Perspective
Coagulation Abnormalities in Acute Lung Injury and Sepsis
Edward Abraham
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center,
Denver, Colorado
Intraalveolar and intravascular fibrin deposition is fre-
quently found in the setting of acute lung injury (ALI) or
acute respiratory distress syndrome (ARDS) (1, 2). Fibrin
deposits enhance inflammatory response by increasing vas-
cular permeability, activating endothelial cells to produce
proinflammatory cytokines and other mediators, inducing
the accumulation of activated neutrophils, and modulating
immunoregulatory responses in the lung. Infusions of en-
dotoxin produce fibrin deposits in the lung and other or-
gans, and these widespread intravascular alterations are
postulated to contribute to multiple organ dysfunction in
sepsis (3, 4, 5). Fan and colleagues now show that hemor-
rhagic shock can potentiate the effects of small doses of
endotoxin, creating a procoagulant milieu in the lungs, in
which reactive oxygen intermediates (ROI) and tumor
necrosis factor-␣ (TNF-␣) produced by alveolar macro-
phages have important roles (6).
Procoagulant activity is enhanced in the lungs of patients
with ARDS (7, 8). Levels of tissue factor, a pivotal mediator
in the extrinsic coagulation pathway, are increased in
ARDS bronchoalveolar lavage (BAL) specimens, and tis-
sue factor appears to occupy an important role in the
ARDS-associated procoagulant state (9, 10). In addition,
fibrinolytic processes are inhibited in ALI, as shown by
increased BAL concentrations of plasminogen activator
inhibitor 1 (PAI-1), and may also contribute to fibrin gener-
ation in ALI (11). In experimental models of endotoxemia,
early increases in the anticoagulant tissue plasminogen acti-
vator are rapidly followed by sustained elevations in PAI-1,
leading to a prolonged antifibrinolytic state (12).
Coagulation Activation and Modulation
Recent experimental studies in humans and nonhuman
primates demonstrate that activation of coagulation after
endotoxemia, bacterial infusion, or administration of proin-
flammatory cytokines, such as TNF-␣, is driven primarily
(Received in original form February 2, 2000 )
Address correspondence to: Edward Abraham M.D., Division of Pulmo-
nary Sciences and Critical Care Medicine, University of Colorado Health
Sciences Center, Box C272, 4200 E. Ninth Avenue, Denver, CO 80262.
Abbreviations: acute lung injury, ALI; acute respiratory distress syndrome,
ARDS; antithrombin III, ATIII; bronchoalveolar lavage, BAL; dissemi-
nated intravascular coagulation, DIC; lipopolysaccharide, LPS; nuclear
factor ␬B, NF-␬B; plasminogen activator inhibitor 1, PAI-1; reactive oxy-
gen intermediates, ROI; tumor necrosis factor-␣, TNF-␣; tissue factor
pathway inhibitor, TFPI.
Am. J. Respir. Cell Mol. Biol. Vol. 22, pp. 401–404, 2000
Internet address: www.atsjournals.org
by the extrinsic pathway (13, 14). Regulatory mechanisms
that prevent coagulation from being generalized under
normal conditions involve antithrombin III (ATIII), pro-
tein C, protein S, and tissue factor pathway inhibitor
(TFPI) (Figure 1). Each of these inhibitory mechanisms is
presently being investigated as a therapeutic intervention
to improve outcome from severe sepsis.
Tissue factor occupies a central position in the extrinsic
coagulation pathway (14, 15). Tissue factor is highly throm-
bogenic, and, under normal conditions, only minute amounts
are exposed to the circulating blood. However, under patho-
physiologic conditions, alveolar macrophages, neutrophils,
and endothelial cells can express tissue factor on their sur-
face, thereby leading to development of a coagulopathy
(15, 16). Endotoxin, activated complement, and cytokines,
such as TNF-␣ or interleukin-1␤, can all upregulate tissue
factor expression (14, 17, 18). Infusion of endotoxin or
bacteria in primates results in activation of coagulation di-
rectly dependent on tissue factor activity, since antitissue
factor antibodies completely prevent such sepsis-associ-
ated coagulopathies (14, 19).
Exposed tissue factor binds and activates factor VII,
which cleaves factor X to Xa. Factor Xa converts prothrom-
bin to thrombin, activating factor V. Activated factor V is a
potent cofactor for factor Xa, and enhances the ability of
factor Xa to generate thrombin. TFPI regulates extrinsic
pathway activity by suppressing the activity of tissue factor/
VIIa/Xa complexes (20). The role that TFPI plays in regu-
lating coagulation cascades in ARDS or sepsis is incom-
pletely understood. Plasma levels of TFPI are not generally
diminished in patients with disseminated intravascular co-
agulation (DIC) (21). However, because there are different
pools of TFPI, of which the largest is endothelial associated,
plasma levels may not provide an accurate reflection of
TFPI reserve. Administration of TFPI improves survival
and organ function when given to rabbits with septic perito-
nitis or to baboons infused with endotoxin or Escherichia
coli (22, 23). A recent small Phase II human study also sug-
gested that TFPI administration could reduce mortality as-
sociated with sepsis.
ATIII inhibits activated proteases, including factors
IXa, Xa, and thrombin (24). Plasma levels of ATIII de-
crease in experimental and clinical sepsis and inversely
correlate with survival in these settings (25). Reconstitut-
ing ATIII to supraphysiologic concentrations may offer
protection against DIC and related morbidity. Evidence
suggests that administering ATIII to septic patients may
improve survival (26). A large clinical trial is presently in-
vestigating this hypothesis.
402 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL. 22 2000
Figure 1. The intrinsic and extrinsic coagulation pathways and the points at which coagulation inhibitors exert their action. Inhibitor ef-
fects: TFPI, purple concaved rectangle; ATIII, red concaved rectangle; APC, yellow concaved rectangle.
Protein C is a vitamin K–dependent protein, which is
activated by the thrombin–thrombomodulin complex on
endothelial cells (27). Activated protein C (APC), with the
cofactor protein S, cleaves and inactivates the procoagu-
lant activity of activated factors V and VIII. Low plasma
levels of protein C predict poor clinical outcome in pa-
tients with DIC or sepsis (28). Case studies in purpura ful-
minans due to meningococcemia, in which DIC plays an
important role in contributing to morbidity and mortality,
suggest that administration of protein C can improve out-
come (29). A limited clinical study also suggested benefit
when APC was given to septic patients.
Interactions between TNF-␣ and Coagulation
TNF-␣ induces the expression of tissue factor and down-
regulates thrombomodulin on endothelial surfaces, thereby
enhancing coagulation (12, 18). Local injection of TNF-␣
leads to deposition of fibrin (30). Infusion of TNF-␣ into
humans produces a procoagulant state, accompanied by
inhibition of fibrinolysis (31, 32). In particular, administra-
tion of TNF-␣ to control subjects led to activation of the
extrinsic, but not intrinsic, coagulation pathway, with in-
creases in circulating levels of factor Xa and prothrombin
fragment F1+2. Although TNF-␣ injection into humans in-
duced a brief increase in fibrinolytic activity, as shown by
increases in plasminogen activator and D-dimer levels, in-
creases in PAI-1 were evident starting one hour after
TNF-␣ administration, resulting in overall inhibition of fi-
brinolysis at later time points.
The results of Fan and associates (6) are consistent with
those described previously and demonstrate a central role
for TNF-␣ in inducing pulmonary procoagulant activity in
their model of hemorrhagic shock followed by intratracheal
endotoxin. Anti–TNF-␣ treatment prevented lipopolysac-
charide (LPS)-induced increases in tissue factor and PAI-1
expression in the lungs. Interestingly, the TNF-␣ blockade
did not modulate endotoxin-induced accumulation of neu-
trophils into the lung, but it did appear to diminish neutro-
phil activation, as assessed by chemiluminescence assays.
Such results, showing that the migration of neutrophils to
the lungs occurs by mechanisms distinct from those induc-
ing their activation, are consistent with experiments in mod-
els of endotoxemia-induced ALI (33).
Interrelationships between ROI and Coagulation
Both hemorrhage and endotoxemia result in increased
production of ROI (34, 35), an effect expected to be en-
hanced by the combination of the two pathophysiologic
insults, such as in the experiments of Fan and coworkers.
ROI have been demonstrated to be increased in patients
with ARDS (36). ROI also appear to have an important
role in initiating inflammatory cascades leading to ALI
(34, 35).
ROI are involved in the activation of the transcriptional
regulatory factor nuclear factor-␬B (NF-␬B) in many, but
not all, cell types (38). Exposure to increased levels of ROI
can lead to enhanced translocation of NF-␬B to the nucleus
Perspective
and upregulated expression of NF-␬B–dependent genes. In
experimental models of hemorrhage or endotoxemia, ad-
ministration of ROI scavengers, such as pyrrolidine dithio-
carbamate (PDTC) or N-acetyl cysteine (NAC), or inhibi-
tion of the ROI-generating enzyme, xanthine oxidase,
decrease NF-␬B activation in the lungs (35, 38, 39). Recent
data from our laboratory show that xanthine oxidase block-
ade prevents increases in NF-␬B–dependent proinflamma-
tory cytokines, such as TNF-␣ and macrophage inflamma-
tory peptide-2 (MIP-2), which are normally seen in lung
neutrophils after hemorrhage (40). However, even though
xanthine oxidase inhibition diminishes neutrophil activa-
tion, there is no effect on the accumulation of neutrophils
in the lungs after hemorrhage.
Transcriptional activation of the human tissue factor
gene in monocytic cells exposed to LPS is mediated by
binding of NF-␬B heterodimers to a ␬B site in the tissue
factor promoter (41). Incubation of human monocytes with
either PDTC or NAC blocks LPS-induced expression of
tissue factor (42, 43). Similarly, increases in myocardial tis-
sue factor levels produced by ischemia/reperfusion are abol-
ished by oxygen radical scavengers (44). The studies by Fan
and colleagues (6) indicate that hemorrhage induces a state
where the lungs are primed to upregulate tissue factor
through a pathway initiated by ROI generation, in which
NF-␬B activation and TNF-␣ expression play pivotal roles.
Such data therefore suggest a mechanism by which ROI
may initiate and potentiate ALI through inducing a tissue
factor–dependent procoagulant state.
How Important Are Coagulation Abnormalities
in ALI?
Despite the fact that endotoxemia, hemorrhage, or expo-
sure to proinflammatory cytokines such as TNF-␣ can lead
to a procoagulant state, several important questions re-
main. Although tissue factor generation and widespread
fibrin deposition accompany ALI, we still don’t know how
important these factors are in modulating the develop-
ment and progression of ARDS. Accumulation of fibrin
may enhance pulmonary inflammation or may simply be a
result of the proinflammatory state that accompanies ALI
and not substantially contribute to lung damage. As men-
tioned previously, experimental models suggest that coag-
ulation abnormalities do contribute in important ways to
endotoxemia- or sepsis-induced organ dysfunction. In those
studies, interventions to correct the procoagulant state
were provided either before or shortly after infusion of
bacteria or endotoxin. Such experiments indicate that co-
agulation abnormalities and fibrin deposition are indeed
important in initiating organ system dysfunction, at least in
acute models where DIC plays a major role. However, the
importance of coagulation alterations and fibrin deposi-
tion has not been explored well in settings where the pro-
gression of infection is more indolent and thus closer to
most clinical situations. Similarly, it is presently unknown
if interventions that affect coagulation will be beneficial
when ALI is already present. We will have to wait for the
results of ongoing clinical trials with TFPI, ATIII, or APC
to know if modulation of coagulation with such agents can
improve outcome from ARDS and sepsis.
403
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