Okamoto et al.

Journal of Intensive Care (2016) 4:23

DOI 10.1186/s40560-016-0149-0

REVIEW Open Access

Sepsis and disseminated intravascular

coagulation
Kohji Okamoto1,2*, Toshihisa Tamura2 and Yusuke Sawatsubashi2

Abstract
Sepsis is frequently complicated by coagulopathy and, in about 35 % of severe cases, by disseminated intravascular
coagulation (DIC). In Japan, aggressive treatment of septic DIC is encouraged using antithrombin and recombinant
thrombomodulin. The macrophages, monocytes, and neutrophils are a source of TF and participate in the direct
activation of the coagulation cascade in the early phases of sepsis. And activated factor X (FXa), which is involved in
hemostasis, thrombogenesis, inflammation, and cellular immune responses, induces TF expression in human peripheral
monocytes and, conversely, that inhibition of FXa activity reduces TF expression. Both inflammation and coagulation
play an important role in DIC due to sepsis. In addition to inflammatory cytokines (TNF-α, IL-1 and so on), HMGB1 has
recently been shown to mediate the lethal late phase of sepsis and caused coagulopathy. TM not only binds HMGB1
but also aids the proteolytic cleavage of HMGB1 by thrombin. There have been many reports of the efficacy of
recombinant TM and antithrombin for treatment of septic DIC from Japan. Further investigation of the efficacy
of recombinant TM and AT in countries other than Japan, as well as the monitoring of medical costs incurred during
hospitalization, will help validate the use of TM and AT for treatment of septic DIC.
Keywords: Sepsis, Disseminated intravascular coagulation (DIC), HMGB1, Antithrombin, Thrombomodulin

Introduction Review
Sepsis is a clinical syndrome defined as a systemic re- Sepsis-induced DIC
sponse to infection. It is frequently complicated by coag- During sepsis, inflammation diffusely activates the co-
ulopathy [1] and, in about 35 % of severe cases, by agulation system, consuming multiple clotting factors
disseminated intravascular coagulation (DIC) [2–4]. In and resulting in DIC [10, 11]. In systemic inflammatory
the European Union and the USA, the 2012 guidelines response syndromes caused by infection, both perturbed
of the Surviving Sepsis Campaign do not recommend endothelial cells and activated mononuclear cells pro-
treatment for septic DIC [5, 6]. In contrast, in Japan, ag- duce proinflammatory cytokines that promote coagula-
gressive treatment of septic DIC is encouraged [7–9]. It tion [12, 13]. Proteins expressed on these cells initiate
is not an exaggeration to state that Japan is one of the coagulation. Thrombin elicits the production of mono-
countries that most effectively treats patients with septic cyte chemoattractant protein 1 and interleukin (IL)-6
DIC. In this article, we review the mechanisms that in monocytes, fibroblasts, and mesothelial cells, and
underlie the interaction between sepsis and DIC and, by the production of IL-6 and IL-8 in vascular endothelial
highlighting our findings, the effects of sepsis on the co- cells by interacting with protease-activated receptors
agulation system. (PARs) 1, 3, and 4. Via PAR 2, factor Xa, and the tissue
factor-VIIa complex also upregulate IL-6 and IL-8 in
vascular endothelial cells [14–16]. In addition, the inhib-
ition of physiologic anticoagulant mechanisms and
* Correspondence: [email protected] fibrinolysis by endothelial cells causes intravascular fi-
1
Department of Surgery, Center for Gastroenterology and Liver Disease, brin deposition.
Kitakyushu City Yahata Hospital, 4-18-1 Nishihon-machi, Yahatahigashi-ku, Initiation of the extrinsic coagulation protease cascade
Kitakyushu 805-8534, Japan
2
Department of Surgery 1, School of Medicine, University of Occupational & requires tissue factor (TF), a 47-KDa transmembrane
Environmental Health, 1-1 Iseiogaka, Yahatanishi-ku, Kitakyushu 807-8555, glycoprotein [17]. We reported that macrophages,
Japan

© 2016 Okamoto et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Okamoto et al. Journal of Intensive Care (2016) 4:23 Page 2 of 8

monocytes, and neutrophils are a source of TF in sepsis to-cell signaling and activates proinflammatory pathways
animal models and participate in the direct activation of [27]. When released into the extracellular space, it elicits
the coagulation cascade in the early phases of sepsis the production of inflammatory cytokines [25], which
[18–20]. We also showed that activated factor X (FXa), further augment the release of HMGB1 into the extra-
which is involved in hemostasis, thrombogenesis, inflam- cellular space [28]. The recent published findings by Lu
mation, and cellular immune responses, induces TF et al. [29] demonstrate that hyperacetylated HMGB1 is a
expression in human peripheral monocytes and, con- novel biomarker for pyroptosis, though necrosis-induced
versely, that inhibition of FXa activity reduces TF ex- HMGB1 release is not acetylated. Moreover, tissue dam-
pression in an experimental model of rat endotoxemia age induces the release of HMGB1 with all-cysteines re-
[21]. Our results indicate that FXa directly modulates TF duced, whereas this form of HMGB1 does not stimulate
expression and that both inflammation and coagulation cytokine release; it recruits leukocytes to the site of in-
play an important role in DIC due to sepsis. Develop- jury. And during infection or later stage of injury,
ment of a procoagulant state in sepsis, due to aberrant HMGB1 released is acetylated or disulfide-bonded, and
expression of tissue factor (TF) and sharp decrease of its it stimulates cytokine release [30]. The various functions
major inhibitor tissue factor pathway inhibitor (TFPI), of HMGB1 are shown in Fig. 1.
could lead to microthrombotic organ failure [22]. TFPI Recently, PAMPs and DAMPs in early phase of sepsis
is a major inhibitor of the TF-FVIIa-initiated coagulation trigger tissue factor expression on monocytes and neu-
in vivo. Tang et al. [22] and Gando S et al. [23] suggested trophil extracellular trap (NET) release by neutrophils,
that during early sepsis, the available TFPI might not ad- promoting immunothrombosis. Although immuno-
equately balance the increased TF-dependent coagula- thrombosis plays a role in early host defense against bac-
tion activation. Moreover Tang et al. suggested that terial dissemination, uncontrolled immunothrombosis
plasmin might be partly responsible for proteolytic deg- may also lead to DIC [31]. Besides, recent studies have
radation of TFPI in the early stages of sepsis. identified histones, the most abundant proteins in the
In addition to inflammatory cytokines, other factors nucleus, as a new class of DAMPs [32–35]. Extracellular
have recently been shown to mediate the lethal late histones promote neutrophil migration, platelet aggrega-
phase of sepsis; these factors include tumor necrosis fac- tion, and endothelial cell death [32, 36, 37]. Histones
tor (TNF)-α, IL-1, high-mobility group box-1 (HMGB1) have been detected in the plasma of mice, baboons, and
protein, and nuclear architectural chromatin-binding human patients with sepsis and trauma, and the total
protein [24]. HMGB1 is secreted by activated monocytes concentration of histones can reach 70, with that of
and macrophages [25] and released from necrotic or histone H3 reaching 15 μg/ml [32, 38]. Nakahara et al.
damaged cells [26]. Extracellular HMGB1 mediates cell- suggested that extracellular histones cause massive

Fig. 1 The various functions of HMGB1 in sepsis. HMGB1 is actively secreted from macrophages and monocytes, which are activated by inflammatory
cytokines, and it is also passively released from necrotic cells. HMGB1 may then cause activation of phagocytic cells, resulting in production of
pro-inflammatory mediators and chemokines. HMGB1 binds to RAGE on endothelial cells. And endothelial cells express RAGE, adhesion molecules, TNF-α,
chemokines, PAI-1, and promote down regulation of TM. RAGE receptor for advanced glycation end-products, IL interleukin, TNF tumor necrosis
factor, PAI-1 plasminogen activator inhibitor-1, DIC disseminated intravascular. Coagulation, SIRS systemic inflammatory response syndrome, MAP
mitogen-activated protein
Okamoto et al. Journal of Intensive Care (2016) 4:23 Page 3 of 8

thromboembolism associated with consumptive coagu- platelet count, and levels of fibrin-related markers, pro-
lopathy, which is diagnostically indistinguishable from vide important information about the degree of coagula-
DIC and that rTM binds to histones and neutralizes the tion factor activation and consumption.
prothrombotic action of histones [39]. A mechanism of Examination of DIC scores (based on the JMHLW cri-
DIC and MOF due to sepsis are shown in Fig. 2. teria) at the beginning of DIC treatment showed that
Moreover, if the severity of the infectious disease is the greater treatment efficacy was achieved in pre-DIC than
same, coagulopathy of infectious disease in surgically pa- in DIC patients [45]. Outcome worsened as the DIC
tients is increased by addition of the coagulation dis- score increased, thus suggesting that both early diagnosis
order due to surgical stress (Fig.3). In treatment of basic and early treatment of DIC are important. To define the
disease, the surgeons and intensivists must take that co- pre-DIC state, we prospectively evaluated global coagu-
agulopathy of the surgical stress deteriorates DIC tem- lation tests, hemostatic molecular markers, and the on-
porarily into consideration. set of DIC within a week after registration [46]. The
levels of D-dimer and FMC were significantly lower in
Diagnostic criteria of septic DIC patients with pre-DIC than in those without DIC,
Different diagnostic criteria of septic DIC have been whereas there were no significant differences in the
established by the International Society on Thrombosis levels of thrombin-antithrombin complex (TAT),
and Haemostasis [40], the Japanese Ministry of Health, plasmin-α2plasmin inhibitor complex (PIC), antithrom-
Labor and Welfare (JMHLW) [41], and the Japanese bin (AT), and thrombomodulin (TM). However, no
Association of Acute Medicine (JAAM) [42]. markers that provided an appropriate cutoff value for
Although the criteria of the JAAM are the most spe- differentiating between “pre-DIC” and “without DIC” (as
cific for septic DIC [42, 43], a prospective study in Japan do DIC scores) were identified.
found no significant differences in the odds ratios for
prediction of DIC outcomes calculated on the basis of Treatment of septic DIC
these three diagnostic criteria [44]. As the mortality rate Common sense dictates that administration of an anti-
of DIC is still high, early diagnosis and treatment are biotic that specifically targets the infection is the most
required. important therapy in septic DIC. After administering an-
tibiotics, surgical drainage at the infection site should be
Laboratory tests performed as soon as possible. Physicians should first
Screening assays (global coagulation tests) using scoring administer treatment for the underlying disease when
parameters, such as prothrombin time, fibrinogen level, sepsis is diagnosed [4, 8].

Fig. 2 A mechanism of DIC and MOF due to sepsis. When the pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and
damage-associated molecular patterns (DAMPs) act on monocytes via TLR and on neutrophils, a reactivated monocyte produce TF, various inflammatory
cytokines, and HMGB1, and moreover, detection of PAMPs and DAMPs trigger neutrophil extracellular traps (NETs) release by neutrophils, promoting
immunothrombosis. The uncontrolled immunothrombosis may lead to disseminated intravascular coagulation. And HMGB1 acts on EC and promotes
upregulation of TF and downregulation of TM from EC, resulting endothelial cell injury, and microcirculation disorder develops DIC and MOF. TF tissue
factor, TM thrombomodulin, TLR Toll-like receptor, IL-1β interleukin-1β, TNF-α tumor necrosis factor-α, EC endothelial cell, HMGB1 high-mobility group
box protein 1, PAI plasminogen activator inhibitor, MOF multiple organ failure, NETs neutrophil extracellular traps
Okamoto et al. Journal of Intensive Care (2016) 4:23 Page 4 of 8

Fig. 3 Effect of surgical stress for coagulopathy (DIC) due to infection. If the severity of the infectious disease is the same, coagulopathy of
infectious disease in surgically patients is increased by addition of the coagulation disorder due to surgical stress. In the treatment of infection
control, the surgeons and intensivists must take that coagulopathy of the surgical stress deteriorates DIC temporarily into consideration

Antithrombin receive AT. This finding suggests that moderate doses of

AT is a single-stranded glycoprotein with a molecular AT (30 IU/kg per day) improve DIC scores, thereby in-
weight of ca. 59,000. It is synthesized in the liver and in- creasing the recovery rate without any risk of bleeding
hibits the activity of thrombin and activated factors X, in patients with septic DIC.
IX, VII, XI, and XII [47]. Extensive clinical studies have Tagami et al. [62] performed an analysis using infor-
been performed in patients with severe sepsis [48–53] to mation collected from a nationwide administrative data-
determine the appropriate dose of AT. Twenty-eight base in Japan. Patients with severe pneumonia and DIC
days of AT treatment did not improve the survival rate (n=9075) were divided into an AT group (n=2663) and a
in the KyberSept trial [48], which was a multicenter, control (no AT) group (n=6412). Propensity score
double-blind phase III study that included 2314 patients matching created a matched cohort of 2194 paired pa-
with severe sepsis (a total of 30,000 IU of AT was ad- tients who did or not receive AT treatment. The 28-day
ministered over 4 days). However, in a subgroup ana- mortality rate was 9.9 % lower in the AT group than in
lysis, an improvement in the survival rate on day 90 was the control group. Multiple logistic regression analyses
observed in patients not receiving concomitant heparin showed an association between AT use and the 28-day
treatment; this finding agrees with the results of previous mortality rate (adjusted odds ratio, 0.85).
phase II studies supporting the efficacy of AT [54–58]. A
recent Japanese study by Iba et al. [59] used a nonrando- Heparin
mized, multi-institutional, post-marketing survey to deter- The British guidelines recommend the use of unfractio-
mine the optimal AT dose for treating septic DIC. They nated heparin (UFH) because of its short half-life and
reported survival rates of 65.2 % in patients receiving availability of antagonists, especially in patients at a high
1500 IU/day and 74.7 % in patients receiving 3000 IU/day. risk of bleeding. Japanese guidelines indicate a prefer-
A logistic regression analysis showed that the higher dose ence for low molecular weight heparin because it proved
(3000 IU/day) was associated with a better survival out- superior in improving coagulation abnormalities and
come [59]. A second survey, in which the baseline AT caused fewer hemorrhagic adverse events in a random-
levels in patients with septic DIC were less than 40 %, ized controlled trial (RCT) conducted in DIC [63]. In
showed a significantly higher rate of DIC resolution and a the HETRASE (A Randomized Clinical Trial of Unfrac-
better survival outcome in patients receiving 3000 IU/day tioned Heparin for Treatment of Sepsis) study [64], the
compared with those receiving 1500 IU/day [60]. The ratio results of which were reported after publication of the
of bleeding events in the two groups was not significantly guidelines, and the efficacy of UFH for sepsis was de-
different. nied. Zarychanski R et al. [65] reported that the risk haz-
We conducted a prospective, randomized, controlled ard ratio for death associated with the use of heparin in
multicenter trial for DIC patients with sepsis and AT septic patients was 0.88 (95 % confidence interval (CI),
levels of 50 to 80 % to test the hypothesis that concen- 0.77–1.00; I2 = 0 %). In addition, Wang et al. [66] also re-
trated administration of AT improves DIC, resulting in ported a decreased mortality associated with heparin use
faster recoveries and better outcomes [61]. Patients re- (odds ratio = 0.656, 95 % CI = 0.562–0.765, P < 0.0001).
ceiving AT for 3 days had significantly lower DIC scores Moreover, Iba et al. [67] reported that both UFH and
and higher recovery rates than did those who did not LMWH attenuated the toxicity of histone H3, in vivo as
Okamoto et al. Journal of Intensive Care (2016) 4:23 Page 5 of 8

well as in vitro, and that the effects of heparins shown in use of recombinant TM may therefore be beneficial for
ex vivo study were independent of their anticoagulant ef- treatment of septic patients.
fect. They suggested that the administration of heparin In a Japanese phase III randomized control trial (RCT)
could become a treatment of choice for patients suffer- in which 227 DIC patients with 125 hematological ma-
ing from severe sepsis. lignancies and 102 infections (sepsis) received recombin-
ant TM or unfractionated heparin (UFH), the rate of
Thrombomodulin resolution of DIC was 66.1 and 49.9 %, respectively [74].
TM is an endothelial anticoagulant cofactor that plays The rate of disappearance of bleeding was 35.2 % in the
an important role in the regulation of intravascular co- recombinant TM group and 20.9 % in the UFH group,
agulation [68]. It accelerates the thrombin-catalyzed and the 28-day mortality rate was 28.0 and 34.6 %, re-
conversion of protein C to activated protein C, which in- spectively. In an analysis of 80 patients with infectious
hibits monocyte and macrophage activation [69, 70] and DIC, the rate of resolution of DIC was 63.2 % in the
consequently suppresses the production of inflammatory UFH group and 73.2 % in the recombinant TM group
cytokines such as TNF-α and IL-1β [70]. In addition, re- [75]. In an international phase II RCT of 750 septic pa-
cent studies have shown that TM binds to HMGB1 to tients with suspected DIC, the 28-day mortality rate
prevent its interaction with the receptors for advanced was 17.8 % in the recombinant TM group and 21.6 %
glycation end-products [71]. We reported that TM not in the placebo group [76]; there was a tendency toward
only binds HMGB1 but also aids the proteolytic cleavage a low rate in the TM group, although the difference
of HMGB1 by thrombin [72]. These findings highlight was not significant (P = 0.273). An international phase
the novel anti-inflammatory actions of TM. III clinical trial evaluating the efficacy of TM in pa-
We investigated the effects of soluble recombinant hu- tients with severe sepsis and coagulopathy is ongoing in
man TM on the production of inflammatory cytokines the USA, South America, Asia, Australia, the European
and the plasma level of HMGB1 in an experimental Union, and other countries (https://clinicaltrials.gov/ct2/
endotoxemia model [73]. Endotoxemia was induced in show/NCT01598831?term=ART-123&rank=2).
rats via a bolus intravenous injection of 4 mg/kg lipo- On the other hand, Tagami et al. [77] found that re-
polysaccharide (LPS). Recombinant TM (1 mg/kg) was combinant TM was not an effective treatment for
administered as a bolus injection 30 min before or 4 h sepsis-associated DIC following severe pneumonia. This
after LPS. LPS increased the plasma levels of TNF-α and conclusion was based on propensity scores and an in-
IL-1β, which peaked at 1 and 3 h, respectively, and over strumental variable analysis of information obtained
time, the plasma levels of HMGB1. Even when its ad- from the Japanese Diagnosis Procedure Combination
ministration was delayed, recombinant TM markedly (JDPC) inpatient database, a nationwide administrative
inhibited the LPS-induced increase in plasma levels of database. No significant difference in the 28-day mortal-
HMGB1 (Fig. 4) and the thrombin-AT complex, as well ity rate was documented between the two groups in a
as the increase in liver dysfunction and mortality. The propensity-matched analysis.

Fig. 4 Effect of rTM on the plasma levels of HMGB1. Temporal changes in plasma HMGB1 concentrations after injection of lipopolysaccharide
(LPS). Rats were given saline plus LPS (closed squares); pretreatment of recombinant human soluble thrombomodulin (rTM), LPS plus saline (closed
circles); or saline, LPS plus delayed treatment of rTM (closed triangles). All data represent the mean and SEM (n = 6 per group). [73] *P < 0.05 (vs.
the LPS group). #P < 0.01 (vs. the LPS group). rTM recombinant thrombomodulin
Okamoto et al. Journal of Intensive Care (2016) 4:23 Page 6 of 8

We also evaluated the efficacy of recombinant TM for Received: 23 November 2015 Accepted: 4 March 2016
DIC using the JDPC database [78–80]. We found that
the frequency of use of AT, heparin, and protease inhibi-
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