(Circulation. 2001;103:2555.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Ability of Recombinant Factor VIIa to Generate Thrombin During Inhibition of Tissue Factor in Human Subjects
From the Department of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam, Netherlands (P.W.F., M.L., D.B., T.K., M.S., H.R.B.); Boston VA Healthcare System and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (K.A.B., S.B.); and Corvas International, Inc, San Diego, Calif (G.P.V., W.E.R.).
Correspondence to Marcel Levi, MD, Department of Vascular Medicine and Internal Medicine (F-4), Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail m.m.levi{at}amc.uva.nl
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Abstract |
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Background—In view of the central role of the tissue factor–factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor–factor VIIa complex, in a double-blind randomized crossover study.
Methods and Results—Administration of nematode anticoagulant protein c2 (3.5 µg/kg) caused a prolongation of the prothrombin time from 13.7±0.6 to 16.9±1.2 seconds. The subsequent injection of rVIIa (90 µg/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75±0.64 to 3.29±6.3 nmol/L and from 2.4±0.6 to 10.7±3.9 µg/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2.
Conclusions—During treatment with an inhibitor of the tissue factor–factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.
Key Words: anticoagulants • coagulation • thrombosis • drugs • inhibitors
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Introduction |
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Recent experimental and clinical studies have shown that under normal physiological conditions, the initiation of blood coagulation is catalyzed by the tissue factor–factor VIIa pathway.1 2 The tissue factor–factor VIIa complex is able to generate factor Xa via direct activation of factor X or indirectly after the activation of factor IX and subsequent formation of the tenase complex with the activated cofactor factor VIII. It is well established that tissue factor plays a crucial role in the many disease processes resulting from the activation of the blood coagulation response or thrombosis. For example, the systemic activation of blood coagulation in disseminated intravascular coagulation was shown to be completely dependent on tissue factor.3 In addition, the abundant presence of tissue factor in the atherosclerotic plaque has linked pathological plaque rupture to the subsequent thrombotic occlusion of a coronary artery leading to acute coronary syndromes.4 5 In view of this central role of tissue factor–factor VIIa in the activation of coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated in experimental and clinical trials.6 7 8 One of these inhibitors is recombinant nematode anticoagulant protein c2 (rNAPc2), a potent and selective inhibitor of the tissue factor–factor VIIa complex in the presence of factor Xa.9 In initial clinical trials, rNAPc2 has been shown to produce a dose-dependent anticoagulant effect with a systemic half-life of >50 hours after subcutaneous administration in normal volunteers.8 The potential clinical success of such inhibitors of the tissue factor–factor VIIa complex as rNAPc2 may be limited by the lack of an appropriate strategy to reverse the effect of these anticoagulants if a serious bleeding event is encountered. Recent reports from in vitro studies indicate that therapeutic doses of recombinant factor VIIa (rVIIa) may be able to induce activation of coagulation, resulting in subsequent thrombin generation possibly independent of tissue factor activity.10 The relevance of this mechanism in vivo, however, has not been confirmed thus far, although recombinant factor VIIa has been shown to be an important agent in controlling bleeding episodes in various clinical scenarios.11 12 13 If tissue factor–independent thrombin generation can be achieved, then the administration of recombinant factor VIIa might be a suitable antidote to the tissue factor–factor VIIa class of anticoagulant agents. Therefore, the aim of the present double-blind, randomized, placebo-controlled crossover study was to investigate the in vivo potential of recombinant factor VIIa to induce thrombin generation in healthy subjects pretreated with rNAPc2.
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Methods |
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Subjects and Study Design
The study was approved by the research and medical ethical committees of the Academic Medical Center, Amsterdam, Netherlands. Written informed consent was obtained from all subjects. The study was designed as a randomized, placebo-controlled multiple-period crossover study. Six healthy male volunteers (mean age 22 years, range 21 to 26 years) were enrolled in the study. All subjects were tested at 3 different occasions in a random order, separated by a washout period of
10 days. Treatment consisted of
rNAPc2, a specific inhibitor of the tissue factor–factor
VII complex, either in combination with recombinant factor VIIa or in
combination with placebo. On a third occasion, they received
recombinant factor VIIa alone (control).
Study Agents
rNAPc2 (Corvas Inc) is a small protein anticoagulant
derived from the family of nematode anticoagulant proteins, which were
originally isolated from hematophagous hookworm nematodes, that is
currently produced as a recombinant protein under good manufacturing
practices established by the FDA. rNAPc2 forms a ternary
inhibitory complex with factor VIIa–tissue factor after
the binding to factor Xa.9
rNAPc2 was administered in a volume of 0.3 mL at a dose of 3.5 µg/kg
as a single subcutaneous injection at the start of the study. The
rationale for the dose of rNAPc2 was based on previous phase-I studies
in humans, in which rNAPc2 was shown to produce a dose-dependent
anticoagulant effect and was considered safe and well tolerated in
doses up to 5
µg/kg.8
rVIIa (NovoSeven, Novo Nordisk) was administered as an intravenous bolus injection at a dose of 90 µg/kg in 10 mL saline, 4 hours after the administration of rNAPc2. The dose rationale for rVIIa was based on the clinically effective dose in patients with bleeding disorders and previous studies with rVIIa in humans using acenocoumarol.14 In the study period in which rNAPc2 was given in combination with placebo, an intravenous injection with 0.15 mL/kg saline was administered. In the study period in which the study subjects received rVIIa alone, the injection of rVIIa was preceded (by 4 hours) by the administration of saline subcutaneously (instead of rNAPc2).
Blood Collection and Assays
Blood was drawn from the forearm by separate
venipunctures into tubes containing the appropriate
anticoagulants before the administration of rNAPc2, 4 hours after the
administration of rNAPc2 but immediately before administration of
rVIIa/placebo, and at 0.5, 1, 1.5, 2, 3, 4, 6, and 20 hours after the
administration of rVIIa or placebo.
Thrombin generation was assessed by measurement of the prothrombin activation fragment F1+2 and thrombin-antithrombin (TAT) complexes (ELISA, Behring).
Factor IX activation peptide and factor X activation peptide were assayed by a radioimmunoassay, as previously described.15 16
Plasma levels of soluble tissue factor and tissue factor pathway inhibitor were measured with commercially available ELISAs (American Diagnostics Inc).
The plasma levels of factor VIIa were determined by use of a newly developed enzyme capture assay for determining factor VIIa activity in human plasma according to a previously described principle.17 Briefly, solid-phase bound monoclonal antibodies raised against rVIIa enabled capture of rVIIa. In the next step, bound rVIIa was allowed to convert a chromogenic substrate during incubation, which was shown to be linearly correlated with rVIIa concentrations.18
The plasma concentration of rNAPc2 was analyzed by sandwich ELISA. The assay used affinity-purified polyclonal antibodies that were raised against rNAPc2. The detector antibody was the same antibody conjugated to horseradish peroxidase.
Statistical Analysis
Statistical analysis was performed by ANOVA
and subsequent Newman-Keuls tests. A value of
P=0.05 was considered to
represent a statistically significant difference. Values are
presented as
mean±SD.
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Results |
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Clotting Times and Factor VIIa Levels
The administration of rNAPc2 caused a prolongation of the prothrombin time (PT), which was similar for all subjects in both study periods in which rNAPc2 was given. As shown in Figure 1A
, the PT increased from 13.0±0.8 seconds at
baseline to 15.4±1.2 seconds at 4 hours after administration of rNAPc2
(P<0.05). The subsequent
injection of rVIIa resulted in an immediate overcorrection of the PT to
9.7±0.5 seconds, which was significant compared with the sustained
prolongation of the PT in the placebo controls
(P<0.001). Treatment with
rVIIa alone also depressed the PT from 12.0±0.8 seconds at baseline to
a minimum of 8.9±0.3 seconds 30 minutes after administration of rVIIa.
The difference in the shortening of the PT between the treatment groups
that received rNAPc2 + rVIIa and rVIIa alone was significant
(P<0.05). The effect of rVIIa
administration on the PT gradually decreased after 4 hours but was
still present at 6 hours after administration. The
activated partial thromboplastin time (aPTT) was not
significantly affected by the administration of rNAPc2 and
rVIIa.
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). On a third occasion, no rNAPc-2 was given, and 90 µg/kg rVIIa was administered at t=0 (
). Data represent mean±SD. *Significant differences (P<0.05) between treatment with rNAPc2/VIIa and rNAPc2 alone; #between rNAPc2/VIIa and rVIIa alone.
The plasma levels of factor VIIa were below the limit of
detection in the period before the administration of rVIIa
(Figure 1B
). The plasma levels increased sharply immediately
after the administration of rVIIa and reached peak values of 23.7±7.5
nmol/L at 30 minutes after administration. Thereafter, the levels
gradually decreased and were below the limit of detection at 20 hours
after administration. The calculated half-life of rVIIa in this
experiment was 
120 minutes (which is slightly shorter than the
reported half-life of rVIIa of 170 minutes in patients with hemophilia
and acquired inhibitors to factor VIII or
IX).11 As shown in
Figure 1B, the administration of rNAPc2 had no effect on the
plasma levels of factor VIIa.
Thrombin Generation
There was a nonsignificant trend toward lower levels of
circulating markers for thrombin generation (F1+2, TAT complexes) after
injection of rNAPc2
(Figure 2). Administration of rVIIa in subjects
pretreated with rNAPc2 resulted in a marked increase in thrombin
generation, as reflected by a sharp rise in plasma levels of both F1+2
and TAT complexes, which reached a maximum 30 to 60 minutes after the
administration of rVIIa. Both F1+2 and TAT complexes showed significant
3.6-fold and 4.5-fold increases with peak levels of 3.2±1.5 nmol/L and
10.7±1.6 µg/L, respectively, in response to rVIIa administration
(Figure 2). The injection of rVIIa alone resulted in an
additional increase in thrombin generation of 25% to 40% over that
observed in subjects receiving both rNAPc2 and rVIIa, with F1+2 and TAT
complex peak levels of 4.0±0.3 nmol/L and 14±1.3 µg/L, respectively
(P<0.05). Therefore, these
results suggest that rNAPc2 significantly blunted thrombin generation
induced by rVIIa.
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Factor IX and X Activation
As shown in
Figure 3, the plasma levels of factor X activation peptide
after the administration of rNAPc2 decreased gradually during the
observation period, but this change was not statistically significant.
The observed thrombin generation after the administration of rVIIa
appeared to be mediated by the activation of factors IX and X, as
evidenced by the significant increase in activation peptides derived
from these zymogens. Pretreatment with rNAPc2 resulted in lower
rVIIa-induced peak levels of factor X activation peptide and a trend
toward lower rVIIa-induced peak levels of factor IX activation peptide
compared with injection of rVIIa alone. Factor IX activation peptide
increased from 221±41 to 839±157 pmol/L after the administration of
rVIIa and pretreatment with rNAPc2 compared with a maximal level of
977±65 pmol/L achieved after the administration of rVIIa alone
(P=0.07). Levels of factor X
activation peptide rose from 87±23 to 302±61 pmol/L after injection
of rVIIa preceded by rNAPc2 and to 387±12 pmol/L after the injection
of rVIIa alone (P<0.05).
Plasma levels of soluble tissue factor and tissue factor pathway
inhibitor did not change during the experiment in any
experimental group.
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Plasma Levels of rNAPc2
Maximum plasma concentrations of rNAPc2 of 60.6±3.7
ng/mL for the rVIIa group and 68.5±4.0 ng/mL for the placebo group
occurred at 6.7±0.6 and 8.5±3.1 hours after the administration of
rNAPc2, respectively
(Figure 4). The area under the plasma concentration-time
curve (AUC 0 to 24) was comparable for each group; 1172±72 ng ·
h-1 · mL-1
for the rVIIa group versus 1298±100 ng ·
h-1 · mL-1
for the placebo group. Estimation of the apparent terminal half-life
(t1/2) was 72.6±9.4 hours for the rVIIa group and 78.2±5.0 hours for
the placebo group.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The initiation of the blood coagulation response to vascular injury or inflammation is mediated by the exposure of tissue factor to factor VIIa that circulates at low levels in the blood.2 The resulting factor VIIa–tissue factor complex catalyzes the proteolytic activation of zymogen factor X to the active protease factor Xa, which is then incorporated into the prothrombinase complex on appropriate membrane surface with factor Va. The prothrombinase complex catalyzes the formation of thrombin through the activation of circulating prothrombin. The tissue factor–factor VIIa–factor Xa complex can also indirectly contribute to factor Xa generation through the activation of zymogen factor IX to factor IXa, which when bound to factor VIIIa on an appropriate membrane surface forms the tenase complex, which generates additional factor Xa.19 We previously confirmed this pivotal role of tissue factor in the initiation of factor Xa– and factor IXa–mediated thrombin generation in a chimpanzee model.20 On the basis of the notion of the essential role of the tissue factor–factor VIIa complex in the initiation of coagulation, recombinant factor VIIa was developed and was indeed shown to be a potent prohemostatic agent in patients with severe coagulation disorders.21 Recent in vitro studies, however, have questioned the tissue factor–dependency of coagulation activation, showing generation of thrombin in the presence of relatively high concentrations of factor VIIa and in the absence of tissue factor–bearing cells.10 22 On the basis of these experiments, it was hypothesized that factor VIIa might be able to contribute to thrombin generation by a tissue factor–independent mechanism, although it was unclear whether this mechanism might play a role in vivo.
Our present experiments in human subjects demonstrate
that during inhibition of the tissue factor–factor VIIa complex with
rNAPc2, the administration of factor VIIa is still able to induce
thrombin generation. Whereas the shortening of the PT and aPTT may be
interpreted as in vitro artifacts, the significant increase in thrombin
activation markers F1+2 and TAT complexes provides convincing evidence
for rVIIa-induced thrombin generation. In fact, the factor VIIa-induced
4- to 5-fold elevation in markers for thrombin generation is blocked
only 25% by pretreatment with rNAPc2.
We can provide a number of possible explanations for these observations. First, the dose of rNAPc2 may not have been sufficient to completely block the amount of tissue factor–factor VIIa complex after the administration of recombinant factor VIIa. This is supported by the fact that administration of a dose of 5 µg/kg in a previous study led to an increase in the extent of PT elevation compared with what was observed with the 3.5-µg/kg dose used in this study.8 An alternative explanation might be provided by the hypothesis that factor VIIa is able to overcome the inhibitory effect of factor VII on thrombin generation, thereby displacing factor VII bound to tissue factor, resulting in additional thrombin generation.20 23 This mechanism may also explain why the plasma level of recombinant factor VIIa required for adequate hemostatic efficiency far exceeds the Kd for binding of factor VIIa to tissue factor.11 Another explanation may be provided by recent studies in a cell-based model of the coagulation system, demonstrating the ability of high concentrations of factor VIIa to restore platelet surface–localized and prothrombinase-mediated thrombin generation.22 Last, and partly in accordance with the previous explanation, it has been shown in a model of thrombus formation on a collagen-coated glass slide (ie, in the absence of tissue factor–bearing cells) that tissue factor might still play a role in the blood clot formation.24
Interestingly, our present observations indicate that factor VIIa–induced activation of factors IX and X is sustained much longer than the effect on thrombin generation. Because differences in plasma elimination time of these molecular markers cannot explain this discrepancy,20 25 the most likely explanation for this phenomenon is the inhibition of thrombin generation by physiological anticoagulant pathways, such as the protein C pathway.26
The ability of factor VIIa to produce thrombin generation during inhibition of tissue factor activity is attractive in view of the upcoming introduction of pharmacological tissue factor inhibitors. Because of the pivotal role of tissue factor in the initiation of blood coagulation and the pathogenesis of thrombosis, it is quite understandable that a novel generation of anticoagulant agents like rNAPc2 or recombinant tissue factor pathway inhibitor is being developed to interfere with this pathway.1 4 5 6 27 The observation that administration of factor VIIa is able to induce transient thrombin generation during the partial inhibition of tissue factor–factor VIIa indicates that rVIIa may be an effective antidote in this situation, which is particularly useful in agents with prolonged elimination half-lives.
The safety of the administration of factor VIIa requires some reflection. We did not observe any clinical effect of the administration of factor VIIa, but our study was limited to a small number of relatively young, healthy volunteers. Although there are some case reports on thrombotic complications probably related to the administration of factor VIIa,28 29 infusion of factor VIIa is generally considered to be safe in patients with coagulation disorders. Previous studies have shown that factor VIIa at doses up to 320 µg could be safely administered to subjects receiving warfarin.14 In addition, in a recently completed trial in 32 patients without any coagulation abnormality undergoing abdominal prostatectomy, the use of factor VIIa (for reduction of perioperative blood loss) was not associated with any thrombotic adverse event during the 10-day study period (P.W.F., manuscript in preparation). Hence, although the use of factor VIIa appears to be relatively safe, the available information is still limited, and the potential occurrence of thrombotic complications (for example, in elderly subjects with atherosclerotic disease or organ failure) cannot be fully excluded at this stage.
In conclusion, we demonstrate the ability of factor VIIa to generate thrombin during inhibition of the tissue factor–factor VIIa complex in vivo. Recombinant factor VIIa may therefore be a suitable antidote if anti–tissue factor pathway–directed anticoagulant treatment is complicated by bleeding.
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Acknowledgments |
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Dr Friederich is a recipient of an AGIKO fellowship of the Netherlands Organization for Scientific Research (NWO), and Dr Levi is an Investigator of the Royal Netherlands Academy of Science. Drs Vlasuk and Rote are employees of Corvas International, Inc, the sponsor of this study.
Received December 13, 2000; revision received February 28, 2001; accepted March 8, 2001.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Rapaport
SI, Rao LV. The tissue factor pathway: how it has become a "prima
ballerina." Thromb Haemost. 1995;74:7–17.[Medline]
[Order article via Infotrieve]
-
Mann KG.
Biochemistry and physiology of blood coagulation.
Thromb Haemost. 1999;82:165–174.[Medline]
[Order article via Infotrieve]
-
Levi M, ten Cate H.
Disseminated intravascular coagulation.
N Engl J Med. 1999;341:586–592.
[Free Full Text]
-
Toschi V, Gallo R,
Lettino M, et al. Tissue factor modulates the thrombogenicity of human
atherosclerotic plaques.
Circulation. 1997;95:594–599.
[Abstract/Free Full Text]
-
Gutstein DE, Fuster
V. Pathophysiology and clinical significance of atherosclerotic plaque
rupture. Cardiovasc Res. 1999;41:323–333.
[Abstract/Free Full Text]
-
Badimon JJ, Lettino
M, Toschi V, et al. Local inhibition of tissue factor reduces the
thrombogenicity of disrupted human atherosclerotic plaques.
Circulation. 1999;99:1780–1787.
[Abstract/Free Full Text]
-
Vlasuk GP, Bergum
PW, Bradbury AE, et al. Clinical evaluation of rNAPc2, an
inhibitor of the fVIIa/tissue factor coagulation complex.
Am J Cardiol. 1997;80:66S.
-
Vlasuk GP, Bradbury
AE, Bergum PW, et al. Early clinical evaluation of rNAPc2, a novel
inhibitor of blood coagulation factor VIIa/tissue factor.
J Am Coll Cardiol. 1999;33:255A–256A.
-
Stassens P, Bergum
PW, Gansemans Y, et al. Anticoagulant repertoire of the hookworm
Ancylostoma caninum.
Proc Natl Acad Sci
U S A. 1996;93:2149–2154.
[Abstract/Free Full Text]
-
Monroe DM,
Hoffman M, Oliver JA, et al. A possible mechanism of action of
activated factor VII independent of tissue factor.
Blood Coagul
Fibrinolysis. 1998;9:S15–S20.
-
Hedner U.
Treatment of patients with factor VIII and factor IX
inhibitors with special focus on the use of recombinant
factor VIIa. Thromb Haemost. 1999;82:531–539.[Medline]
[Order article via Infotrieve]
-
Peters M,
Heijboer H. Treatment of a patient with Bernard-Soulier syndrome and
recurrent nosebleeds with recombinant factor VIIa.
Thromb Haemost. 1998;80:352.[Medline]
[Order article via Infotrieve]
-
Tengborn L,
Petruson B. A patient with Glanzmann thrombasthenia and epistaxis
successfully treated with recombinant factor VIIa.
Thromb Haemost. 1996;75:981–982.[Medline]
[Order article via Infotrieve]
-
Erhardtsen E,
Nony P, Dechavanne M, et al. The effect of recombinant factor VIIa in
healthy volunteers receiving acenocoumarol to an INR above 2.0.
Blood Coagul
Fibrinolysis. 1998;9:741–748.[Medline]
[Order article via Infotrieve]
-
Bauer KA, Kass
BL, ten Cate H, et al. Detection of factor X activation in humans.
Blood. 1989;74:2007–2015.
[Abstract/Free Full Text]
-
Bauer KA, Kass
BL, ten Cate H, et al. Factor IX is activated in vivo by the
tissue factor mechanism. Blood. 1990;76:731–736.
[Abstract/Free Full Text]
-
Gruber A, Griffin
JH. Direct detection of activated protein C in blood from human
subjects. Blood. 1992;79:2340–2348.
[Abstract/Free Full Text]
-
Breederveld D,
Friederich PW, Levi M, et al. A novel enzyme capture assay for
determining recombinant fVIIa activity in human plasma.
Thromb Haemost. 1999;82:1295.
-
Osterud B,
Rapaport SI. Activation of factor IX by the reaction product of
tissue factor and factor VII: additional pathway for initiating blood
coagulation. Proc Natl Acad Sci
U S A. 1977;74:5260–5264.
[Abstract/Free Full Text]
-
ten Cate H, Bauer
KA, Levi M, et al. The activation of factor X and prothrombin by
recombinant factor VIIa in vivo is mediated by tissue factor.
J Clin Invest. 1993;92:1207–1212.
-
Hedner U, Kisiel
W. Use of human factor VIIa in the treatment of two hemophilia A
patients with high-titer inhibitors.
J Clin Invest. 1983;71:1836–1841.
-
Hoffman M, Monroe
DM, Roberts HR. Activated factor VII activates factors
IX and X on the surface of activated platelets.
Blood Coagul
Fibrinolysis. 1998;9:S61–S65.
-
Van’t Veer C,
Cawthern KM, Mann KG. The mechanism of factor VIIa "by-passing"
hemophilia: empirical and theoretical studies.
Thromb Haemost. 1999;82:1294.[Medline]
[Order article via Infotrieve]
-
Giesen PL, Rauch
U, Bohrmann B, et al. Blood-borne tissue factor: another view of
thrombosis. Proc Natl Acad Sci
U S A. 1999;96:2311–2315.
[Abstract/Free Full Text]
-
Levi M, ten Cate
H, Bauer KA, et al. Inhibition of endotoxin-induced activation of
coagulation and fibrinolysis by pentoxifylline or by a
monoclonal anti-tissue factor antibody in chimpanzees.
J Clin Invest. 1994;93:114–120.
-
Van’t Veer C,
Golden NJ, Kalafatis M, et al. Inhibitory mechanism of the
protein C pathway on tissue factor-induced thrombin generation.
J Biol Chem. 1997;272:7983–7994.
[Abstract/Free Full Text]
-
de Jonge E,
Dekkers PE, Creasey AA, et al. Tissue factor pathway
inhibitor (TFPI) dose-dependently inhibits coagulation
activation without influencing the fibrinolytic and cytokine
response during human endotoxemia.
Blood. 2000;95:1124–1129.
[Abstract/Free Full Text]
-
Peerlinck K,
Vermylen J. Acute myocardial infarction following administration of
recombinant activated factor VII in a patient with haemophilia
A and inhibitor. Thromb
Haemost. 1999;82:1775–1776.[Medline]
[Order article via Infotrieve]
-
Hay CR, Negrier
C, Ludlam CA. The treatment of bleeding in acquired haemophilia with
recombinant factor VIIa: a multicentre study.
Thromb Haemost. 1997;78:1463–1467. [Medline]
[Order article via Infotrieve]
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 W. Dietrich, M. Spannagl, H. G. D. Hendriks, J. M. A. A. van der Maaten, J. Th. M. de Wolf, and J. van der Meer Caveat Against the Use of Activated Recombinant Factor VII for Intractable Bleeding in Cardiac Surgery * Response Anesth. Analg., May 1, 2002; 94(5): 1369 - 1371. [Full Text] [PDF]
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A. Lee, G. Agnelli, H. Buller, J. Ginsberg, J. Heit, W. Rote, G. Vlasuk, L. Costantini, J. Julian, P. Comp, et al. Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement Circulation, July 3, 2001; 104(1): 74 - 78. [Abstract] [Full Text] [PDF]
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