International Journal of Clinical Medicine, 2013, 4, 488-495
Published Online November 2013 (http://www.scirp.org/journal/ijcm)
http://dx.doi.org/10.4236/ijcm.2013.411086
Open Access IJCM
The Concept Study of Recombinant Human Soluble
Thrombomodulin in Patients with Acute Respiratory
Distress Syndrome
Kenji Tsushima1,3*, Toshiki Yokoyama2, Tomonobu Koizumi2, Keishi Kubo2, Koichiro Tatsumi3
1Department of Pulmonary Medicine, Shinonoi General Hospital, Nagano, Japan; 2First Department of Internal Medicine, Shinshu
University School of Medicine, Nagano, Japan; 3Department of Respirology, Graduate School of Medicine, Chiba University, Chiba
Japan.
Received August 27th, 2013; revised September 28th, 2013; accepted October 15th, 2013
Copyright © 2013 Kenji Tsushima et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: Recombinant human soluble thrombomodulin (rhTM) was approved for the treatment of disseminated
intravascular coagulation in Japan, and rhTM has anti-inflammatory effects. Disordered coagulation is a part of the
acute respiratory distress syndrome (ARDS) pathophysiology and thus we hypothesize that anticoagulant therapy may
help. This preliminary study was to observe the safety of rhTM administration and the improvement on biomarker lev-
els after the therapy for ARDS-patients. Objectives: Case series of ARDS-patients. Methods: Seventeen ARDS-pa-
tients that required ventilatory management were treated with rhTM and clinical and laboratory data were collected in-
cluding platelets, thrombin-antithrombin complex (TAT), fibrinogen degradation products, oxygen saturation/the frac-
tion of inspired oxygen (SpO2/FIO2), and high-mobility group-1 (HMG-1). The administration of rhTM was started dur-
ing 6 days at a bolus dose of 0.06 mg/kg/day immediately after the diagnosis of ARDS. Results: Eleven of the 17
ARDS-patients were alive at 28 days after the beginning of the administration of rhTM. The serial pattern of the
SpO2/FIO2 showed remarkable differences between the survivors and nonsurvivors from day 5 to day 7. The TAT in the
survivors significantly decreased after treatment, and there were significantly lower levels in the TAT on day 7 in com-
parison to that of the nonsurvivors. The serial changes of HMG-1 showed increased levels in the nonsurvivors until day
5 after the administration of rhTM. Conclusions: Additional rhTM administration can safely improve the parameters in
survival ARDS-patients, as demonstrated by significant improvements in the SpO2/FIO2, HMG-1 and TAT.
Keywords: Acute Respiratory Distress Syndrome; Recombinant Human Soluble Thrombomodulin;
Thrombin-Antithrombin Complex; SpO2/FIO2; High-Mobility Group-1
1. Introduction
Thrombomodulin (TM) is a transmembrane protein ex-
pressed on the endothelial cell surface that plays an im-
portant role in the regulation of intravascular coagulation
[1]. The novel biological agent, recombinant human
soluble thrombomodulin (rhTM), was approved and is
being used clinically for the treatment of disseminated
intravascular coagulation (DIC) in Japan. The effects of
rhTM on DIC were previously examined in a multicenter,
randomized clinical trial in Japan [2], and the resolution
of DIC was significantly better in the group treated with
rhTM than in the group treated with unfractionated heap-
rin. The rhTM binds to thrombin to inactivate coagula-
tion, and the thrombin-rhTM complex activates protein C
to produce activated protein C (APC), which, in the
presence of protein S, inactivates factors VIIIa and Va,
thereby inhibiting the further thrombin formation.
Acute respiratory distress syndrome (ARDS) is also
characterized by excessive intra-alveolar fibrin deposi-
tion, driven at least partly by inflammation [3]. The im-
balance between the activation of coagulation and inhibi-
tion of fibrinolysis in patients with ARDS appears to
occur both systemically in the lungs and the alveoli [4].
The activation of tissue factor (TF) is a critical event that
results in thrombin formation. Thrombin is a key inter-
mediate molecule with several biological functions, in-
*Corresponding author.

The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory
Distress Syndrome
489
cluding the augmentation of vascular permeability [5]
and enhancement of inflammation [6]. Thrombin genera-
tion leads to fibrin polymerization and deposition, with
the resultant formation of hyaline membranes and a pa-
thological hallmark of ARDS. The modulation of coagu-
lation and fibrinolysis has a complex effect on both he-
mostatic and inflammatory pathways. Therefore, antico-
agulation therapy is beginning to be recognized as a po-
tential new strategy for the treatment of ARDS patients.
The aim of the present preliminary study was to evalu-
ate whether the additional administration of rhTM has
the improvement in biomarker levels with the onset of
therapy between survival and nonsurivival patients with
ARDS.
2. Methods
Our study was approved by the ethics committee of Shi-
nonoi General Hospital, and all patients or their family
gave written informed consent on admission. We per-
formed a prospective study of adult patients with ARDS
who were admitted between April 2010 and September
2012. Our clinical study was registered to Shinonoi Gen-
eral Hospital, Chikuma Central Hospital and Shinshu
University School of Medicine.
3. The Diagnosis of ARDS
The criteria for the diagnosis of ARDS, as set by the Ber-
lin Definition [7], were used as follows: acute onset of
lung injury, diffuse bilateral infiltrates seen upon chest
X-ray, a PaO2/FIO2 (PF) ratio for ARDS, pulmonary ar-
tery occlusion pressure <19 mmHg, or no clinical evi-
dence of congestive heart failure. To rule out congestive
heart failure, we performed echocardiographic examina-
tions. Enrolled patients were diagnosed as having ARDS
on admission.
4. Noninvasive Ventilation and Endotracheal
Intubation
Enrolled patients were performed chest X-ray on admis-
sion. All patients initially received oxygen via a nasal
cannula to maintain an oxygen concentration of more
than 60 mmHg. If they could not maintain oxygen satu-
ration (SpO2) of more than 90% or an oxygen concentra-
tion (PaO2) of more than 60 mmHg with 3 - 5 L/ minute
of oxygen via the nasal cannula, we recommended non-
invasive ventilation (NIV) with an oronasal mask and
bi-level positive airway pressure ventilation (BiPAP)
with a BiPAP Vision device (Respironics; Murrysville,
PA). All patients received NIV with the bilevel mode at a
maximal positive pressure of 30 cmH2O. The spontane-
ous timing mode was used for all patients, with a back-up
rate of 10 breaths/minute. Inspiratory positive airway
pressure (IPAP) was commenced at 4 cm H2O, and ad-
justed to achieve a respiratory rate of less than 30
breaths/minute. The expiratory positive airway pressure
(EPAP) was adjusted to achieve the target level of oxy-
genation with minimum carbon dioxide rebreathing. The
oronasal mask or full face mask was fitted by a trained
pulmonologist. Straps were adjusted to allow one finger
to pass easily between the strap and the patient’s face.
The fraction of inspired oxygen (FIO2) and IPAP were
adjusted to maintain a SpO2 of more than 90% or a PaO2
of more than 60 mmHg.
Initial settings for NIV were chosen empirically by the
attending pulmonologists. Patients were initiated on
IPAP of 4 cmH2O and a FIO2 of 100%, after which the
NIV was titrated by the pulmonologist to maintain pa-
tient comfort and to keep the respiration rate at <35
breaths/minute, pH >7.3, and oxygen saturation >90%.
If the patients could not maintain an oxygen saturation
of more than 90% or an arterial oxygen concentration of
more than 60 mmHg with the BiPAP Vision at 2 hours
and 24 hours after initiation of NIV, we recommended
endotracheal intubation. Endotracheal intubation was
performed for patients with decreased alertness or major
agitation requiring sedation, clinical signs of exhaustion
(active contraction of the accessory muscles with para-
doxical abdominal or thoracic motion), hemodynamic
instability, cardiac arrest, refractory hypoxemia, or a
PaO2/FIO2 (PF) ratio of less than 100 after treatment with
NIV. When an improvement of the respiration rate and a
decrease of the oxygen requirement became evident, the
patients were gradually weaned off ventilation during the
daytime and then during sleeping hours. Patient or family
refusal of invasive mechanical ventilation was an exclu-
sionary criterion for endotracheal intubation. These pa-
tients were excluded from this study.
5. Treatment
Standard microbiological investigations (e.g., blood and
sputum cultures) were performed before the start of
treatment to exclude pulmonary infection. Bronchoal-
veolar lavage (BAL) was performed at admission, except
in patients with refractory hypoxaemia despite sufficient
mechanical ventilation, those with hemodynamic insta-
bility, and those who rejected BAL. BAL fluid was as-
sessed to exclude infectious disease. The administration
of rhTM (recomodulin®) was started during 6 days at a
bolus dose of 0.06 mg/kg/day. Microbiological investiga-
tions (e.g., blood and sputum cultures) were performed
before the start of antibiotic therapy. The exclusion of
this study was done on suspicion of infection at admis-
sion when the microbiological cultures were assessed as
positive. Broad-spectrum antibiotics were then adminis-
tered until the offending pathogen was identified for all
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The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory
Distress Syndrome
490
ARDS patients.
6. Data Collection
rhTM administration can use for 6 days, and is effective
for acute phase of ARDS patients. Therefore, patients
were followed until 28 days after entry into the study.
Patients were defined as survivors and nonsurvivors if
they were alive or dead 28 days after beginning rhTM
treatment, respectively. The collected data were age, sex,
PF ratio, SpO2/FIO2, Sequential Organ Failure Assess-
ment (SOFA) score and DIC score on admission. We
evaluated the 28-day mortality after admission, and the
physiological and biochemical variables. White blood
cell counts (WBC, normal range: 4000-9000/μL), platelet
counts (normal range: 14 - 30 × 104/μL), the serum lac-
tate dehydrogenase level (LDH, normal range: 120 - 235
IU/L), fibrinogen degradation products (FDP, normal
range: less than 5 μg/mL), and C-reactive protein (CRP,
normal range: less than 0.3 mg/dl) were recorded on days
0 (before), 1, 2, 3, 5, and 7 after admission. The Krebs
von den Lungen-6 (KL-6, normal range: less than 500
U/mL) and thrombin-antithrombin complex (TAT, nor-
mal range: less than 4 ng/ml) values were recorded on
days 0 (before), and 7 after admission. Cytokines (inter-
leukin-6 (IL-6, normal range: less than 4.0 pg/mL), and
high-mobility group-1 (HMG-1) protein were measured
on days 0 (before), 1, 3, and 7 after starting the treatment.
The presence of serious adverse events was defined as
follows: fatal bleeding, nonfatal serious bleeding (de-
fined as intracranial hemorrhage confirmed by brain im-
aging, gastrointestinal or respiratory tract bleeding un-
controllable by conservative treatments, and bleeding at a
critical location, such as retinal hemorrhage, major he-
marthrosis or spinal hemorrhage) or any life-threatening
bleeding that led to discontinuation of the administered
study drug. The SpO2/FIO2 ratio was calculated at 1 hour
and on days 1, 2, 3, 5, and 7 after initiation of NIV on
behalf of the PF ratio.
7. Outcomes
The primary outcome was whether rhTM administration
was safe treatment without adverse events for ARDS
patients. The secondary outcome is whether the addi-
tional administration of rhTM has a beneficial effect in
biomarker levels with the onset of therapy for patients
with ARDS.
8. Statistical Analysis
The data are expressed as the group means plus or minus
the standard error. Continuous variables were compared
between groups by using Student’s t-tests. Categorical
variables were analyzed by using Fisher’s exact test. A
univariate analysis of the time to mortality was compared
by using a log-rank test. The comparisons of the WBC
and platelet counts, CRP, FDP, LDH, SpO2/FIO2, IL-6,
and HMG-1 between groups over time were analyzed by
repeated measure analysis of variance (ANOVA) ad-
justed for the baseline values as a covariate. A p value <
0.05 was considered to be statistically significant.
9. Results
9.1. Baseline Characteristics
Seventeen patients with ARDS were enrolled. The etiol-
ogy of ARDS patients was 12 direct ARDS including 3
aspiration pneumonias and 5 indirect ARDS patients with
sepsis. The bacteria or fungus in the BAL were not de-
tected. Their mean age was 75.5 ± 19.9 years. Enrolled
ARDS patients were included in 1 mild ARDS, 12 mod-
erate ARDS and 4 severe ARDS patients. Table 1 show-
ed that thrombosis showing elevated plasma TAT and
FDP levels in the pulmonary vasculature due to lung in-
flammation was present in patients with ARDS.
9.2. The Effects of Treatment on Mortality
The 28-day mortality rate was 35.3%. The cause of death
among the patients who died was the deterioration of
ARDS. Enrolled patients were classified into survivors
and nonsurvivors at 28 day after administration of rhTM.
Table 1 showed that endotracheal intubation was re-
quired for13 with ARDS, and NIV was performed for 4
patients with ARDS. Nonsurvivors showed significantly
increased levels of TAT on admission compared to that
of survivors (P = 0.0081). Five of the 6 nonsurvivors
showed high levels of serum KL-6 on admission, without
fibrosis and traction bronchiectasis on chest HRCT.
ARDS patients were classified into high KL-6 (abnormal
levels, more than 500 U/mL) and normal KL-6 sub-
groups according to their serum KL-6 levels on admis-
sion. There was a significant difference in the mortality
rate between normal KL-6 and high KL-6 groups (P=
0.005) (Figure 1).
9.3. The Effects of Treatment on the Clinical
Data in the Patients with ARDS
In the serial changes in survivors, there was a significant
difference in the WBC counts (Figure 2(a)) on days 5
and 7 as compared to that in nonsurvivors (P = 0.024 and
0.0076, respectively). There were no significant differ-
ences in the serial changes in the CRP (Figure 2(b)) and
LDH (Figure 2(c)) from before treatment until day 7 be-
tween the two groups. The SpO2/FIO2 (Figure 2(d)) rap-
idly increased on 1hour in survivors, and increased from
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The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory
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491
Table 1. Characteristics on admission.
Survivor (n = 11) Nonsurvivor (n = 6) P value
Age (years) 73.7 ± 4.3 77.2 ± 1.2 0.66
Sex, M/F 8/3 4/2 0.40
Mild ARDS 1 0
Moderate ARDS 8 4
Severe ARDS 2 2
Direct/Indirect 7/4 5/1 0.39
Infectious/Noninfectious 8/3 6/0 0.16
WBC (/μL) 15216 ± 1232 15640 ± 1181 0.77
Platelet (x104/μL) 15.2 ± 2.4 20.1 ± 3.9 0.52
Fibrinogen (mg/dL) 397 ± 45.7 501 ± 76.8 0.57
PT(sec) 1.15 ± 0.02 1.68± 0.10 0.22
APTT (sec) 29.9 ± 0.29 41.5 ± 1.2 0.038
FDP (μg/mL) 45.2 ± 4.4 164 ± 39.1 0.16
TAT (ng/mL) 22.7 ± 2.1 49.6 ± 2.6 0.0081
LDH (IU/L) 468 ± 45.1 866 ± 109 0.16
CRP (mg/mL) 13.2 ± 2.3 17.7 ± 2.0 0.46
KL-6 (U/mL) 403 ± 62.4 656 ± 46.8 0.26
SOFA score 8.1 ± 0.3 7.8 ± 0.6 0.81
DIC score 5.5 ± 0.3 5.2 ± 0.6 0.82
PF ratio (mmHg) 145 ± 8.5 107 ± 5.3 0.14
SpO2/FIO2 (%) 155 ± 9.3 142 ± 6.6 0.44
Intubation/NIV (n) 9/2 4/2 0.40
AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; ARDS, acute respiratory distress syndrome; M, male; F, female; WBC, w8hite blood cell; PT,
prothrombin time; APTT, activated partial thromboplastin time; FDP, fibrinogen degradation products; TAT, thrombin-antithrombin complex; LDH, lactate
dehydrogenase; CRP, C-reactive protein; KL-6, Krebs von den Lungen-6; SOFA, Sequential Organ Failure Assessment; DIC, disseminated intravascular co-
agulation; PF, PaO2/FIO2; NIV, noninvasive ventilation.
Figure 1. A comparison of the survival curves. The survival
curves of normal KL-6 ARDS and high KL-6 ARDS pa-
tients. The ARDS patients were classified into high KL-6
and normal KL-6 groups on the basis of their initial serum
KL-6 levels. There was a significant difference in the mor-
tality rate between normal KL-6 and high KL-6 patients (P
= 0.045). ＊P < 0.05 compared to the high KL-6 ARDS
group. KL-6, Krebs von den Lungen-6.
day 3 in survivors, and continued to improve until day 7.
There was a significantly higher SpO2/FIO2 in survivor
compared to that of nonsurvivors on day 5 and 7 after
treatment (P = 0.049 and 0.046, respectively).
9.4. The Effect of Treatment on the Coagulation
Data in the Patients with ARDS
The serial changes of coagulation data in the patients
with ARDS are shown in Figure 3. There were no sig-
nificant differences in the serial changes in the platelet
counts (Figure 3(a)) and fibrinogen (Figure 3(b)) be-
tween the two groups. The serial changes of the FDP in
nonsurvivors were tended to be higher than those of sur-
vivors (Figure 3(c)).There was a significant difference in
the serial change of the fibrinogen and TAT in survivors
(Figures 3(b) and 3(d)) (P = 0.015 and 0.039, respec-
tively) on day 7 compared to the initial data. In survivors,
TAT showed significantly lower levels in comparison to
that of nonsurvivors on admission and on day 7 after
treatment of rhTM (P = 0.0081 and 0.0089, respectively).
9.5. Cytokine Levels after the Administration of
rhTM
The serum IL-6 (Figure 4(a) decreased in survivors, and )

The Concept Study of Recombinant Human Soluble Thrombomodulin in Patients with Acute Respiratory
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492
Figure 2. The serial changes of the WBC count, CRP, LDH and SpO2/FIO2. The data are expressed as the group means ±
standard error of the mean. (a) The serial changes of the WBC count in survivor were significant difference on day 5 and 7 in
comparison to nonsurvivor. (b) There were not significant differences in the change of the CRP level between two groups. (c)
There were no significant differences in the changes in the LDH level between the two groups. (d) The SpO2/FIO2 increased
from day 3 in survivor, and continued to improve until day 7. There was a significantly higher SpO2/FIO2 in survivor com-
pared to that of nonsurvivor on day 5 and 7 after treatment. *P < 0.05 compared to the nonsurvivor, †P < 0.05 compared to
before treatment. WBC, white blood cell; CRP, c-reactive protein; LDH, lactate dehydrogenase; SpO2/FIO2, oxygen satura-
tion/the fraction of inspired oxygen.
was closer to the initial levels in nonsurvivors. The IL-6
level in survivor on day 7 was significantly decreased
compared to the initial level (P = 0.019). The serial
changes of HMG-1 (Figure 4(b)) showed increased lev-
els in nonsurvivors until day 7 after administration of
rhTM. On day 7, the HMG-1 level in nonsurvivors was
significantly higher compared to the initial level in non-
survivosr and the level on day 7 in survivors (P = 0.011
and 0.0002, respectively). Serum KL-6 on day 7 in sur-
vivor was a significantly lower level than that of nonsur-
vivor (P = 0.027), and serum KL-6 on day 7 in nonsur-
vivors was a significant higher levels than that on admis-
sion (P = 0.049).
9.6. Adverse Events
No adverse events according to bleeding had after the
administration of rhTM. There were no other potential
adverse events, such as liver, renal function, or cardio-
vascular systems.
10. Discussion
Our present study suggests that activated intravascular
coagulation disturbances occurred in ARDS patients be-
cause of elevated levels of plasma FDP and TAT. The
modulation of the coagulation disturbance by our con-
ventional therapy with rhTM administration may be re-
lated to the mortality of ARDS patients, because the se-
rial changes in the fibrinogen and plasma TAT, and the
SpO2/FIO2 level showing the respiratory conditions sig-
nificantly increased in ARDS patients. We found addi-
tional rhTM administration appeared to be safe, without
any major adverse effects.
TF expression, a key mediator of the activation of co-
agulation in the lungs, and fibrin deposition, were de-
tected by the presence of specific antibodies in the al-
veolar space and the pathogeesis of the early phase of n
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Figure 3. The serial changes in the coagulation data. The data are expressed as the group means ± standard error of the mean.
(a) There were no differences in the serial changes in the platelet counts between the two groups. (b) There was a significantly
lower level in nonsurvivor compared to that on day 7 after treatment. (c) There were no differences in the serial changes in
the plasma FDP between the two groups. (d) The plasma TAT showed significantly lower levels in survivors before the ad-
ministration of rhTM. On day 7, the plasma TAT level in survivors was significantly lower that the initial level and the level
of nonsurvivors *P < 0.05 compared to the nonsurvivor, †P < 0.05 compared to before treatment. FDP, fibrinogen degradation
products; TAT, thrombin-antithrombin comple x.
ARDS [3]. The imbalance between the activation of co-
agulation and inhibition of fibrinolysis in patients with
ARDS appears to occur both systemically and in the al-
veolar space. Therefore, rhTM, which can modulate the
coagulation pathway, such as the protein C pathway and
the antithrombin pathway, may be useful for the treat-
ment of ARDS.
The use of activated protein C for ARDS patients,
however, was a negative trial [8]. The rhTM plays an
important role in regulating not only coagulation, but
also inflammation, under conditions of sepsis. Two dif-
ferent mechanisms have been described for the antico-
agulant effects of rhTM [1,9]. Thrombin is one of the key
molecules involved in coagulation, and has several bio-
logical functions, including augmentation of vascular
permeability [5] and enhancement of inflammation [6].
Thrombin formation leads to fibrin polymerization and
deposition, with resultant formation of hyaline mem-
branes, a pathological hallmark of ARDS. Direct binding
of rhTM to thrombin can lead to its disruption. Therefore,
the major mechanism of rhTM binding to thrombin is a
pathway through the production of activated protein C.
Recently, another mechanism underlying the anti-in-
flammatory effect has been reported, wherein the N-ter-
minal lectin-like domain of rhTM sequesters and cleaves
HMG-1, which is released from necrotic cells and
modulates several signals that induce a proinflammatory
response leading to severe cell damage [10-12] and by
lipopolysaccharide in the plasma in an experimental en-
dotoxin model [11]. Nagato et al. reported that rhTM
inhibits the production of inflammatory cytokines, de-
creases the plasma HMG-1 levels and reduces the mor-
tality in experimental endotoxemia in rats [13]. In the
present study, the levels of serum IL-6, as inflammatory
cytokines, were significantly increased in non-survivors
on day 7 after administration of rhTM, and the HMG-1 in
non-survivors could not be suppressed by increasing the
administration of rhTM. Supporting their poorer progno-
sis, Abraham et al. described that an increase in HMG-1
may be related to the development of lung inflammation,
resulting in mortality [14]. Moreover, the mortality of
ARDS patients was related to the development of fibrosis
related to the increased levels of serum KL-6 [15]. In our
study, serum KL-6 level was related to the mortality and
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Figure 4. The serial changes in the inflammatory cytokines and serum KL-6 in survivors and nonsurvivors. The data are
expressed as the group means ± standard error of the mean. The serum IL-6 (a) decreased until day 7 in survivor, and was
close to the initial levels in nonsurvivor compared to survivors. (b) The serial changes of HMG-1 showed increased levels in
nonsurvivor until day 7 after the administra tion of rhTM. On day 7, the HMG-1 level in nonsurvivor was significantly higher
that the initial level and the level of survivors. (c) on day 7, serum KL-6 levels in survivor showed significant lower compared
to that of nonsurvivor and serum KL-6 levels in nonsurvivor showed significant higher compared to before the administra-
tion of rhTM. *P < 0.05 compared to the nonsurvivor, †P < 0.05 compared to before treatment. IL-6, interleukin-6; HMG-1,
high-mobility group-1 protein; KL-6, Krebs von den Lungen-6.
therapeutic effects (Figures 1 and 4(c)). The six patients
who died in our study showed worse results in most of
the biomarker levels although they received the same
treatment as the survival ARDS patients. We interpret
them as a phenomenon of non-responders. As shown in
Figure 1, the oxygenation has been shown to be a sig-
nificant predictor of responders because of the deteriora-
tion of their lung parenchyma [16].
There were a few limitations to our preliminary study.
First, we could not obtain lung tissue specimens to con-
firm the existence of microvascular thrombus formation
in the lungs of ARDS patients before and after treatment.
We speculated that intra-alveolar thrombin formation and
fibrin deposition in the local alveoli occurs at the same
time as when the systemic thrombin formation develops
in blood. Second, the study involved a small number of
patients, and it was also a prospective study, not a ran-
domized trial. A double blind prospective study with a
substantially larger sample size is therefore needed to
further validate our findings to evaluate clinical outcome.
11. Conclusion
In conclusion, the additional administration of rhTM
improved the biomarker levels in patients with survival
ARDS, as demonstrated by significant improvements in
the SpO2/FIO2, HMG-1 and microvascular coagulation
and there was no adverse event. Further clinical investi-
gations such as survival outcome are necessary to evalu-
ate the effect of rhTM on ARDS patients.
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