REVIEW
Coagulation and ﬁbrinolysis in human acute lung injury –New therapeutic targets?
Lorraine B. Ware, Julie A. Bastarache and Ling Wang
Division of Allergy, Pulmonary, and Critical Care, Department of Medicine
Vanderbilt University School of Medicine, Nashville, TN, USA(Received for publication on May 3, 2005)(Accepted for publication on July 21, 2005)

Abstract. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common,
life-threatening causes of acute respiratory failure that arise from a variety of local and systemic insults.
The need for new speciﬁc therapies has led a number of investigators to examine the role of alteredcoagulation and ﬁbrinolysis in the pathogenesis of ALI/ARDS. This review summarizes our current
understanding of coagulation and ﬁbrinolysis in human ALI/ARDS with an emphasis on pathways that
could be potential therapeutic targets including the tissue factor pathway, the protein C pathway andmodulation of ﬁbrinolysis via plasminogen activator inhibitor-1. The available data suggest that clinical
ALI and ARDS are characterized by profound alterations in both systemic and intra-alveolar coagulation and ﬁbrinolysis. Fibrin deposition in the airspaces and lung microvasculature likely results fromboth activation of the coagulation cascade and impaired ﬁbrinolysis, triggered by inﬂammation. Modulation of ﬁbrin deposition in the lung through targeting activation and modulation of coagulation as
well as ﬁbrinolysis may be an important therapeutic target in clinical ALI/ARDS that deserves further
exploration. (Keio J Med 54 (3): 142–149, September 2005)
Key words: ﬁbrin deposition, thrombosis, activated protein C, tissue factor, plasminogen activator
inhibitor

Introduction
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common, life-threatening
causes of acute respiratory failure that arise from a variety of local and systemic insults.1 Despite some improvement in mortality with a lung-protective ventilator
strategy,2 both morbidity3 and mortality remain high.4
The need for new speciﬁc therapies has led a number ofinvestigators to examine the role of altered coagulationand ﬁbrinolysis in the pathogenesis of ALI/ARDS. Although the presence of intra-alveolar ﬁbrin lining thedenuded alveolar surface has long been recognized as apathological hallmark of ALI/ARDS,5 the mechanismsthat govern ﬁbrin deposition in the acutely injured lungare poorly understood. This review will summarize ourcurrent understanding of coagulation and ﬁbrinolysis in
human ALI/ARDS with an emphasis on pathways that
could be potential therapeutic targets. These pathways are summarized in Fig. 1 and include the tissue

factor pathway, the protein C pathway and modulationof ﬁbrinolysis via plasminogen activator inhibitor-1(PAI-1).
Tissue Factor and Tissue Factor Pathway Inhibitor
Initiation of coagulation through the extrinsic pathway is likely the predominant mechanism of activationof coagulation in the lung in ALI/ARDS. Tissue factor(TF) is a potent initiator of the extrinsic coagulationcascade. TF is a membrane bound protein that whencomplexed to factor VIIa converts factor X to Xa leading to the downstream generation of thrombin andconversion of ﬁbrinogen to insoluble ﬁbrin (Fig. 1). In
the normal human lung, both alveolar macrophages andalveolar epithelial cells stain positive for TF6 and inculture, both alveolar macrophages and alveolar epithelial cells have TF activity.7 Initiation of coagulation
through the TF pathway is modulated by the balance
between TF and tissue factor pathway inhibitor (TFPI),

Reprint requests to: Dr. Lorraine B. Ware, T1218 MCN, 1161 21 st Avenue S, Nashville, TN 37232-2650, e-mail: lorraine.ware@vanderbilt.edu
142Keio J Med 2005; 54 (3): 142–149

143

Fig. 1 Summary of coagulation and ﬁbrinolytic pathways that may be therapeutic targets in clinical ALI/ARDS. A. Activation of coagulation
by Tissue Factor (TF). TF initiates the extrinsic pathway of coagulation by acting as a cofactor for the activation of factor VII to VIIa. The
factor VIIa-TF complex activates factor X to Xa which catalyzes the conversion of prothrombin to thrombin, leading to ﬁbrin deposition. Tissue
factor pathway inhibitor (TFPI) can bind to the TF : VIIa : Xa complex thus inhibiting downstream thrombin formation and ﬁbrin deposition. B.
The protein C pathway. The protein C pathway is a major endogenous inhibitor of coagulation. Once generated, thrombin binds to the cellsurface receptor thrombomodulin (TM), activating the zymogen protein C to the activated protein C (APC). APC (along with protein S)
inhibits Xa and thrombin formation through the inactivation of factors V and VIII (not shown). C. Fibrinolysis. Fibrinolysis is initiated byurokinase (uPA) and tissue plasminogen activator (tPA) both of which cleave plasmin from plasminogen. Plasmin degrades ﬁbrin into ﬁbrindegradation products (FDP). Plasminogen activator inhibitor-1 (PAI-1) depresses ﬁbrinolysis by inhibiting uPA and tPA. PAI-1 can be neutralized by APC. The net result of upregulated coagulation and downregulated ﬁbrinolysis in the acutely injured lung is ﬁbrin deposition.

an endogenous inhibitor of TF. TFPI is secreted by
the vascular endothelium and circulates in the plasma
and bound to the surface of platelets.8 TFPI can prevent the activation of X to Xa through binding to the
TF : VIIa : X complex thereby inhibiting downstream
formation of thrombin and deposition of ﬁbrin. Thus,
the balance between TF and TFPI levels in the lungmay be an important determinant of intra-alveolar
ﬁbrin deposition.
An important role for TF in initiating intra-alveolar
coagulation in clinical ALI/ARDS was ﬁrst reported by
Idell.9 In serial bronchoalveolar lavage (BAL) samples
from patients with ARDS, procoagulant activity was
upregulated by three days after the onset of ARDS andresolved by seven days.9 TF activity was primarily responsible for the procoagulant activity in the BAL sincealmost all of the procoagulant activity was blocked byan antibody to TF. TF-dependent procoagulant activity
in the alveolar compartment has also been reported
in patients at risk for ALI/ARDS.10 Upregulation of
TF-dependent procoagulant activity is not completely
speciﬁc for ALI/ARDS, however. Gunther et al. foundincreases in TF-dependent procoagulant activity in the
BAL of patients with pneumonia even in the absence of
respiratory failure or ARDS.11 Upregulation of the TF
pathway also occurs systemically in clinical ALI/ARDS.
Circulating levels of TF were increased in patients with

ARDS but not in patients at risk for ARDS or without
ARDS.12
Levels of TFPI, the endogenous TF inhibitor, havealso been measured in the plasma and BAL of patientswith ALI/ARDS. Sabharwal et al.13 reported a modest
increase in levels of TFPI compared to normals in theplasma of patients at risk (1.3-fold) and those withestablished ARDS (1.8-fold) while Gando et al.14 foundno difference in TFPI levels between control, at risk
patients or patients with ARDS. By contrast, substantial increases in TFPI were seen in the BAL in thoseat risk (7-fold) and with established ARDS (20-fold)compared to normals.13 TF levels were not measured inthat study. Thus, changes in TFPI levels appear to be
more pronounced in the alveolar compartment in ALI/
ARDS than in the plasma. The effect of the balance of
TF and TFPI on overall procoagulant activity has notbeen studied in ALI/ARDS but has been reported inother lung diseases. The procoagulant activity of BAL
was increased in patients with bacterial or Pneumocystis
carinii pneumonia or interstitial lung disease compared
to controls but TFPI levels were similar to controls15
suggesting that increases in TF activity were not balanced by comparable increases in TFPI. In patientswith idiopathic pulmonary ﬁbrosis, both TF and TFPI
levels were increased in the BAL and correlated withseverity of disease; however, the procoagulant activity

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Ware LB, et al: Coagulation and ﬁbrinolysis in acute lung injury

of the BAL was increased compared to controls, again
demonstrating that the increases in TF were not balanced by increases in TFPI.16
The fundamental role of TF in initiation of coagulation combined with the systemic and intra-pulmonary
abnormalities of TF and TFPI in clinical ALI/ARDS
makes the TF pathway an attractive target for therapeutic intervention. Blockade of TF activity either prior
to or in the early stages of ALI with TFPI is protective
in several animal models of sepsis and ALI.17,18 However, human studies to date have been disappointing.
A recent phase III trial of recombinant TFPI in sepsis,the most common cause of ALI/ARDS, had no effecton mortality19 despite a prior encouraging phase II
study.20 A site inactivated form of factor VIIa (factor
VIIai) that binds to and inhibits TF activity has beendeveloped as an anticoagulant. In a baboon model ofsepsis factor VIIai was protective.21–23 A clinical trial
in patients with ALI/ARDS is currently underway.
Protein C and Thrombomodulin
The protein C pathway is an important endogenous
regulator of coagulation and ﬁbrinolysis. Synthesized
by the liver, protein C is a vitamin K-dependent glycoprotein that circulates as an inactive zymogen.24 It istransformed to its active form on the cell surface by theTM-thrombin complex. Another cell surface protein,
the endothelial cell protein C receptor (EPCR) canfurther enhance protein C activation by binding to
the TM-thrombin complex.25 Activated protein C proteolytically destroys coagulation factors Va and VIIIa,
suppressing further thrombin formation (Fig. 1).26,27
Activated protein C has anti-inﬂammatory and antiapoptotic effects in addition to its anti-coagulant
properties that include suppression of production of
pro-inﬂammatory cytokines, inhibition of leukocyte
attachment to the endothelium,28,29 and inhibition of
p53 mediated apoptosis.30 Activated protein C also canneutralize PAI-1, thereby promoting ﬁbrinolysis.31
Thus, modulation of the protein C pathway could have
key regulatory effects on coagulation, ﬁbrinolysis andinﬂammation in ALI/ARDS.
The majority of studies of the protein C pathway
have focused on the endothelium as the primary site foractivation of protein C. However, recent studies suggest that the lung epithelium can actively modulate
the protein C pathway. Cultured human airway epithelial cells express protein C, EPCR and thrombomodulin
and protein C was activated by these cells in the presence of thrombin.32 Exposure to inﬂammatory cytokines downregulated the activation of protein C.32
Alveolar epithelial cells also may modulate the protein
C pathway. We reported that both a human alveolar
epithelial cell line (A549) and primary isolates of hu-

man alveolar epithelial type II cells release thrombomodulin in response to stimulation by a mixture ofpro-inﬂammatory cytokines or hydrogen peroxide (Fig.
2).33 Thus, the alveolar epithelium may modulate intraalveolar coagulation and inﬂammation through theprotein C pathway similar to the well-described role ofthe vascular endothelium in modulating this pathway.
In humans, most of the clinical studies of the protein
C pathway have been in patients with sepsis. In 70
patients with severe sepsis34 plasma protein C levels
were markedly reduced compared to normal levels andlower levels were associated with higher mortality, ventilator dependency and a higher prevalence of ARDS.
Patients with severe sepsis also vary in their ability togenerate activated protein C.35 In a study of 32 patientswith severe sepsis, activated protein C levels werehigher in survivors although in that study there was nodifference in protein C levels between survivors andnonsurvivors. Thrombomodulin levels in the plasma
are elevated in patients with sepsis, and high levels
correlate with the development of multiple organ failure.36,37 Levels of soluble EPCR are also high inpatients with sepsis.38 However, there was no correlation between the soluble EPCR levels and clinical outcomes including multiple organ failure score or survival.38
There have been relatively few studies of the protein C pathway in patients with ALI/ARDS. In a single
center study, plasma protein C levels were lower in
ALI/ARDS compared with normal controls even in theabsence of sepsis.33 Levels of protein C in the alveolar
compartment were even lower than plasma levels andlower levels of both plasma and edema ﬂuid protein C
were associated with worse clinical outcomes.33 Like
patients with sepsis, patients with ALI/ARDS havehigh circulating levels of thrombomodulin. In addition,
thrombomodulin levels in the alveolar compartment
in ALI/ARDS were 2-fold higher than simultaneous
plasma samples, suggesting an intra-alveolar source(Fig. 3). High thrombomodulin levels in the plasma or
alveolar compartment were associated with worse clinical outcomes.33 Thus, abnormalities of the protein C
pathway in ALI/ARDS are similar to abnormalities insepsis and are strongly associated with adverse outcomes.
The observation that protein C and activated protein C levels are low in patients with severe sepsis led
to a phase III randomized, multicenter clinical trial ofrecombinant human activated protein C (drotecoginalfa activated) in patients with severe sepsis and at least
one organ failure. In this landmark trial, administrationof recombinant human activated protein C signiﬁcantly
improved survival compared to placebo. The absoluterisk reduction in mortality at 28 days was 6.1%.39 This
study was not designed to speciﬁcally evaluate the role

Keio J Med 2005; 54 (3): 142–149

Fig. 2 Alveolar epithelial cells release soluble thrombomodulin in
response to injurious stimuli. Conﬂuent monolayers of human alveolar epithelial type II-like cells (A549 cells) were exposed for 6 hours
to varying concentrations of H2 O2 or cytomix (equal amounts of
TNF-a, IL-1b, IFN-g), and conditioned media was collected for assayof thrombomodulin by ELISA. *p < 0:01 compared with 0.01% H2 O2or control. **p < 0:01 compared with 10 ng/ml cytomix or control.
Reproduced with permission from American Journal of Physiology
Lung Cellular and Molecular Physiology.33

of activated protein C in ALI/ARDS. However, a retrospective analysis showed that in the group of patientswith respiratory system dysfunction, many of whom
likely had ALI/ARDS, the time to resolution of respiratory dysfunction was signiﬁcantly shorter in thetreated group compared to the placebo group.40 A
multicenter phase II trial of recombinant activatedprotein C in ALI and ARDS is currently underway.
Interestingly, in a human model of pulmonary inﬂammation produced by instillation of endotoxin into the
distal airspaces, intravenous administration of recombinant activated protein C produce sustained elevations
in BAL levels of activated protein C41 that wereaccompanied by reduced leukocyte accumulation in theairspaces and reductions in neutrophil chemotaxis, independent of pulmonary cytokine or chemokine release.42 These ﬁndings suggest that in addition to its
anticoagulant effects, systemically administered activated protein C may have potent anti-inﬂammatory
effects in the distal airspaces that are mediated throughmodulation of neutrophil function.
Plasminogen Activators and Inhibitors
The balance between activation of coagulation andactivation of ﬁbrinolysis is likely an important determinant of the amount and duration of ﬁbrin deposition in
the injured lung. Plasminogen activator (PA) and plasminogen activator inhibitor-1 (PAI-1) regulate ﬁbrinol-

145

Fig. 3 Boxplot summary of thrombomodulin levels in normal plasmaand pulmonary edema ﬂuid from 45 patients with ALI or ARDS. Box
encompasses 25 th to 75 th percentile, error bars encompass 10 th to 90 th
percentile, and horizontal bar shows the median. *p ¼ 0:001 compared with normal plasma or ALI/ARDS plasma. Reproduced withpermission from American Journal of Physiology Lung Cellular andMolecular Physiology.33

ysis, the dissolution of ﬁbrin clots, through modulationof the conversion of plasminogen to plasmin, a major
ﬁbrinolytic enzyme (Fig. 1). There are two forms ofplasminogen activator (PA), urokinase-type plasminogen activator (uPA) and tissue-type plasminogenactivator (tPA). uPA is a cell surface protein that is responsible for activating ﬁbrinolysis at the tissue level43
while tPA is a soluble protein that activates intravascular ﬁbrinolysis.44 Plasminogen activator inhibitor1 (PAI-1) is a major endogenous inhibitor of both uPAand tPA.
There are multiple cellular sources of PA and PAI-1
that may be relevant to human ALI/ARDS. Unstimulated alveolar macrophages are pro-ﬁbrinolytic. Primary isolates of human alveolar macrophages have PA
activity and degrade a ﬁbrin matrix in the presence ofplasminogen.45 By contrast, stimulated alveolar macrophages are anti-ﬁbrinolytic. Human alveolar macrophages exposed to endotoxin inhibit ﬁbrinolysis throughan increase in PAI-1 activity.46,47 Increased PAI-1
activity has also been observed in macrophages isolated
from patients with lung disease. For example, alveolar
macrophages from patients with idiopathic pulmonaryﬁbrosis (IPF) have increased PAI-1 staining compared
to normal controls48 and alveolar macrophages from146

patients with ARDS have increased PAI-1 mRNA as
demonstrated by in situ hybridization.47 Overall, theseﬁndings suggest that when the lung is exposed to injurious stimuli there is a decrease in the ﬁbrinolytic
activity of alveolar macrophages through decreased PA
activity and increased PAI-1 activity.
Like macrophages, human lung microvascular endothelial cells can secrete both PA49 and PAI-1.50 Proinﬂammatory stimuli increase PA secretion severalfold49,50 but the net effect on ﬁbrinolysis is unclear.
In one study of human lung microvascular endothelial
cells isolated from patients with ARDS, the cells from
ARDS patients constitutively expressed more PAI-1
than controls and had a lower ﬁbrinolytic potential asmeasured by the PA/PAI-1 ratio.51 Although the data
are not completely concordant, the studies from ARDS
patients suggest that similar to alveolar macrophages,
the pulmonary microvascular endothelium in its basal
state favors ﬁbrinolysis. Injurious stimuli shifts the balance away from ﬁbrinolysis.
The lung epithelium can also express both plasminogen activators and inhibitors and is thus capable ofregulating intra-alveolar ﬁbrinolysis. However, there
are relatively few studies of human lung epithelial cells.
Primary isolates of rat alveolar epithelial cells express
both PA and PAI-1; levels increase with time in culture
as the cells differentiate from a type II cell phenotype
to a type I phenotype.52,53 Exposure of the cells to
lipopolysaccharide or TNF-a, increased PAI-1 anduPA suggesting that inﬂammatory mediators modulate
the ﬁbrinolytic capacity of alveolar epithelial cells. A
human alveolar epithelial type II cell line (A549) had
increases in uPA mRNA, protein, and activity following
exposure to IL-1b and TNF-a, but unlike rat alveolar
epithelial cells, there was no change in PAI-1 expression.54 By contrast, freshly isolated alveolar type I cells
do express PAI-1 mRNA.55 Thus, PAI-1 expression
may be a phenotype of alveolar type I cells and not type
II cells, similar to the ﬁndings with rat alveolar epithelial cells. Taken together, the in vitro data suggests thatthe lung epithelium is probably capable of modulating intra-alveolar ﬁbrinolysis through expression of PA,
and PAI-1.
There are only a few studies that address ﬁbrinolysis
in patients with ALI/ARDS. In a study comparing normal controls to four groups of patients (patients withpneumonia who were spontaneously breathing, patientswith pneumonia requiring mechanical ventilation, patients with ARDS without pneumonia and patients with
ARDS with pneumonia) there was reduced ﬁbrinolytic
capacity and an increase in uPA in all groups compared
to control as well as an increase in PAI-1 activity in allgroups except those with pneumonia who were spontaneously breathing.11 Prabhakaran et al. measured PAI1 antigen levels in plasma and simultaneous undiluted

Ware LB, et al: Coagulation and ﬁbrinolysis in acute lung injury

Fig. 4 Plasma and edema ﬂuid PAI-1 antigen in patients with acutelung injury (ALI) and hydrostatic pulmonary edema (HYDRO).
PAI-1 values were measured in simultaneously drawn plasma (openboxes) and edema ﬂuid (ﬁlled boxes) by ELISA from patients withclinical ALI or hydrostatic edema. Data are plotted in box plot format (median, 25–75%) on a log scale and compared using MannWhitney’s U-test. P values are as indicated. Reproduced with permission from American Journal of Physiology Lung Cellular andMolecular Physiology.56

pulmonary edema ﬂuid from patients with ALI/ARDS
and compared them to control patients with pulmonary edema due to hydrostatic causes.56 Levels of PAI1 were higher in both the edema ﬂuid and plasma of
patients with ALI/ARDS compared to the control
patients (Fig. 4) and correlated with mortality inpatients with ALI/ARDS. In patients with ALI/ARDS,
PAI-1 levels were substantially higher in the edema
ﬂuid than the plasma suggesting an intra-alveolar
source of PAI-1. In other studies that only examined
plasma levels, patients with ARDS and those at risk
for ARDS had higher circulating levels of PAI-1 thancontrols.57,58 However, plasma levels did not correlatewith lung injury score, pulmonary microvascular permeability, or clinical outcome.58 Taken together, theseﬁndings suggest that alterations in the intra-alveolar
ﬁbrinolytic environment may have more impact on outcomes in ALI/ARDS than alterations in systemic ﬁbrinolytic pathways. Although there are no studies to datein patients with ALI/ARDS, polymorphisms in the
promoter region of PAI-1 have been studied in two
populations of patients at risk for ALI/ARDS, patientswith meningococcal septicemia and patients with severe
trauma at risk for ALI/ARDS.59 Deletions in the promoter region lead to impaired ﬁbrinolytic ability andare associated with disease severity and outcome in
meningococcal disease60–62 and with susceptibility tosepsis and multi-organ failure in patients with severe
trauma.63

Keio J Med 2005; 54 (3): 142–149

To summarize, there is substantial evidence that theﬁbrinolytic system is profoundly altered in patients with
ALI/ARDS, both systemically and in the alveolar compartment. Upregulation of PAI-1, the major inhibitor ofﬁbrinolysis, appears to play a primary role in the shift
from pro-ﬁbrinolytic to anti-ﬁbrinolytic phenotypes in avariety of cell types including endothelium, lung epithelium and alveolar macrophages. A variety of strategies are being explored to develop inhibitors of PAI164 that might be of therapeutic use in ALI/ARDS orother diseases associated with high levels of PAI-1 suchas cardiovascular disease. However, no inhibitor of
PAI-1 is currently clinically available.
Conclusions
Clinical ALI and ARDS are characterized by profound alterations in both systemic and intra-alveolar
coagulation and ﬁbrinolysis. Fibrin deposition in theairspaces and the lung microvasculature likely resultsfrom inﬂammation-induced activation of the coagulation cascade and impairment of ﬁbrinolysis. Activationof coagulation with resultant ﬁbrin deposition also has
proinﬂammatory consequences, serving to further amplify the inﬂammatory cascade. Current evidence fromhuman studies suggests that in the acutely injured lungthere is activation of tissue factor, downregulation ofprotein C activation, and increased production of PAI1. Together these abnormalities shift the intra-alveolar
environment from anticoagulant and proﬁbrinolytic toprocoagulant and antiﬁbrinolytic. Modulation of ﬁbrin
deposition in the lung through targeting coagulationand ﬁbrinolysis may be an important therapeutic target
in clinical ALI/ARDS. Because the lung epithelium
appears to be an important site for modulation of
intra-alveolar ﬁbrin deposition, it represents a uniquetherapeutic target. Targeting the lung epithelium withinhaled therapies to modulate intra-alveolar ﬁbrin deposition might avoid the deleterious side effects of systemic therapies and deserves further study.

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5.

6.

7.

8.
9.

10.

11.

12.

13.

14.

15.

16.

References
17.
1. Ware LB, Matthay MA: Medical progress: The acute respiratory
distress syndrome. N Engl J Med 2000; 342: 1334–1349
2. The Acute Respiratory Distress Syndrome Network: Ventilation
with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distresssyndrome. New Engl J Med 2000; 342: 1301–1308
3. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, DiazGranados N, Fatma A-S, Cooper AB, Guest CB, Mazer CD,
Mehta S, Stewart TE, Barr A, Cook D, Slutsky AS, for the
Canadian Critical Care Trials Group: One-year outcomes insurvivors of the acute respiratory distress syndrome. N Engl J
Med 2003; 348: 683–693
4. Brun-Buisson C, Minelli C, Bertolini G, Brazzi L, Pimentel J,

18.

19.

Lewandowski K, Bion J, Romand J-A, Villar J, Thorsteinsson A,
Damas P, Armaganidis A, Lemaire F, for the ALIVE Study
Group: Epidemiology and outcome of acute lung injury in European intensive care units. Intensive Care Med 2004; 30: 51–61
Bachofen M, Weibel ER: Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest
Med 1982; 3: 35–56
Drake TA, Morrissey JH, Edgington TS: Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134:
1087–1097
Prudhomme JB, Geiser T, Matthay MA, Ware LB: The alveolar
epithelium can initiate the extrinsic coagulation cascade throughexpression of tissue factor on the cell surface. Am J Respir Crit
Care Med 2004; 169: A414
McVey JH: Tissue factor pathway. Bailleres Best Pract Res Clin
Haematol 1999; 12: 361–372
Idell S, Koenig K, Fair D, Martin T, McLarty J, Maunder R:
Serial abnormalities of ﬁbrin turnover in evolving adult respiratory distress syndrome. Am J Physiol 1991; 261: L240–L248
Fuchs-Buder T, de Moerloose P, Ricou B, Reber G, Viﬁan C,
Nicod L, Romand J, Suter P: Time course of procoagulant
activity and D dimer in bronchoalveolar ﬂuid of patients at risk
for or with acute respiratory distress syndrome. Am J Respir Crit
Care Med 1996; 153: 163–167
Gunther A, Mosavi P, Heinemann S, Ruppert C, Muth H, Markart P, Grimminger F, Walmrath D, Temmesfeld-Wolbruck B,
Seeger W: Alveolar ﬁbrin formation caused by enhanced procoagulant and depressed ﬁbrinolytic capacities in severe pneumonia. Comparison with acute respiratory distress syndrome.
Am J Respir Crit Care Med 2000; 161: 454–462
Gando S, Nanzaki S, Morimoto, Kobayashi s, Kemmotsu O:
Systemic activation of tissue-factor dependent coagulation pathway in evolving acute respiratory distress syndrome in patientswith trauma and sepsis. J Trauma 1999; 47: 719–723
Sabharwal AK, Bajaj SP, Ameri S, Tricomi SM, Hyers TM,
Dahms TE, Taylor FB, Bajaj MS: Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory
distress syndrome and in a primate model of sepsis. Am J Respir
Crit Care Med 1995; 151: 758–767
Gando S, Kameue T, Matsuda N, Hayakawa M, Morimoto Y,
Ishitani T, Kemmotsu O: Imbalances between the levels of tissue
factor and tissue factor pathway inhibitor in ARDS patients.
Thromb Res 2003; 109: 119–124
de Moerloose P, de Benedetti E, Nicod L, Viﬁan C, Reber G:
Procoagulant activity in bronchoalveolar ﬂuids: no relationshipwith tissue factor pathway inhibitor activity. Thromb Res 1992;
65: 507–518
Fujii M, Hayakawa H, Urano T, Sato A, Chida K, Nakamura H,
Takada A: Relevance of tissue factor and tissue factor pathway
inhibitor for hypercoagulable state in the lungs of patients with
idiopathic pulmonary ﬁbrosis. Thromb Res 2000; 99: 111–117
Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FBJ, Hinshaw LB: Tissue factor pathway inhibitor reduces mortality from
Escherichia coli septic shock. J Clin Invest 1993; 91: 2850–2856
Enkhbaatar P, Okajima K, Murakami K, Uchiba M, Okabe H,
Okabe K, Yamaguchi Y: Recombinant tissue factor pathway inhibitor reduces lipopolysaccharide-induced pulmonary vascular
injury by inhibiting leukocyte activation. Am J Respir Crit Care
Med 2000; 162: 1752–1759
Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez
AL, Beale R, Svoboda P, Laterre P, Simon S, Light B, Spapen
H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R,
Pettila V, Artigas A, Percell S, Shu V, Zwingelstein C, Tobias J,
Poole L, Stolzenbach J, Creasey A, OPTIMIST Trial Study
Group: Efﬁcacy and safety of tifacogin (recombinant tissue fac-

148

20.

21.

22.

23.

24.

25.

26.

27.
28.
29.

30.

31.

32.

33.

34.

35.

36.

37.

Ware LB, et al: Coagulation and ﬁbrinolysis in acute lung injury
tor pathway inhibitor) in severe sepsis: a randomized controlled
trial. JAMA 2003; 290: 238–247
Abraham E, Reinhart K, Svoboda P, Seibert A, Olthoff D, Dal
Nogare A, Postier R, Hempelmann G, Butler T, Martin E,
Zwingelstein C, Percell S, Shu V, Leighton A, Creasey AA:
Assessment of the safety of recombinant tissue factor pathway
inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit
Care Med 2001; 29: 2081–2089
Welty-Wolf KE, Carraway MS, Miller DL, Ortel TL, Ezban M,
Ghio AJ, Idell S, Piantadosi CA: Coagulation blockade prevents
sepsis-induced respiratory and renal failure in baboons. Am J
Respir Crit Care Med 2001; 164: 1988–1996
Miller DL, Welty-Wolf K, Carraway MS, Ezban M, Ghio A,
Suliman H, Piantadosi CA: Extrinsic coagulation blockade
attenuates lung injury and proinﬂammatory cytokine release
after intratracheal lipopolysaccharide. Am J Respir Cell Mol
Biol 2002; 26: 650–658
Carraway MS, Welty-Wolf KE, Miller DL, Ortel TL, Idell S,
Ghio AJ, Petersen LC, Piantadosi CA: Blockade of tissue factor:
treatment for organ injury in established sepsis. Am J Respir
Crit Care Med 2003; 167: 1200–1209
Esmon CT, Stenﬂo J, Suttie JW: A new vitamin K-dependent
protein. A phospholipid-binding zymogen of a serine esterase. J
Biol Chem 1976; 251: 3052–3056
Stearns-Kurosawa DJ, Kurosawa S, Mollica JS, Ferrell GL,
Esmon CT: The endothelial cell protein C receptor augments
protein C activation by the thrombin-thrombomodulin complex.
Proc Natl Acad Sci USA 1996; 93: 10212–10216
Esmon CT: The anticoagulant and anti-inﬂammatory roles ofthe protein C anticoagulant pathway. J Autoimmun 2000; 15:
113–116
Esmon CT: The protein C pathway. Chest 2003; 124: 26S–32S
Esmon CT: Role of coagulation inhibitors in inﬂammation.
Thromb Haemost 2001; 86: 51–56
Shimuzu S, Gabazza EC, Taguchi O, Yasui H, Taguchi Y, Hayashi T, Ido M, Shimizu T, Nakagaki T, Kobayashi H, Fukudome
K, Tsuneyoshi N, D’Alessandro-Gabazza C, Izumizaki M, Iwase
M, Homma I, Adachi Y, Suzuki K: Activated protein C inhibits
the expression of platelet-derived growth factor in the lung. Am
J Respir Crit Care Med 2003; 167: 1416–1426
Cheng t, Liu D, Grifﬁn JH, Fernandez JA, Castellino F, Rosen
ED, Fukudome K, Zlokovic BV: Activated protein C blocks
p53-mediated apoptosis in ischemic human brain endothelium
and is neuroprotective. Nat Med 2003; 9: 338–342
Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Grifﬁn JH:
Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 1986; 68: 1218–1223
Hataji O, Taguchi O, Gabazza EC, Yuda H, Fujimoto H, Suzuki
K, Adachi Y: Activation of protein C pathway in the airways.
Lung 2002; 180: 47–59
Ware LB, Fang X, Matthay MA: Protein C and thrombomodulinin human acute lung injury. Am J Physiol Lung Cell Mol Physiol
2003; 285: L514–L521
Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR:
Low levels of protein C are associated with poor outcome insevere sepsis. Chest 2001; 120: 915–922
Liaw PC, Esmon Ct, Kahnamoui K, Schmidt s, Kahnamoui S,
Ferrell G, Beaudin S, Julian JA, Weitz JI, Crowther M, Loeb M,
Cook D: Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood 2004; 104: 3958–3964
Iba T, Yagi Y, Kidokoro A, Fukunaga M, Fukunaga T: Increased plasma levels of soluble thrombomodulin in patientswith sepsis and organ failure. Surg Today 1995; 25: 585–590
Krafte-Jacobs B, Brilli R: Increased circulating thrombomodulinin children with septic shock. Crit Care Med 1998; 26: 933–938

38. Kurosawa S, Stearns-Kurosawa DJ, Carson CW, D’Angelo A,
Della Valle P, Esmon CT: Plasma levels of endothelial protein
C receptor are elevated in patients with sepsis and systemic
lupus erythematosis: lack of corrrelation with thrombomodulinsuggests involvement of different pathological processes. Blood
1998; 91: 725–727
39. Bernard G, Vincent J-L, Laterre P-F, La Rosa S, Dhainaut J-F,
Lopez-Rodriguez A, Steingrub J, Garber G, Helterbrand J, Ely
E: Efﬁcacy and safety of recombinant human activated protein C
for severe sepsis. N Engl J Med 2001; 344: 699–709
40. Dhainaut J-F, Laterre P-F, Janes JM, Bernard GR, Artigas A,
Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG,
Vincent JL, Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group: Drotrecogin alfa (activated) in the treatment of severe sepsis
patients with mutiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003; 29: 894–903
41. van der Poll T, Levi M, Nick JA, Abraham E: Activated protein
C inhibits local coagulation after intrapulmonary delivery ofendotoxin in humans. Am J Respir Crit Care Med 2005; in press
42. Nick JA, Coldren CD, Geraci MW, Poch KR, Fouty BW,
O’Brien J, Gruber M, Zarini S, Murphy R, Kuhn K, Richter D,
Kast K, Abraham E: Recombinant human activated protein C
reduces human endotoxin-induced pulmonary inﬂammation via
inhibition of neutrophil chemotaxis. Blood 2004; 104: 3878–3885
43. Mondino A, Blasi F: uPA and uPAR in ﬁbrinolysis, immunityand pathology. Trends Immunol 2004; 25: 450–455
44. Yepes M, Lawrence DA: New functions for an old enzyme:
nonhemostatic roles for tissue-type plasminogen activator in thecentral nervous system. Exp Biol Med 2004; 229: 1097–1104
45. Chapman HA, Stone OL, Vavrin Z: Degradation of ﬁbrin andelastin by intact human alveolar macrophages in vitro. Characterization of a plasminogen activator and its role in matrix
degradation. J Clin Invest 1984; 73: 806–815
46. Chapman HA, Stone OL: A ﬁbrinolytic inhibitor of humanalveolar macrophages. Induction with endotoxin. Am Rev
Respir Dis 1985; 132: 569–575
47. Chapman HA, Yang XL, Sailor LZ, Sugarbaker DJ: Developmental expression of plasminogen activator inhibitor type I
by human alveolar macrophages. Possible role in lung injury. J
Immunol 1990; 145: 3398–3405
48. Kotani I, Sato A, Hayakawa H, Urano T, Takada Y, Takada A:
Increased procoagulant and antiﬁbrinolytic activities in the lungs
with idiopathic pulmonary ﬁbrosis. Thromb Res 1995; 77: 493–
504
49. Takahashi K, Uwabe Y, Sawasaki Y, Kiguchi T, Nakamura H,
Kashiwabara K, Yagyu H, Matsuoka T: Increased secretion of
urokinase-type plasminogen activator by human lung microvascular endothelial cells. Am J Physiol 1998; 275: L47–L54
50. Muth H, Maus U, Wygrecka M, Lohmeyer J, Grimminger F,
Seeger W, Gunther A: Pro-and antiﬁbrinolytic properties ofhuman pulmonary microvascular versus artery endothelial cells:
impact of endotoxin and tumor necrosis factor-alpha. Crit Care
Med 2004; 32: 217–226
51. Grau GE, de Moerloose P, Bulla O, Lou J, Lei Z, Reber G, MiliN, Ricou B, Morel DR, Suter PM: Haemostatic properties ofhuman pulmonary and cerebral microvascular endothelial cells.
Thromb Haemost 1997; 77: 585–590
52. Gross TJ, Simon RH, Kelly CJ, Sitrin RG: Rat alveolar epithelial
cells concomitantly express plasminogen activator inhibitor-1
and urokinase. Am J Physiol Lung Cell Mol Physiol 1991; 260:
L286–L295
53. Gross TJ, Simon RH, Sitrin RG: Expression of urokinase-type
plasminogen activator by rat pulmonary alveolar epithelial cells.
Am J Respir Cell Mol Biol 1990; 3: 449–456
54. Marshall BC, Xu Q-P, Rao NV, Brown BR, Hoidal JR: Pulmo-

Keio J Med 2005; 54 (3): 142–149

55.

56.

57.

58.

59.

nary epithelial cell urokinase-type plasminogen activator. J Biol
Chem 1992; 267: 11462–11469
Qiao R, Zhou B, Liebler JM, Li C, Crandall ED, Borok Z:
Identiﬁcation of three genes of known function expressed byalveolar epithelial type I cells. Am J Respir Cell Mol Biol 2003;
29: 98–105
Prabhakaran P, Ware L, White K, Cross M, Matthay M, Olman
M: Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema ﬂuid are associated with mortality in acute lunginjury. Am J Physiol Lung Cell Mol Physiol 2003; 285: L20–L28
Moalli R, Doyle JM, Tahhan HR, Hasan FM, Braman SS, Saldeen T: Fibrinolysis in critically ill patients. Am Rev Respir Dis
1989; 140: 287–293
Groeneveld AB, Kindt I, Raijmakers PG, Hack CE, Thijs LG:
Systemic coagulation and ﬁbrinolysis in patients with or at risk
for the adult respiratory distress syndrome. Thromb Haemost
1997; 78: 1444–1449
Texereau J, Pene F, Chiche JD, Rousseau C, Mira JP: Importance of hemostatic gene polymorphisms for susceptibility toand outcome of severe sepsis. Crit Care Med 2004; 32: S313–
S319

149
60. Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA,
de Groot R, Levin M: 4G/5G promoter polymorphism in theplasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease: Meningococcal Research Group. Lancet 1999;
354: 556–560
61. Westendorp RG, Hottenga JJ, Slagboom PE: Variation inplasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999; 354: 561–563
62. Haralambous E, Hibberd ML, Hermans PW, Ninis N, Nadel S,
Levin M: Role of functional plasminogen-activator-inhibitor-1
4G/5G promoter polymorphism in susceptibility, severity, andoutcome of meningococcal disease in Caucasian children. Crit
Care Med 2003; 31: 2788–2793
63. Menges T, Hermans PW, Little SG, Langefeld T, Boning O,
Engel J, Sluijter M, de Groot R, Hempelmann G: Plasminogenactivator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 2001; 357: 1096–1097
64. Gils A, Declerck PJ: The structural basis for the pathophysiological relevance of PAI-1 in cardiovascular diseases and thedevelopment of potential PAI-1 inhibitors. Thromb Haemost
2004; 91: 425–437