, were centrifuged
at 3000 rpm for 15 minutes at 4°C, and plasma was stored at
 20°C until assays were performed.
Assays
Plasma levels of TFPI were measured in a validated sandwich
immunoassay. The assay uses a monoclonal antibody directed against the
first Kunitz domain of TFPI for capture and a fluorescein-labeled polyclonal antibody to TFPI for detection. These antibodies also recognize endogenous native human TFPI. All samples were assayed in
triplicate. The lower limit of quantitation was 40 ng/mL. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured by 1-stage clotting assays with thromboplastin PT-fibrinogen and thromboplastin APTT-SP, respectively, on an ACL 7000 analyzer (Instrumentation Laboratory, Lexington, MA). The plasma concentrations of prothrombin fragment F1 + 2 and thrombin-antithrombin complexes (TATc) were measured by enzyme-linked immunosorbent assay (ELISA; Beringwerke AG, Marburg, Germany). Tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor type 1 (PAI-1) antigen were assayed by ELISA (Asserachrom tPA; Diagnostica Stago, Asnieres-sur-Seine, France; and PAI-ELISA kit; Monozyme,
Charlottenlund, Denmark). Plasmin-a2-antiplasmin complexes (PAPc)
complexes were measured by ELISA (Enzygnost PAP micro; Behring
Diagnostics GmbH, Marburg, Germany). Tumor necrosis factor
(TNF), IL-6, and IL-10 were measured by ELISA according to
the manufacturer's instructions (Central Laboratory of the Netherlands
Red Cross Blood Transfusion Service, Amsterdam, The Netherlands).
Soluble TNF receptor type 1 was measured by an enzyme-linked
immunobound assay produced by Hoffmann La Roche (Basel, Switzerland) as
described previously.24
Statistical analysis
Values are given as means ± SEM. Differences in results between
the TFPI and control experiments were tested by repeated measurement analysis of variance. Changes in time within a group were analyzed by
one-way analysis of variance. P < .05 was considered significant.
| |
Results |
TFPI plasma concentrations
Endogenous TFPI plasma concentrations did not increase after
endotoxin administration (Figure 1). After
TFPI infusion, peak plasma concentrations increased from 54 ± 4
to 175 ± 8 ng/mL (P < .01; TFPI vs placebo) in the
low-dose group and from 65 ± 6 to 456 ± 34 ng/ml in the
high-dose group (P < .01; TFPI vs placebo).
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| Fig 1.
Mean ± SEM plasma TFPI concentrations after endotoxin
administration and infusion of TFPI or placebo.
Endotoxin administration was given as a bolus injection (4 ng/kg) at
t = 0. Infusion of TFPI ( ) and placebo ( ) started at t = 0
and was continued until t = 6 hours. P values indicate the
differences in results of TFPI and placebo experiments.
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Clinical features and hematologic responses
Injection of endotoxin induced a febrile response, peaking after 3.5 hours, together with tachycardia and transient flu-like symptoms,
including headache, nausea, malaise, and chills. In addition, endotoxin
administration resulted in a biphasic change in white blood cell
counts, characterized by initial leukopenia followed by leukocytosis.
None of these changes were influenced by TFPI (Table
1 and data not shown). No adverse events
attributable to TFPI infusion were observed, and no episodes of
increased bleeding occurred.
Activation of the coagulation system
Administration of endotoxin resulted in the activation of thrombin
generation, as reflected by increases in the plasma levels of the
prothrombin fragment F1 + 2 and TATc (P = .001; Figure 2). The endotoxin-induced increase in
F1 + 2 was diminished by low-dose TFPI (peak values 2.69 ± 0.73
and 8.31 ± 2.54 nmol/L for TFPI and placebo, respectively,
P < .01). It was completely abolished by high-dose TFPI
(peak value 1.29 ± 0.30 and 9.95 ± 2.83 nmol/L for TFPI and
placebo, respectively, P < .01). The endotoxin-induced
increase in TATc was almost completely prevented by high-dose TFPI
(peak values, 17.9 ± 3.9 vs 95.6 ± 30.2 µg/L; P < .01). Low-dose TFPI also decreased TATc formation, but
this decrease did not reach statistical significance (peak values, 52.6 ± 17.2 and 92.6 ± 35.3 µg/L for TFPI and placebo,
respectively; P = .19).
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| Fig 2.
TFPI dose-dependently inhibits coagulation activation.
Mean ± SEM plasma concentrations of thrombin-antithrombin (TAT)
complexes and prothrombin fragment F1 + 2 after endotoxin
administration and infusion of TFPI () or placebo (). Endotoxin
(4 ng/kg) was given as a bolus injection at t = 0. Infusion of TFPI
started at t = 0 and was continued until t = 6 hours. P
values indicate the differences in results of TFPI and placebo
experiments.
|
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After endotoxin injection, APTT values decreased and reached a
nadir after 3 hours (P < .01; Figure
3). Initially, TFPI increased the aPTT
values; in the high-dose experiments, it prevented the endotoxin-induced decrease in aPTT (P < .01; Figure 3). PT
values slightly increased after endotoxin injection and reached the
maximum value after 5 hours (P < .01; Figure 3). Treatment
with TFPI resulted in the additional prolongation of PT. In the
low-dose group, PT increased from 12.7 ± 0.1 to 14.5 ± 0.2
seconds during TFPI treatment versus 12.8 ± 0.1 to
13.8 ± 0.2 seconds in the placebo study period (P = .04). In the high-dose group, PT values increased from
12.2 ± 0.2 to 15.6 ± 0.4 seconds in the TFPI study period
and from 12.4 ± 0.2 to 13.2 ± 0.2 seconds in the placebo
study period (P < .01; Figure 3).
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| Fig 3.
Mean ± SEM values of PT and aPTT after endotoxin
administration and infusion of TFPI or placebo.
Endotoxin (4 ng/kg) was given as a bolus injection at t = 0. Infusion
of TFPI () or placebo () started at t = 0 and was continued
until t = 6 hours. P values indicate the differences in
results of TFPI and placebo experiments.
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Activation of the fibrinolytic system
The injection of endotoxin was associated with an early
release of tPA (peaking after 3 hours) followed by the appearance of
PAI-1 (peaking after 4 hours) (both P < .01). Activation of the fibrinolytic system was confirmed by a transient increase in the
plasma concentrations of PAPc, peaking after 2 hours
(P < .01). Neither low-dose TFPI nor high-dose TFPI
influenced the endotoxin-induced release of tPA, PAI-1, or PAPc (Figure
4).
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| Fig 4.
TFPI does not influence the fibrinolytic response.
Mean ± SEM plasma concentrations of tPA, PAI-1, and PAPc after
endotoxin administration and TFPI infusion () or placebo ().
Endotoxin (4 ng/kg) was given as a bolus injection at t = 0. Infusion
of TFPI started at t = 0 and was continued until t = 6 hours.
P values indicate the differences in results of TFPI and
placebo experiments.
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Cytokines
One hour after endotoxin administration, TNF plasma levels increased
and reached peak values after 2 hours (P < .01). The TNF
response on endotoxin injection was not influenced by either low- or
high-dose TFPI (Figure 5). IL-6 levels
increased from 90 minutes after endotoxin administration and peaked
after 3 hours (P < .01). IL-6 responses after endotoxin
injection were diminished after low-dose TFPI compared with after
placebo, but this difference was not statistically significant. No
difference was observed in IL-6 response between the high-dose TFPI
group and the placebo-treated subjects (Figure 5). Endotoxin also
elicited an antiinflammatory cytokine response, as reflected by
transient increases in the plasma levels of the type 1 soluble TNF
receptor (sTNF-R1) and IL-10. Neither of these endotoxin-induced
increases was influenced by low- or high-dose TFPI (data not shown).
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| Fig 5.
Mean ± SEM plasma concentrations of TNF and IL-6 after
endotoxin administration and infusion of TFPI or placebo.
Endotoxin (4 ng/kg) was given as a bolus injection at t = 0. Infusion
of TFPI () or placebo () started at t = 0 and was continued
until t = 6 hours. P values indicate the differences in
results of TFPI and placebo experiments.
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| |
Discussion |
Activation of the TF/VIIa pathway is considered crucial for the
initiation of the coagulation system during bacteremia and endotoxemia.
It has been suggested that besides its effect on coagulation, the
TF/VIIa pathway can influence other inflammatory mediator systems.
Therefore, we considered it of interest to determine the effect of TFPI
on the coagulant, fibrinolytic, and cytokine responses during human
endotoxemia. The current study is the first to show the anticoagulant
effect of recombinant TFPI in humans. In the high-dose TFPI
experiments, endotoxin-induced thrombin generation, as determined by
increases in plasma F1 + 2 and TATc levels, was almost completely
prevented; even in the low-dose TFPI studies, a reduction in thrombin
production was observed. Hence, our data confirm the importance of TF
in the endotoxin-induced procoagulant response in humans and further
demonstrate that the effect of TFPI on thrombin generation is
dose-dependent. However, TFPI was without any effect on fibrinolysis or
cytokine release. The results suggest that, at least during low-grade
endotoxemia, TFPI selectively attenuates coagulation activation.
The role of endogenous TFPI in sepsis and endotoxemia is not completely
clear. Exposure of TF to circulating blood initiates the coagulation
cascade by binding to factor VIIa, after which the TF/VIIa complex
activates factor X and factor IX. Recent evidence suggests that TF may
be present in an inactive, encrypted form and that the mere presence of
TF on the cell surface is insufficient for initiating blood
coagulation. Some additional stimulus may be required to express this
latent procoagulant activity.25,26 TFPI is an approximately
43-kd, trivalent, Kunitz-type inhibitor that directly inhibits factor
Xa with its second Kunitz domain. After factor Xa is bound, it rapidly
inhibits the TF/VIIa complex with the first Kunitz
domain.27 The third Kunitz domain has no known inhibitory
role, but it may be involved in the lipoprotein binding of
TFPI.28 Most of the body's TFPI is located in endothelial cells, and only 10% to 25% is found in circulating blood. Circulating TFPI is predominantly bound to lipoproteins.29 Blood
platelets also carry native TFPI (approximately 10% of the plasma
pool), which is released after thrombin stimulation.30 In
vitro studies suggest that there may be a slight increase in TFPI
produced by endothelial cells and monocytes by stimulation with
endotoxin.31 Furthermore, (slightly) increased levels of
TFPI have been observed in a number of illnesses, including malignancy
and septicemia.32-35 In previous studies, plasma
concentrations of TFPI only increased after severe injury. Thus, a
sublethal dose of E. coli only induced a minimal (approximately
1.2-fold) increase in plasma TFPI concentrations, whereas infusion of
an LD100 dose E. coli resulted in a 2-fold rise in
plasma TFPI levels.36 In our study, endogenous TFPI levels
did not increase in plasma after endotoxin administration, which could
be considered a relatively mild stimulus. Together, these data suggest
that the dose of endotoxin used in our human volunteer studies was
insufficient to elicit an endogenous TFPI response in plasma.
In our experiments TFPI infusion was started immediately after
endotoxin administration and was continued for 6 hours after a bolus
injection. Two different dosages were compared. Both were chosen
because of pharmacokinetic studies in healthy humans to achieve plasma
TFPI levels of 86 and 346 ng/mL, respectively (investigational brochure; Searle Research & Development, Skokie, IL). In earlier studies these plasma levels were efficacious in reducing mortality in a
sepsis model in rabbits.23 Low-dose TFPI infusion resulted in mean peak plasma TFPI concentrations of 175 ng/mL (3.5-fold higher
than baseline) and steady state concentrations of 2.5-fold baseline. In
the high-dose experiments, mean peak concentrations of 456 ng/mL
(8-fold baseline) and steady state concentrations of 4.5-fold baseline
were achieved. These TFPI concentrations resulted in minor
prolongations of PT values of 1.8 and 3.4 seconds, respectively, that
were slightly larger than the prolongation (1 second) attributable
to endotoxin observed in the control experiments. Endotoxin
induced a decrease in aPTT values. Previous observations and the time
course of this effect suggests that the most likely explanation could
be the endotoxin-induced release of von Willebrand factor (vWF) from
the endothelium and the associated rise in factor VIII
levels.37,38 Indeed, we could confirm a rapid release of
vWF on endotoxin infusion in our study (data not shown). Interestingly, the endotoxin-induced decrease of aPTT values was attenuated by high-dose TFPI. Because vWF levels were not affected by TFPI, this
probably resulted from a slight direct effect of TFPI on the aPTT.
In accordance with earlier studies,39,40 the activation of
coagulation after endotoxin administration was preceded by a rapid
activation and subsequent inhibition of the fibrinolytic system, as
reflected by increased levels of tPA and PAPc followed by an increase
in PAI-1 levels. Infusion of TFPI did not have any effect on the
fibrinolytic response. These findings show that during low-grade
endotoxemia in humans, the fibrinolytic response occurs independent of
the generation of thrombin. Previous studies of low-grade endotoxemia
in chimpanzees have revealed that blockade of endotoxin-induced
coagulation activation by the administration of various anticoagulant
agents, including anti-TF and anti-factor VIIa monoclonal antibodies,
and the specific thrombin inhibitor hirudin, similarly did not result
in the inhibition of plasmin generation.12,14,41 TNF is
considered the major denominator of fibrinolysis activation in
endotoxemia.42-44 Consistent with our finding that the
endotoxin-induced activation of fibrinolysis in humans was not
influenced by TFPI is the observation that TNF plasma concentrations
were also unaffected by TFPI.
It should be noted that blocking the TF pathway in lethal E. coli sepsis in baboons not only prevented DIC, it protected against lethality.13,16,17 In addition, the administration of other physiological coagulation inhibitors has been shown to ameliorate the
coagulation defect and to prevent death.45 More downstream interventions in the coagulation cascade, by the administration of
active-site degraded factor Xa (DEGR-Xa), failed to influence lethality
in bacteremic baboons whereas it completely inhibited the activation of
coagulation.19 Because it has been suggested that the TF
pathway exerts effects on other inflammatory responses besides its
effects on coagulation,20 the inhibition of these effects
by TFPI may have contributed to the TFPI-mediated protection against
lethality. Indeed, in lethal sepsis models the inhibition of TF
attenuated the IL-6 and IL-8 responses after E. coli infusion in baboons.15-17 It is uncertain how TFPI may influence
cytokine production. Interestingly, clotting blood has been found to
produce IL-8 but not IL-6 in vitro. The addition of endotoxin to
coagulating blood resulted in a synergistic enhancement of IL-8
production that could be attenuated by the thrombin inhibitor hirudin
or TFPI.46 In addition, end products of the coagulation
cascade ie, factor Xa, thrombin, and fibrincan induce the synthesis
of IL-6, IL-8, or both by various cell types in vitro.47-50
Hence, the inhibition of coagulation by TFPI may reduce IL-6 and IL-8
release during sepsis. Furthermore, in vitro TFPI has been found to
bind endotoxin and to block its effects on cells by interfering with
its transfer to CD14.51 In the current study, we did not
find any influence of TFPI on endotoxin-induced cytokine responses, as
reflected by unaltered plasma concentrations of TNF, IL-6, IL-10, and
sTNF-R1. IL-8 release was unchanged (data not shown). Our model differs from the lethal primate models in many important aspects. Although endotoxin infusion in healthy humans leads to the moderate activation of coagulation without organ dysfunction, lethal sepsis models induce
massive thrombin generation with marked thrombus deposition at autopsy,
leading to organ failure and death. The fact that the inhibition of
coagulation by TFPI attenuates cytokine production in lethal sepsis
models but not in the human endotoxin model could be a reflection of
the amounts of thrombin formed in the different models. An alternative
explanation could be that monocytes are the predominant source of
cytokines during low-grade endotoxemia (which is associated with the
transient release of cytokines) and that the endothelium contributes to
more prolonged release, especially of IL-6 and IL-8, found in models of
lethal sepsis. Indeed, endothelial cells predominantly produce IL-6 and
IL-8 after stimulation.50,52 In baboons with sepsis, TFPI
attenuated the IL-6 and IL-8 responses without affecting the early and
transient TNF peaks.16 Hence, it can be speculated that
TFPI in part attenuates the cytokine response by endothelial cells and
has a much smaller effect on endotoxin-induced cytokine production by
monocytes. Finally, it may be that cytokine production in the lethal
sepsis model is not caused by thrombin but by ischemia and organ
failure that result from occlusive thrombi in the microcirculation. If so, the effective inhibition of coagulation during sepsis may prevent
the development of organ failure and thereby the secondary increase in
cytokine levels.
Knowledge of the mechanisms involved in the activation of the
hemostatic mechanism during severe infection has increased considerably in past years. The current study confirms in humans the pivotal role of
the TF/VIIa pathway in endotoxin-induced coagulation activation and the anticoagulant potential of TFPI. Recombinant TFPI
dose-dependently inhibited the activation of coagulation after
endotoxin administration to healthy humans, without influencing the
fibrinolytic and cytokine responses. TFPI is a selective anticoagulant
drug during low-grade human endotoxemia.
| |
Acknowledgments |
The authors thank Dr Abraham van den Ende and the staff of the
Hemostasis Laboratory for excellent technical assistance.
| |
Footnotes |
Submitted June 28, 1999; accepted September 13, 1999.
Reprints: Evert de Jonge, Department of Intensive Care,
Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, Netherlands.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction