Acta Anaesthesiologica Taiwanica 53 (2015) 16e22

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Acta Anaesthesiologica Taiwanica

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Review Article

Coagulation abnormalities in sepsis

Cheng-Ming Tsao 1, 2, 3 *, Shung-Tai Ho 1, 2, 3, Chin-Chen Wu 4, 5
1
Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, Taiwan
2
Department of Anesthesiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan
3
Department of Anesthesiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
4
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
5
Department of Pharmacology, Taipei Medical University, Taipei, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Although the pathophysiology of sepsis has been elucidated with the passage of time, sepsis may be
Received 5 November 2014 regarded as an uncontrolled inflammatory and procoagulant response to infection. The hemostatic
Received in revised form changes in sepsis range from subclinical activation of blood coagulation to acute disseminated intra-
16 November 2014
vascular coagulation (DIC). DIC is characterized by widespread microvascular thrombosis, which con-
Accepted 24 November 2014
tributes to multiple organ dysfunction/failure, and subsequent consumption of platelets and coagulation
factors, eventually causing bleeding manifestations. The diagnosis of DIC can be made using routinely
Key words:
available laboratory tests, scoring algorithms, and thromboelastography. In this cascade of events, the
coagulation;
disseminated intravascular
inhibition of coagulation activation and platelet function is conjectured as a useful tool for attenuating
coagulation (DIC); inflammatory response and improving outcomes in sepsis. A number of clinical trials of anticoagulants
organ dysfunction; were performed, but none of them have been recognized as a standard therapy because recombinant
platelet; activated protein C was withdrawn from the market owing to its insufficient efficacy in a randomized
sepsis controlled trial. However, these subgroup analyses of activated protein C, antithrombin, and thrombo-
modulin trials show that overt coagulation activation is strongly associated with the best therapeutic
effect of the inhibitor. In addition, antiplatelet drugs, including acetylsalicylic acid, P2Y12 inhibitors, and
glycoprotein IIb/IIIa antagonists, may reduce organ failure and mortality in the experimental model of
sepsis without a concomitant increased bleeding risk, which should be supported by solid clinical data.
For a state-of-the-art treatment of sepsis, the efficacy of anticoagulant and antiplatelet agents needs to be
proved in further large-scale prospective, interventional, randomized validation trials.
Copyright © 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction dysfunction syndrome (MODS) reached 27.6%, although the mor-

Sepsis, defined as infection-induced systemic inflammatory
response syndrome (SIRS), is widely recognized as a clinical syn-
drome that carries significant morbidity and mortality. A large
investigation that reviewed national data in the United States from
1979 to 2000 revealed an 8.7% annual increase in incidence of
sepsis,1 despite improvements in the medical field and intensive
care setting. In Taiwan, the annual increase in incidence of sepsis
was 3.9% from 1997 to 2006, and the incidence of multiple organ
Conflicts of interest: None of the authors received any financial support for the
preparation of the manuscript.
* Corresponding author. Department of Anesthesiology, Taipei Veterans General
Hospital, Number 201, Section 2, Shipai Road, Beitou District, Taipei 11217, Taiwan.
E-mail address: cm.cmtsao@gmail.com (C.-M. Tsao).
tality rate in hospitals did not change too much, at about 30.8%.2
Coagulation abnormalities, particularly a prothrombotic state,
frequently occur during sepsis.3 In severe sepsis, the dysregulation
of hemostatic system may lead to disseminated intravascular
coagulation (DIC) and result in microvascular thrombosis, hypo-
perfusion, and ultimately MODS, and death.4 The activation of
coagulation, the downregulation of anticoagulant pathways, and
the impairment of fibrinolysis play a crucial role in the pathogen-
esis of microvascular thrombosis in DIC associated with sepsis.5,6
However, studies demonstrate that the physical entrapment of
bacteria by fibrin induced by infection may limit the bacterial ca-
pacity to disseminate into nearby tissues and systemic circula-
tion.7,8 Thus, therapeutics that control DIC are required for
protection against the development of MODS in sepsis, while
maintaining the host defense mechanisms.

http://dx.doi.org/10.1016/j.aat.2014.11.002
1875-4597/Copyright © 2014, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
Coagulation in sepsis
This review will outline the coagulation changes associated with
sepsis and highlight the potential use of anticoagulation and
platelet agents in the treatment of sepsis.
2. Sepsis
In sepsis, an uncontrolled infection results in progressive and
dysregulated inflammation, which can lead to SIRS.9 During SIRS,
production of multiple pro- and anti-inflammatory cytokines within
the bloodstream are exacerbated.10 The abnormal production of cy-
tokines contributes to the abundant activation of coagulation factor
and platelets as well as damage to vascular endothelial cells, which
give rise to vascular leakage and DIC. In addition to ensuring throm-
bosis generation after activation of the coagulation system, advanced
DIC may result in bleeding at the time that platelets and coagulation
factors are exhausted.11 These conditions often result in extensive
cross-talk that exists between inflammation and coagulation, with a
potential final outcome of MODS and eventual death.5,12
3. Coagulation cascades
3.1. Coagulation activation
During sepsis, coagulation activation is ubiquitous and induced
by pathogen-associated molecular patterns, such as lipopolysac-
charide (LPS) and exotoxins. The coagulation cascade, such as
upregulated fibrinogen and factor V, is thought to be mediated by
the expression of tissue factor (TF) on monocytes and macro-
phages,13 and by the TF-expressing microparticles from platelets,
monocytes, and macrophages.14
This procoagulant reaction is partially reversed by temporal
activation of fibrinolysis attributable to increased expression of
endogenous tissue plasminogen activator. And this reaction is
rapidly inhibited by an increased synthesis of plasminogen acti-
vator inhibitor-1.15 Thrombin-activatable fibrinolysis inhibitor
(TAFI) is also involved in sepsis-associated hypofibrinolysis. In pa-
tients with severe sepsis complicated DIC, the levels of TAFI in-
crease, and the enhancement of TAFI activation further accelerate
the thrombogenic pathway.16 In animal models, this univocal
sequence induces a procoagulant and antifibrinolytic state in less
than 3 hours.17 In humans, if septic injury is controlled, this he-
mostatic imbalance diminishes in a few days with a final progres-
sive fibrinolytic stage. However, if the insult is explosive, the
hemostatic sequence loses control continuously and induces
widespread thrombosis and hemorrhages, recognized as DIC.
3.2. Anticoagulation pathways
Under physiological conditions, the surface of endothelial cells
expresses various components of the anticoagulant pathways,
which are rapidly and significantly decreased in the sepsis-induced
DIC process.18 This explains why decreased antithrombin (AT),
protein C (PC), or tissue factor pathway inhibitor (TFPI) activities
are observed in sepsis even if their coagulation appears moderately
activated.19,20 Moreover, a rapid depletion of AT and PC is associated
with a poor prognosis.21,22
In addition, a rise in soluble plasma thrombomodulin (TM) and
endothelial PC receptor was consistently observed, suggesting that
damage of endothelial activation by inflammatory mediators does
occur in vivo.5,22
3.3. Network microbial trapping
Following bacterial invasion, extracellular chromatin threads
are formed as a fibrin network contributing to the host defense
17
against microbial dissemination. They also enhance platelet adhe-
sion and aggregation, impair TM-dependent PC activation, and thus
activate the coagulation process.23 The activation of coagulation
contributes to compartmentalization of bacteria and reduces bac-
terial invasion.7,8,24 By contrast, an early inhibition of fibrin for-
mation by recombinant AT or activated protein C (APC) did not
modify inflammation, increased pulmonary edema, and exacer-
bated lung pathologic changes in the rat model of Pseudomonas
aeruginosa-induced lung injury.25,26 Therefore, the potential risk
induced by coagulation inhibition at the early stage of sepsis should
be kept in mind.
4. Organ failure
Contrasting with the determinism of coagulation activation as a
host defense mechanism, excessive deregulation of hemostasis is
associated with subsequent organ failure and death. Overall, a high
DIC score is strongly associated with mortality and, in some studies,
stronger than general severity scores.6 Concerning fibrinolysis, the
correlation between the secondary increase in plasminogen acti-
vator inhibitor-1 levels and organ failure is supported by numerous
studies.5 Similarly, sequential studies of the natural coagulation
inhibitors AT and PC were equally consistent with a correlation
between severely decreased plasma levels and death or organ
failure.21,22 Continuous or worsening of decreases in AT and PC
activities within the 1st day of severe sepsis was associated with
increased development of new organ failure and 28-day mortal-
ity,21,27 suggesting that prolonged and disproportionate coagula-
tion and antifibrinolysis are at least partly contribute to organ
failure and death.
5. Diagnosis
The current diagnostic criteria for sepsis include such general
variables as hypo- or hyperthermia, tachycardia, tachypnea, hypo-
tension, hyperglycemia, edema, and an altered mental status.28 In
addition, abnormal white blood cell count and elevated plasma
levels of C-reactive protein and procalcitonin, can assist in
diagnosis.
The original diagnostic criteria for DIC was established by the
Japanese Ministry of Health and Welfare in 1983, followed by the
overt-DIC diagnostic criteria proposed by the International Society
on Thrombosis and Haemostasis in 2001.29 Then, the Japanese As-
sociation for Acute Medicine introduced a new set of criteria,
including SIRS score, platelet counts, prothrombin time, and fibrin/
fibrinogen degradation products, to help initiate treatment at the
appropriate time.30 Treatment with AT or APC may not improve the
outcomes of patients with sepsis at the early stage, although they
may improve the outcomes in those with DIC. Thus, new diagnostic
criteria for determining the appropriate time to start anticoagulant
treatment are required.31
Thromboelastography (TEG) might give a reliable assessment of
hemostatic status in sepsis.32,33 Furthermore, TEG variables have
been reported to moderately correlate with the severity of organ
dysfunction34 and predict survival in patients with severe
sepsis.35,36 Our previous studies also reported that TEG could be a
potential tool to assess the extent of liver injury in endotoxemia32
and to evaluate the efficacy of pharmacological intervention.37
6. Potential treatment in sepsis
The current strategy for handling sepsis-associated DIC pri-
marily focuses on the treatment of infection and use of supple-
mental clotting factors or platelets depending on the necessity.38
Dysregulation of the hemostatic system is well known to lead to
18
DIC, which results in microvascular thrombosis, hypoperfusion, and
subsequent multiple organ failure and death in severe sepsis.
At the same time, a considerable number of experimental and
clinical studies demonstrate that natural anticoagulants modulate
intracellular signaling, cytokine secretion, cellular or lymphocyte
apoptosis, and leukocyteeendothelial interactions.39 This indicates
that, in addition to their role as anticoagulants, they also have
important functions in modulating inflammation. Therefore, these
findings promote the rationalization that the inhibition of the
overactivated coagulation cascade by natural anticoagulants or
antiplatelet agents could help the resolution of DIC and reduce the
mortality of sepsis.
7. Treatment with endogenous anticoagulation agents
7.1. TFPI
TFPI inhibits the activity of TF Factor VII complex and Factor X on
prothrombinase complex, thus suppressing the primary steps of
thrombin generation.13 In addition, anti-inflammatory effects
of TFPI depend on its ability to suppress the inflammatory intra-
cellular signaling of thrombin binding to protease-activated re-
ceptor-1.
Several studies evaluating the protecting effects of recombinant
TFPI (rTFPI, Tifacogin) on sepsis found that rTFPI significantly de-
creases thrombin generation, but no conclusions have been verified
from Phase 1 or 2 clinical trials.40e42 A large-scale randomized
controlled trial (RCT), the optimized phase 3 tifacogin in multi-
center international sepsis trial (OPTIMIST), showed an absence of
any improvement in 28-day mortality in severe sepsis after rTFPI
treatment.40 However, exploratory analysis revealed that rTFPI
treatment improved survival in patients with severe community-
acquired pneumonia not receiving concomitant heparin.42 In
addition, the other placebo-controlled Community Acquired
Pneumonia Tifacogin Intra Venous Administration Trial for Efficacy
(CAPTIVATE) trial was discontinued earlier than planned because
no beneficial trend was validated.43
7.2. AT
AT inhibits several serine proteases, including FXa, IXa, XIa, and
thrombin. It is a direct 1:1 thrombin inhibitor, leading to throm-
bineantithrombin complex formation and subsequent elimination.
Furthermore, its activity is maximized after binding with glycos-
aminoglycans serving as cofactors on the endothelial surface.44
The anti-inflammatory effects of AT inhibit rolling and adhesion
of leukocyte activation partly due to the release of prostacyclin45
and the suppression of P-selectin.46 In addition, after binding to
heparin sulfate proteoglycan on the endothelial surface, AT ham-
pers the expression of proinflammatory cytokines.47,48
AT levels are diminished by consumption as a consequence of
sustained thrombin generation49 and cytokine-induced down-
regulation of endothelial heparin sulfate proteoglycans in sepsis.50
The early administration of high doses of recombinant AT improves
the outcome in experimentally induced sepsis probably because of
its combined anticoagulation and anti-inflammatory effects.51
An observational nationwide study demonstrates that AT
administration may be associated with reduced 28-day mortality in
patients with severe pneumonia and sepsis-associated DIC.52 In
patients with severe sepsis, a maintenance dose of 1500 IU/d of AT
has been reported to induce a decrease in mortality accompanied
by a considerably shorter stay in the intensive care unit (ICU), and a
lower incidence of new organ failure.53 Moderate doses (30 IU/kg/
d) of AT improve DIC scores, thereby increasing the recovery rate
from DIC without any risk of bleeding in DIC patients with sepsis.52
C.-M. Tsao et al.
Unfortunately, high-dose (7500 IU/d) AT therapy had no effect on
28-day all-cause mortality in adult patients with severe sepsis and
septic shock in KyberSept trial.54 However, in the Phase 3 KyberSept
trial, it was shown that high-dose AT treatment without concom-
itant heparin may result in a significant mortality reduction in
septic patients with DIC.55
Recently, results from a Phase 4 study in patients with septic DIC
indicated that higher initial AT activity, AT supplement dose of
3000 IU/d, and younger age were significant factors for improved
survival without an increased risk of bleeding.56,57
7.3. APC
PC, a vitamin K-dependent protein, is converted to its activated
form (APC) by proteolysis on the thrombineTM complex. APC in-
activates factors Va and VIIIa, which effectively limits further
thrombin generation. As with thrombin, most of the profibrinolytic
actions of APC are mediated through binding of endothelial protein
C receptor and inhibition of protease-activated receptor-1.58
In addition to its anticoagulant and profibrinolytic activity, APC
has important anti-inflammatory effects: downregulation of
proinflammatory cytokines and TF in activated leukocytes, antiox-
idant properties, antiapoptotic activity, and endothelial barrier
stabilization.59e62 Moreover, APC exerts additional cytoprotective
functions through the degradation of histones released in fibrin
networks.63
Based on these observations, recombinant APC (rAPC; Dro-
trecogin alfa) was produced, and the efficacy of this agent was
tested in a single large-scale RCT with benefits shown in only one
subgroup analysis in 2001.64 Drotrecogin alfa was then heavily
promoted in the Surviving Sepsis Campaign guidelines,65 and was
initially acclaimed as the most promising therapy in the treatment
of sepsis. However, concerns exist regarding its cost-effectiveness
and inconsistent results observed in more recent studies.66 More-
over, the production and distribution of rAPC was discontinued in
2011 inasmuch as the Prospective Recombinant Human Activated
Protein C Worldwide Evaluation in Severe Sepsis and Septic
Shock (PROWESS-SHOCK) trial revealed that the 28-day mortality
did not have a significant improvement after rAPC treatment in
patients with septic shock.67 Nevertheless, its subgroup analysis
reveals that the relative risk of death is lower in patients with
markedly reduced protein C activity at the time of entry into the
study.
However, more than a few investigators may feel dissatisfied
with the withdrawal of rAPC on the basis of the results of a single
RCT. Casserly et al68 found that the inhospital mortality rate was
significantly lower in the rAPC treatment group than in the placebo
group after analyzing the Surviving Sepsis Campaign's database
containing 15,022 registered cases. The demonstrated efficacy of
rAPC is statistically significant in cases complicated by multiple
organ failure, but not in those with only single organ dysfunction.
The meta-analysis reported by Kalil and LaRosa69 revealed an 18%
reduction of the inhospital mortality following rAPC treatment,
although the incidence of severe bleeding rose to 5.6%. The authors
concluded that rAPC elevated the risk of bleeding, but nonetheless
improved the outcome of severe sepsis.
7.4. TM
TM binds to thrombin and then converts PC to APC, providing a
critical negative feedback regulation of thrombin generation.70 In-
dependent of anticoagulation activity, its anti-inflammatory effect
is considered through interference with complement activation,
neutralization of LPS, and suppression of leukocyteeendothelial
interaction.71,72
Coagulation in sepsis
When compared with heparin therapy, a Phase 3 study reveals
that recombinant TM (ART-123) therapy has a more significant
improvement in DIC recovery and alleviation of bleeding symptoms
in DIC patients with hematologic malignancy or infection.73 In
addition, Phase 2B studies validated the hypothesis that TM
downregulated the mediators/markers of thrombin generation in
sepsis-associated DIC without increasing the risk of severe hem-
orrhage.74,75 Their subgroup analyses reveal that the survival
benefit is greater in patients combined with respiratory or cardiac
dysfunction and coagulopathy. According to these results, a Phase 3
study is currently being conducted in the United States among
patients suffering from severe sepsis with coagulopathy.76
A significant number of hemorrhagic adverse effects are
observed in the randomized trials testing the above anticoagulants.
The frequency of bleeding events in the treatment group is more
than 1.7 times higher in the PROWESS APC trial and in the Kyber-
Sept AT trial.54,64 It is not surprising as anticoagulants efficiently
suppress thrombin generation. But at the same time, we have
learned that this adverse event often counteracts the beneficial
effects of anticoagulants.
More importantly, many randomized trials of TFPI, AT, or APC were
designed to include septic patients without any criteria of coagulation
activation and regardless of its time sequence. In more severely ill
patients who benefited from the treatment, the criteria for overt DIC
were already fulfilled at inclusion. In addition, a significant reduction
in mortality is observed in open trials of AT or recombinant TM, when
overt DIC is required for inclusion.77,78 By contrast, patients with less
severe diseases and without excessive coagulation activation exhibit
no beneficial effect or even an upward trend in mortality. It is sus-
pected that a possible adverse effect of anticoagulants when used
“preventively” cancels out their favorable effect on DIC.
7.5. Heparin
Heparin is expected to modulate the hemostatic abnormalities
through maximizing the effect of AT for the treatment of septic DIC.
A retrospective analysis showed that the mortality rate tended
to be lower in septic patients with low-dose heparin treatment
than those with the placebo treatment.79 In addition, low-dose
heparin improves the hypercoagulable state of sepsis, which sub-
sequently reduces the incidence of DIC or MODS, and decreases the
total stay in ICU.80 However, the use of unfractionated heparin is
generally not recommended for patients with a tendency to bleed.
However, in a meta-analysis study, it was shown that heparin may
reduce 28-day mortality in patients with severe sepsis, whereas
there was no increase in the risk of bleeding in the heparin group.81
8. Treatment with antiplatelet agents
8.1. Acetylsalicylic acid
Acetylsalicylic acid (ASA), popularly known as aspirin, can
suppress the production of prostaglandins and thromboxanes
because of its irreversible inactivation of cyclooxygenases.82 It also
stimulates the synthesis of 15-epi-lipoxin A4, which in turn in-
creases the synthesis of nitric oxide, which inhibits the interactions
between leukocytes and endothelial cells, resulting in recruitment
of decreased polymorphonuclear neutrophil.83
Observational studies reveal that pretreatment with ASA in
critically ill patients is associated with shorter length of stay and
fewer ICU admissions,84 and might prevent organ dysfunction at
least in the absence of active bleeding.85 ASA therapy prior to
admission significantly reduces the development of acute lung
injury and need for mechanical ventilation in critically ill pa-
tients,86,87 as well as mortality associated with septic shock.88
19
Furthermore, patients who are treated with low-dose ASA during
their ICU stay have a significantly lower mortality at the time of the
development of SIRS and sepsis.89e91 However, some studies show
that the use of ASA therapy prior to the diagnosis of severe sepsis or
septic shock is not associated with decreased hospital mortality.87,92
8.2. P2Y12 inhibitors
Activation of P2Y12 receptors, a chemoreceptor for adenosine
diphosphate (ADP), is essential for ADP-mediated complete acti-
vation of glycoprotein (GP) IIb/IIIa and Ia/IIa, and further stabilizes
platelet aggregates.93 The thienopyridines, including clopidogrel,
prasugrel, and ticagrelor, bind to P2Y12 receptors and thereby
inhibit platelet activation and aggregation stimulated by ADP.94
P2Y12 receptors may also be expressed in other cells of the im-
mune system, indicating that thienopyridines could directly influ-
ence the immune system rather than only through platelets.95,96
Recent evidence shows that a reduction in LPS-mediated
thrombocytopenia, fibrin deposition in the lungs, and inflamma-
tory mediator upregulation occurs in mice pretreated with clopi-
dogrel.84 Moreover, in mice with polymicrobial sepsis,
pretreatment with clopidogrel can attenuate sepsis-associated
decrease in the clot formation rate of TEG as a consequence of an
effect of clopidogrel on the number of circulating platelets; how-
ever, an effect on fibrinogen level remains to be tested.97
This finding comes in line with recent data indicating that
pretreatment with ticagrelor appears to reduce pulmonary
neutrophil recruitment and lung injury in mice with abdominal
sepsis.98 In addition, strong in vivo blockade of P2Y12 with pre-
treated prasugrel inhibits a broad spectrum of platelet aggregation
pathways in human with endotoxemia.99
Clinical studies also suggest that P2Y12 inhibitors may be
associated with better outcomes in patients with pneumonia and
critical illness.84,85 Prior treatment with antiplatelet agents,
including clopidogrel, is associated with a favorable length of stay
and fewer ICU admissions, even though community-acquired
pneumonia appears to be more common among patients taking
clopidogrel.84,100 Later clinical studies also report an association of
antiplatelet drug therapy including clopidogrel with favorable
outcome in critical illness85e87; however, these results are mainly
driven by the large number of patients receiving ASA.
Moreover, in the PLATelet inhibition and patient Outcomes
(PLATO) study of patients with acute coronary syndromes, tica-
grelor reduced the mortality risk following pulmonary adverse
events and sepsis compared to clopidogrel, but the mechanisms for
this mortality reduction remain uncertain.101
8.3. GPIIb/IIIa antagonists
The platelet GPIIb/IIIa receptor has been identified as the pivotal
mediator of platelet aggregation. GPIIb/IIIa antagonists block
fibrinogen binding to the GPIIb/IIIa receptor on activated platelets
and exert a strong antiplatelet effect by inhibiting the final common
step of platelet aggregation.102
There are only a few reports on GPIIb/IIIa inhibitors, including
abciximab eptifibatide and tirofiban, in the animal model of
endotoxin-induced inflammatory responses and/or organ failure. In
rats with endotoxemia, GP IIb/IIIa inhibition, using abciximab, pro-
tects against endothelial dysfunction and prevents an increase in
leukocyte adherence to the vascular wall.103 Of note, eptifibatide at-
tenuates platelet granzyme B-mediated apoptosis and prolongs sur-
vival in a murine model of abdominal sepsis.104 However, in humans
with low-grade endotoxemia, eptifibatide or tirofiban does not seem
to influence TF-induced coagulation activation.105 Therefore, whether
these results can be extrapolated to humans remains unclear.
20
9. Conclusion
Considerable evidence of activation of coagulation and down-
regulation of anticoagulation and fibrinolysis are the predominant
features of the proinflammatory condition in sepsis, and contribute
to the outcome of the disease. Indeed, in the early stages of sepsis,
excessive coagulation develops and stimulates microthrombosis
formation within small vessels, thereby serving as a factor
responsible for the disturbed circulation through organs. Therefore,
it would be useful to suppress the interaction of excessive coagu-
lation and inflammation to maintain circulation in the treatment of
sepsis.
A number of clinical trials of anticoagulants were performed,
but none of them have been recognized as a standard therapy.
However, a subgroup analysis of these trials shows that overt
coagulation activation is strongly associated with the best thera-
peutic effect of the inhibitor. In addition, antiplatelet drugs may
reduce organ failure and mortality in critically ill patients, whereas
uncertain conclusions are extrapolated in the absence of inter-
ventional and prospective randomized trials. Therefore, even if the
efficacy of anticoagulant and antiplatelet agents is acceptable, there
remain many unanswered questions such as when to initiate
therapy, and the tendency to underestimate the importance of
bleeding. We have to address each of these questions, and the
effectiveness needs to be proved in future large-scale prospective
validation trials.
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