Disseminated intravascular coagulation
at an early phase of trauma is associated
with consumption coagulopathy and
excessive fibrinolysis both by plasmin
and neutrophil elastase
Mineji Hayakawa, MD,a Atsushi Sawamura, MD,a Satoshi Gando, MD,a Nobuhiko Kubota, MD,a
Shinji Uegaki, MD,a Hidekazu Shimojima, MD,a Masahiro Sugano, MD,a and Masahiro Ieko, MD,b
Sapporo and Tobetsu, Japan
Background. The aims of the present study were to confirm the consumption coagulopathy of disseminated
intravascular coagulation with the fibrinolytic phenotype at an early phase of trauma and to test the
hypothesis that thrombin-activatable fibrinolysis inhibitor, neutrophil elastase, and plasmin contribute to the
increased fibrinolysis of this type of disseminated intravascular coagulation. Furthermore, we hypothesized
that disseminated intravascular coagulation at an early phase of trauma progresses dependently to
disseminated intravascular coagulation with a thorombotic phenotype from 3 to 5 days after injury.
Methods. Fifty-seven trauma patients, including 30 patients with disseminated intravascular
coagulation and 27 patients without disseminated intravascular coagulation, were studied prospectively. Levels of thrombin-activatable fibrinolysis inhibitor, tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin alpha2 plasmin inhibitor complex, D-dimer, neutrophil
elastase, and fibrin degradation product by neutrophil elastase were measured on days 1, 3, and 5 after
trauma. The prothrombin time, fibrinogen, fibrin/fibrinogen degradation product, antithrombin, and
lactate also were measured.
Results. Independent of the lactate levels, disseminated intravascular coagulation patients showed a
prolonged prothrombin time, lesser fibrinogen and antithrombin levels, and increased levels of fibrin/
fibrinogen degradation product on day 1. Disseminated intravascular coagulation diagnosed on day
1 continued to late-phase disseminated intravascular coagulation on days 3 and 5 after trauma.
Increased levels of tissue-type plasminogen activator plasminogen activator inhibitor-1 complex, plasmin
alpha2 plasmin inhibitor complex, D-dimer, neutrophil elastase, and fibrin degradation product by
neutrophil elastase but not thrombin-activatable fibrinolysis inhibitor were observed in the disseminated
intravascular coagulation patients. No correlation was observed between plasmin alpha2 plasmin
inhibitor complex and fibrin degradation product by neutrophil elastase in disseminated intravascular
coagulation patients. Multiple regression analysis showed the disseminated intravascular coagulation
score and the tissue-type plasminogen activator plasminogen activator inhibitor-1 complex levels on day
1 to correlate with the total volume of transfused blood. Patient prognosis deteriorated in accordance with
the increasing disseminated intravascular coagulation severity.
Conclusion. Disseminated intravascular coagulation at an early phase of trauma is associated with
consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase independent of hypoperfusion and continues to disseminated intravascular coagulation at a late phase of
trauma. Increased fibrinolysis requires more blood transfusions, contributing to a poor patient outcome.
(Surgery 2011;149:221-30.)
From the Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care
Medicine,a Hokkaido University Graduate School of Medicine, Sapporo; and Department of Internal Medicine,b School of Dentistry, Health Sciences University of Hokkaido, Tobetsu, Japan
Supported by Grants-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports, and Culture in Japan
(Grants 2007-19390456 and 2009-21249086).
Medicine, N17W5, Kita-ku, Sapporo 060-8638, Japan. E-mail:
[email protected].
Accepted for publication June 14, 2010.
Ó 2011 Mosby, Inc. All rights reserved.
Reprint requests: Satoshi Gando, MD, Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical
Care Medicine, Hokkaido University Graduate School of
doi:10.1016/j.surg.2010.06.010
0039-6060/$ - see front matter
SURGERY 221
222 Hayakawa et al
IN
TRAUMA PATIENTS, DISSEMINATED INTRAVASCULAR COAG-
(DIC) WITH CONSUMPTION COAGULOPATHY may
exist at the time of patient arrival at the emergency
department and is unrelated to hemodilution and
hypothermia.1 Brohi et al2 reconfirmed this phenomenon and concluded that an acute coagulopathy is attributable to the injury itself. Although the
activation of the tissue-factor dependent pathway
at the top of the cascade is identical, DIC is subdivided into the fibrinolytic and thrombotic
phenotypes.3,4 DIC occurring at an early phase of
trauma yields the fibrinolytic phenotype contributing to a poor patient prognosis resulting from massive bleeding.5 Tissue ischemia induced by
hypoperfusion but not by acidemia is involved in
the pathogenesis of increased fibrinolysis in this
type of DIC.1,5,6 In contrast, another view is that coagulation factors do not decrease and that the coagulation times are not prolonged in trauma
patients without shock.7,8 Brohi et al have insisted
that no evidence exists to suggest a process of DIC
in trauma-induced coagulation and the fibrinolysis
disorder.8
In addition to plasmin, the degradation of
fibrin and fibrinogen is mediated through neutrophil elastase, and the degradation products by
neutrophil elastase are different from plasmin
digests.9,10 A recent clinical application of a monoclonal antibody specific to the neutrophil elastasefragment D species of human fibrinogen and
fibrin allowed for the discrimination of the degradation products from these 2 fibrinolytic pathways.11 Thrombin-activatable fibrinolysis inhibitor
(TAFI) is activated by the thrombin thrombomodulin complex on the vascular endothelial surface
and is another type of fibrinolysis modulator.12
TAFI activated by the thrombin thrombomodulin
complex down regulates fibrinolysis by removing
carboxy-terminal lysines from fibrin. Therefore, a
decreased rate of TAFI activation contributes to
bleeding disorders, and an increased rate of activation may lead to thrombotic disorders. A massive
production of thrombin, plasmin, and neutrophil
elastase has been recognized at an early phase of
trauma, especially in those patients with DIC.1,13
Soluble thrombomodulin as a direct marker of endothelial cell injury also increases in proportion to
the levels of neutrophil elastase in patients with
trauma-associated DIC.13,14 In contrast, a recent
study suggests that soluble thrombomodulin possesses only a small level of activity after its release
into the circulation by endothelial cells.15
The aims of the present study were to reconfirm
the consumption coagulopathy of DIC with the
fibrinolytic phenotype at an early phase of trauma
ULATION
Surgery
February 2011
and to test the hypothesis that TAFI, neutrophil
elastase, and plasmin contribute to the increased
fibrinolysis of this type of DIC. Furthermore, we
hypothesized that DIC at an early phase of trauma
progresses dependently to DIC with a thorombotic
phenotype from 3 to 5 days after injury.
MATERIALS AND METHODS
Patient selection. With the approval of the
Institutional Review Board and after written informed consent was obtained from either the
patients or their next of kin, 57 severe trauma
patients defined as having an Injury Severity Score
(ISS) $9 (at 1 abbreviated injury scale $3) were
enrolled in the present study. Trauma patients
under 12 yeas of age or older than 90 years of age,
those with cardiac arrest or who had been resuscitated from cardiac arrest, and individuals receiving anticoagulant therapy and having known
clotting disorders such as hematopoietic malignancies and severe liver cirrhosis were excluded from
the present series. Furthermore, any patients who
succumbed within 24 hours after arrival at the
emergency department also were excluded. Fifteen
healthy volunteers served as control subjects.
Definitions. The severity of illness of the patients
was evaluated according to the Acute Physiology
and Chronic Health Evaluation (APACHE) II score
at the time of enrollment.16 Organ failure was assessed by the Sequential Organ Failure Assessment
(SOFA) score.17 The systemic inflammatory response syndrome (SIRS) and sepsis were defined according to the American College of Chest
Physicians/Society of Critical Care Medicine consensus conference as published previously.18 Infection was defined as any localization with clinical
evidence of infection and the identification of microorganisms grown from bacteriological samples.
The DIC diagnosis was performed based on the
Japanese Association for Acute Medicine (JAAM)
DIC diagnosis criteria.19 The overt DIC scores by
the International Society on Thrombosis and Haemostasis (ISTH) also were calculated.20 The scoring systems are presented in Tables I and II. The
fibrin/fibrinogen degradation product (FDP) was
used as the fibrin-related marker in the ISTH
criteria. No increase, moderate increase, and
strong increase were defined as having FDP values
<9, 10--24, and >25 mg/L, respectively. When the
total score was $4 and $5, respectively, the
JAAM and ISTH overt DIC was established. Based
on the JAAM DIC diagnostic criteria, 57 patients
were classified into 2 subgroups---30 patients with
DIC and 27 patients without DIC.
Hayakawa et al 223
Surgery
Volume 149, Number 2
Table I. Scoring system for DIC as established by
the JAAM
Table II. Scoring system for overt DIC as
established by the ISTH
Score
SIRS criteria
>3
0--2
Platelet counts (109/L)
<80 or more than 50% decrease
within 24 h
>80<120 or more than 30% decrease
within 24 h
>120
Prothrombin time (value of patient/
normal value)
>1.2
<1.2
FDP (mg/L)
>25
>10<25
<10
Diagnosis
4 points or more
Criteria for SIRS
Temperature >38°C or <36°C
Heart rate >90 beats/min
Respiratory rate >20 breath/min or
PaCO2<32 mm Hg (<4.3 kPa)
White cell blood counts >12,000 cells/mm3,
<4,000 cells/mm3, or 10% immature (band)
forms
1
0
3
1
0
1
0
3
1
0
DIC
Based on the Surviving Sepsis Campaign Guideline, tissue hypoperfusion was defined as a blood
lactate level of $ 4 mmol/L.21 The outcome measure was 28-day mortality.
Study protocol and measurement methods.
Blood samples were collected by either direct
puncture of the femoral artery or by an arterial
catheter within 12 hours after patient arrival to the
emergency department (day 1) as well as on days 3
and 5. Immediately after the blood samples were
taken, the blood was placed into individual tubes
and centrifuged at 3,000 rpm for 5 minutes at 4°C.
The plasma was stored at --80°C until the analyses
were performed.
We measured the following variables: TAFI
antigen (original enzyme-linked immunosorbent
assay, using an enzyme immuno assay [EIA]
from Affinity Biologicals Inc., Ancaster, Ontario,
Canada); neutrophil elastase (neutrophil elastase
and alpha1-proteinase complex; Neutrophil
Elastase EIA; Sanwa-Kagaku, Nagoya, Japan); fibrin
degradation product by neutrophil elastase
(EXDP; E-XDP; Mitsubishi Chemical Medience,
Tokyo, Japan); plasmin alpha2 plasmin inhibitor
complex (PPIC; LPIA-ACE PPI II; Mitsubishi
Score
Platelet counts (109/L)
<50
>50<100
>100
Elevated fibrin-related marker
(eg, soluble fibrin monomers/
fibrin degradation products)
Strong increase
Moderate increase
No increase
Prolonged prothrombin time (s)
>6
>3<6
<3
Fibrinogen level (g/mL)
<100
>100
Diagnosis
5 points or more
2
1
0
3
2
0
2
1
0
1
0
overt DIC
*The fibrin-related marker used in the present study and its cutoff points
are described in the Methods section.
Chemical Medience), a marker of plasmin production; tissue plasminogen activator (t-PA) plasminogen activator inhibitor-1 complex (PAI-1; tPAIC;
LPIA-tPA test; Mitsubishi Chemical Medience), a
marker of t-PA release from endothelial cells; and
cross-linked fibrin degradation products, D-dimer
(LPIA-ACE D-D-dimer II; Mitsubishi Chemical
Medience). The platelet count, prothrombin
time, fibrinogen, FDP, and antithrombin also
were measured in patient plasma for the diagnosis
and treatment of DIC. In addition, the ABL SYSTEM
620 (Radiometer, Copenhagen, Denmark) was used
for lactate measurements.
To maintain the hemodynamics and to treat
hemostatic disorders, a sufficient amount of platelet concentrates, fresh frozen plasma (FFP), and
packed red blood cells (PRBC) were transfused
based on the repeatedly obtained laboratory data.
Standard surgical protocols and intensive--care
unit managements were performed for patients
who required an operation and intensive care.
Statistical analysis. All measurements are expressed as the mean ± standard deviation. The
SPSS 13.0 for MAC OSX software program (SPSS
Inc., Chicago, IL) was used for statistical analyses
and calculations. Comparisons between the 2
groups were performed with the Mann--Whitney U
test and either the v2 test or the Fisher exact test
when required. To compare the 3 groups, the
Kruskal--Wallis analysis of variance was used. Correlations were evaluated by the Spearman’s rank test.
224 Hayakawa et al
Surgery
February 2011
Table III. Baseline characteristics of the patients*
Age (years)
Sex (male/female)
ISS
APACHE II score
SIRS criteria
SOFA score
Sepsis (yes/no)
Operative intervention (yes/no)
Head injury (yes/no)
Platelet concentrate (U)
Packed red blood cell (mL)
FFP (mL)
Lactate (mmol/L)
Outcome (survived/died)
Non-DIC
(n = 27)
DIC
(n = 30)
P value
50 ± 19
19/8
26.0 ± 14.0
19.2 ± 6.6
2.6 ± 0.8
3.6 ± 2.1
2/25
13/14
16/11
3.5 ± 8.9
491 ± 748
441 ± 771
2.9 ± 1.5
26/1
48 ± 21
14/16
29.0 ± 11.8
20.0 ± 11.8
3.1 ± 0.7
6.1 ± 3.5
2/28
21/9
16/14
13.2 ± 24.7
1,371 ± 1,349
1,473 ± 2,384
5.0 ± 3.9
26/4
.755
.061
.195
.737
.022
.003
.991
.079
.790
.079
.002
.018
.009
.211
*The data at day 1 are shown. Transfusion data indicate the total volume from days 1--5.
The relationships between the dependent and the
independent variables were analyzed by a simple
or multiple (stepwise method) regression analysis,
and the results were reported as a regression line, regression coefficient, and 95% confidence intervals
(CIs). Differences with a P value less than .05 were
considered to be statistically significant.
RESULTS
Baseline patient characteristics. Table III indicates that although the ISS and APACHE II scores
are identical between the 2 groups, DIC patients
demonstrate a severe degree of SIRS and organ
dysfunction (SOFA) and were transfused with
more blood products. Increased lactate levels in
DIC patients suggest tissue hypoperfusion in this
group. The prevalence of sepsis during the study
period was 7% (4/57) and was distributed identically between the groups.
Serial changes in the DIC scores, platelet
counts, coagulation, and fibrinolysis variables. Significant differences were observed in the JAAM
and ISTH overt DIC scores between the patients
with and without DIC from days 1--5. Prolonged
prothrombin time and lesser fibrinogen and antithrombin levels on day 1 suggest the consumption
of coagulation factors in DIC patients. Increased
levels of FDP, a greater FDP/D-dimer ratio, and
decreased fibrinogen levels are results of fibrinolysis and fibrinogenolysis. These results were more
pronounced if the DIC patients were subdivided
into patients who met only the JAAM criteria and
those who met both the JAAM and the ISTH
criteria. The DIC patients who met both DIC
criteria showed a greater rate of death (P = .018).
These results indicate that the prognosis of the
Table IV. DIC scores, platelet counts, coagulation
and fibrinolysis variables
JAAM DIC score
Day 1
Day 3
Day 5
ISTH overt DIC score
Day 1
Day 3
Day 5
Platelet counts (109/L)
Day 1
Day 3
Day 5
Prothrombin time (s)
Day 1
Day 3
Day 5
Fibrinogen (g/L)
Day 1
Day 3
Day 5
FDP (mg/L)
Day 1
Day 3
Day 5
FDP/D-dimer ratio
Day 1
Day 3
Day 5
Antithrombin (%)
Day 1
Day 3
Day 5
Non-DIC
DIC
P value
2.0 ± 0.9
2.0 ± 1.6
1.8 ± 1.4
5.0 ± 1.2
3.5 ± 1.9
3.5 ± 2.4
<.001
.007
.29
1.7 ± 0.8
1.4 ± 1.1
1.7 ± 1.2
3.9 ± 1.0
2.4 ± 1.4
2.7 ± 1.6
<.001
.013
.040
154 ± 64
136 ± 60
157 ± 73
132 ± 64
103 ± 47
109 ± 52
.362
.032
.036
12.9 ± 1.4 14.9 ± 3.1
12.5 ± 1.4 13.1 ± 2.3
11.9 ± 0.6 12.9 ± 2.2
.002
.137
.017
2.46 ± 0.9 1.63 ± 0.6
4.46 ± 1.6 3.92 ± 1.0
5.39 ± 1.4 4.80 ± 1.5
.001
.144
.149
19.1 ± 20.8 83.6 ± 102.7 <.001
21.8 ± 58.4 32.3 ± 65.2
.020
14.3 ± 11.0 25.5 ± 20.2
.053
1.8 ± 1.9
1.6 ± 1.1
1.6 ± 1.8
2.2 ± 1.3
1.7 ± 1.1
1.4 ± 1.0
77.8 ± 18.4 67.8 ± 18.8
93.6 ± 26.6 80.2 ± 16.0
96.0 ± 29.3 87.0 ± 17.3
.046
.686
.532
.033
.119
.532
Hayakawa et al 225
Surgery
Volume 149, Number 2
Table V. Effect of ISTH overt DIC and lactate level on the platelet counts, coagulation, and fibrinolysis
variables at day 1 and outcome
Total
Platelet counts (109/L)
Prothrombin time (s)
Fibrinogen (g/L)
FDP (mg/L)
Antithrombin (%)
Outcome (survived/died)
Lactate <4 mmol/L
Platelet counts (109/L)
Prothrombin time (s)
Fibrinogen (g/L)
FDP (mg/L)
Antithrombin (%)
Lactate $4 mmol/L
Platelet counts (109/L)
Prothrombin time (s)
Fibrinogen (g/L)
FDP (mg/L)
Antithrombin (%)
Non-DIC
ISTH (--)
DIC ISTH (+)
(n = 27)
154 ± 64
12.9 ± 1.4
2.46 ± 0.9
19.1 ± 20.8
77.8 ± 18.4
26/1
(n = 20)
157 ± 66
12.8 ± 1.3
2.66 ± 1.0
17.5 ± 18.2
76.3 ± 15.7
(n = 7)
142 ± 61
13.4 ± 1.4
1.86 ± 0.7
23.3 ± 28.3
82.1 ± 25.4
(n = 21)
141 ± 55
13.7 ± 1.5
1.88 ± 0.59
55.0 ± 36.3
71.7 ± 18.5
20/1
(n = 9)
149 ± 39
13.8 ± 1.2
1.81 ± 0.6
57.8 ± 38.0
72.3 ± 14.2
(n = 12)
135 ± 65
13.5 ± 1.7
1.72 ± 0.6
52.8 ± 36.5
71.2 ± 16.7
(n = 9)
109 ± 80
17.9 ± 3.9
1.03 ± 0.16
150.6 ± 166.7
59.6 ± 23.9
6/3
(n = 2)
186 ± 63
22.3 ± 1.8
1.05 ± 0.01
63.1 ± 16.9
73.5 ± 58.6
(n = 7)
87 ± 74
16.6 ± 3.2
1.01 ± 0.2
175.6 ± 183
54.6 ± 9.9
JAAM DIC patients deteriorated in accordance
with increasing DIC severity. These results are presented in Tables IV and V. According to the lactate
levels (4 mmol/L), the DIC patients were subdivided into 2 groups---11 patients with increased lactate levels and 19 patients with low lactate levels.
Irrespective of the lactate levels, DIC patients exhibited a prolonged prothrombin time, lesser fibrinogen levels, and greater FDP levels in
comparison with non-DIC patients (Table V).
Serial changes in variables relate to fibrinolysis and
an independent predictor of transfusion. As presented in Fig 1, DIC and non-DIC patients showed
no differences in TAFI levels in comparison with
control subjects on days 1 and 3; however, at day 5,
the TAFI levels in DIC patients were increased significantly compared with the control subjects. We
observed increased levels of tPAIC, PPIC, and
D-dimer of the DIC patients in comparison with control subjects and with non-DIC patients on day 1.
These results, which are presented in Fig 2, suggest
an increased production or release of t-PA and
plasmin followed by excessive secondary fibrinolysis
at an early phase of trauma, particularly in DIC
patients. Figure 3 contains neutrophil-related variables. Greater levels of neutrophil elastase and
EXDP in DIC patients were observed, which indicated neutrophil activation followed by an increase
in neutrophil elastase-mediated fibrinolysis.
Using the data from day 1, the relationships
among PPIC, D-dimer, and EXDP levels were investigated. Figure 4 shows the relationship between the
P value
.295
<.001
<.001
.008
.014
.018
.572
.010
.012
.001
.649
.169
.012
.001
.015
.025
Fig 1. Box plot showing no difference in the TAFI levels
between DIC (dark boxes) and non-DIC patients (white
boxes). +P < .001 versus control.
levels of PPIC (0 < 1.0 mg/mL, 1.0 < 10.0 mg/mL,
and >10.0 mg/mL) and of the D-dimer or EXDP in
patients with or without DIC. Although stepwise increases in the levels of D-dimer were observed in
both the DIC and non-DIC patients in accordance
with increases in the levels of PPIC, stepwise increases in the levels of EXDP in accordance with
the increases in the levels of PPIC were observed
only in non-DIC patients. Table VI shows that
226 Hayakawa et al
Surgery
February 2011
Fig 3. Box plots showing EXDP (top) and neutrophil
elastase (bottom). Two variables in DIC patients (gray
boxes) on day 1 were increased in comparison with the
non-DIC patients (white boxes). +P < .001 versus control;
*P < .05 versus non-DIC patients.
Fig 2. Box plots showing the D-dimer (top), PPIC (middle), and tPAIC (bottom) levels. All 3 variables of the
DIC patients (gray boxes) on day 1 showed greater values
than those without DIC (white boxes). +P < .001 versus
control; *P < .05; ** P < .01 versus non-DIC patients.
Spearman’s rank correlation and a simple regression analysis (EXDP as a dependent variable) did
not show the presence of a significant relationship
between the levels of PPIC and EXDP levels in
DIC patients. A clear difference in Spearman’s rho
(rs) for the correlation of D-dimer and EXDP values
was detected between the patients with DIC (0.420)
and without DIC (0.729).
A multiple regression analysis with the stepwise
method was applied using the JAAM DIC score,
platelet count, global coagulation and fibrinolysis
Surgery
Volume 149, Number 2
Hayakawa et al 227
simultaneously met the ISTH overt DIC criteria,
continued to exhibit DIC at days 3 and 5. Six of the
27 non-DIC patients had newly developed DIC at
day 3 or day 5. A clear difference was noted in the
prevalence of late-phase DIC between patients with
DIC and without DIC at an early phase of trauma
(P < .001; Table VII).
Fig 4. Box plots showing the EXDP (top) and the D-dimer
(bottom). DIC and non-DIC patients were subdivided into
3 groups based on the levels of PPIC (0 to <1.0 mg/mL,
white boxes; 1.0 to <10.0 mg/mL, gray boxes; and >10.0
mg/mL; dark gray boxes). The P values of the Kruskal--Wallis
analysis of variance are shown in the figure.
markers, and markers related to fibrinolysis on day
1 as independent variables and using the total
volume of transfused red blood cells as a dependent variable. The results demonstrated that the
JAAM DIC score (standardized coefficient beta
0.380; 95% CI, 106.2--430.5; P = .002) and tPAIC
(standardized coefficient beta 0.467; 95% CI,
0.561--1.647; P < .001) correlated with the total volume of transfused PRBC.
DIC at an early phase of trauma continues to be
DIC at the late phase of trauma. The JAAM DIC
patients, especially more severe cases who
DISCUSSION
The members of the Educational Initiative on
Critical Bleeding in Trauma (EICBT) announced
the new disease entities of acute coagulopathy of
trauma shock and coagulopathy of trauma.22 They
did not, however, propose clear definitions or diagnostic criteria, and a rebuttal has been made to
these concepts.23 The acute coagulopathy of
trauma has not been defined by the EICBT, but
the EICBT has reconfirmed the presence of
trauma-related DIC.1,24,25 Although traumatic coagulopathy is multifactorial, clinical, and experimental, evidence has demonstrated that DIC is
the predominant and initiative pathogenesis of
trauma-related coagulopathy and that the acute coagulopathy of trauma shock and coagulopathy of
trauma equal DIC with a fibrinolytic phenotype
at an early phase of trauma.1,5,23,26-28
The JAAM DIC diagnostic criteria have an
acceptable validity for the diagnosis of DIC at an
early phase of trauma, and the JAAM DIC exists
along with a continuum to the ISTH overt DIC.5,29
In the present study, on day 1, significantly prolonged prothrombin time and lesser fibrinogen
and antithrombin levels were observed in DIC patients. Greater levels of D-dimer in DIC patients indicated disseminated fibrin formation. In addition,
increased levels of FDP, a greater FDP/D-dimer ratio, and decreased fibrinogen levels resulted from
fibrinolysis and fibrinogenolysis in DIC patients.
These changes were more prominent when those
patients met simultaneously the ISTH overt DIC,
subsequently resulting in a poor patient outcome.
These results suggested that coagulation factors
and antithrombin decrease as a result of consumption in accordance with the progression of DIC.
Despite a hypoperfusion definition as a lactate
level of $4 mmol/L,21 DIC patients exhibited coagulation factor consumption. Greater levels of
FDP and lesser levels of fibrinogen and antithrombin in a group of patients with lactate levels of $4
mmol/L may indicate that hypoperfusion induces
more pronounced changes in coagulation and fibrinolysis. These results are distinct from the studies of Brohi et al7,8 in which the authors used the
base deficit as a marker of hypoperfusion and in
228 Hayakawa et al
Surgery
February 2011
Table VI. Spearman’s correlation and simple regression analysis between PPIC, D-dimer and EXDP on day 1
DIC (n = 30)
PPIC -- EXDP
D-dimer--EXDP
PPIC -- EXDP
Regresssion line
Non-DIC (n = 27)
rs
P value
rs
P value
0.196
0.420
0.300
0.021
0.532
0.729
.004
.001
r
P value
r
P value
0.925
0.394
0.018
y = –0.12X + 31.5
0.042
y = 0.85X + 9.3
rs, Spearman’s coefficient (rho); r, regression coefficient.
Table VII. DIC at an early phase of trauma continues to DIC at late phase of trauma
Days 3 and 5
Day 1
(n)
JAAM DIC (yes/no) (%)
JAAM DIC (30)
ISTH overt DIC (+) (9)
ISTH overt DIC (--) (21)
Non-DIC (27)
P value for incidence
18/12 (60.0)
8/1 (88.9)
10/11 (52.6)
6/21 (22.2)
<.001
which unclear stratification was found of the base
deficit levels. The present study demonstrated
that DIC at an early phase of trauma is associated
with the consumption of coagulation factors independently of hypoperfusion followed by disseminated fibrin formation.
TAFI antigen levels and activity in DIC patients
decrease presumably because of the consumption30,31; however no changes in TAFI levels were
observed in the present study, which was consistent
with the results of a previous study.32 The activation of TAFI requires a high concentration of
thrombin and is enhanced by the thrombinthrombomodulin complex on the endothelium.
Although massive thrombin production and activation have been confirmed in trauma patients with
DIC, high soluble thrombomodulin levels in these
patients suggest endothelial injury as well as a loss
of functional thrombomodulin.13,14,27 Furthermore, soluble thrombomodulin has only 20%
activity in comparison with endothelial thrombomodulin.15 These results indicate a lesser availability of thrombomodulin both for the regulation of
thrombin and for TAFI activation in DIC patients.
We demonstrated previously that increased t-PA
antigen levels, substantial plasmin production and
activation, followed by massive secondary fibrinolysis occur in DIC patients immediately on arrival to
the emergency department.1 The results of tPAIC,
PPIC, and D-dimer in the present study coincided
with the results of our previous study and support
the hypothesis that t-PA-induced plasmin
Scores of DIC patients
5.4
6.3
5.0
4.5
± 1.4
± 1.5
± 1.2
± 0.5
—
formation is one of the factors contributing to increased fibrinolysis in DIC that occurs at an early
phase of trauma. Markedly increased levels of
FDP and the FDP/D-dimer ratio in patients with
DIC may be attributable to massive t-PA- and
plasmin-mediated fibrinogenolysis. High FDP immediately after trauma is an independent predictor of massive bleeding.5 Multiple regression
analysis with the stepwise method indicated the
JAAM DIC score and tPAIC as being independent
predictors of the increased PRBC transfusion.
These results suggest t-PA-induced plasmin formation is involved importantly in the bleeding of DIC
with the fibrinolytic phenotype at an early phase of
trauma. DIC that becomes more severe and also
meets the ISTH DIC criteria simultaneously contributes to a poor patient outcome.
Neutrophil elastase has important roles in the
pathogenesis of DIC after trauma.13,14 Increases in
EXDP in DIC patients suggest that the activation of
the neutrophil-mediated alternative pathway of fibrinolysis also contributes to increased fibrinolysis
at an early phase of trauma. Patients with deep vein
thrombosis without any systemic inflammation
showed a good correlation between EXDP and
D-dimer (r = 0.972); however, in septic DIC patients with SIRS and high PAI-1 levels, a low correlation (r = 0.553) was observed between these 2
variables.33,34 Similar results were obtained in the
present study. Furthermore, we detected no correlation between PPIC and EXDP at a low PPIC concentration. Because of a high expression level of
Hayakawa et al 229
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Volume 149, Number 2
PAI-1 after induction by inflammatory cytokines in
trauma patients with DIC, the production of plasmin and plasmin-mediated fibrinolysis is insufficient to prevent intravascular coagulation.35 The
result of the present study suggests that
neutrophil-mediated fibrinolysis may compensate
for the insufficient plasmin-mediated fibrinolytic
pathway at an early phase of trauma.
The serial measurements of global and molecular markers of coagulation and fibrinolysis
have demonstrated repeatedly that DIC at an
early phase of trauma (24--48 hours) progresses
dependently to DIC at a late phase until 5 or 6
days after the trauma.1,13,14,23,27,35 During this period, the prevalence of sepsis is low 8.5%,13
5.2%,14 and 6.9%.35 Furthermore, a large, epidemiologic cohort study of patients with trauma revealed a lesser incidence of sepsis (2%), which
was similar to that of generalized hospitalized
patients.36 The present study reconfirmed these results and furthermore showed that two-thirds of
DIC patients diagnosed on day 1 continued to demonstrate DIC until day 5 after trauma. This prevalence increased to 89% when the patients
simultaneously met the ISTH overt DIC criteria.
The more severe the DIC at an early phase of
trauma, the greater the number of patients that
continue to the late phase of DIC. The concept7,8,22
of acute coagulopathy of trauma shock and coagulopathy of trauma terminate at an early phase of
trauma, and then either sepsis-induced or sepsislike coagulopathy, but not DIC, develop at the
late phase of trauma and have been described previously; however, we speculate that this hypothesis
may be incorrect.23,27
Clinical implications and study limitations. Our
relatively small number of patients may have limited the relevance of the present study’s results.
The present prospective study and the previous
studies considering the same subject, however,
have suggested the following:5,29 (1) After admission to the emergency department, the JAAM
DIC score should be calculated repeatedly. When
the patients meet the DIC criteria, they are more
likely to have major hemorrhage and require a
massive transfusion according to the hyperfibrinolysis caused by plasmin and neutrophil elastase.
PRBCs and enough FFP should be ordered as
soon as possible. (2) When the DIC becomes
more severe, the patient prognosis will be poorer.
Even if the patients override the massive
bleeding-induced shock, they will progress to DIC
at a late phase of trauma associated with systemic,
thrombosis-related organ dysfunction. (3) The
key to the treatment of DIC is the specific and
vigorous treatment of the underlying disorder
(ie, the trauma itself and trauma-induced shock).37
Simultaneously, substitution therapy with a platelet
concentrate, sufficient FFP, and a fibrinogen concentrate seems to be mandatory.37 The present
study revealed hyperfibrinolyis both by plasmin
and neutrophil elastase; however, the use of antifibrinolytic drugs or neutrophil elastase inhibitor
must be studied in more detail in the future.
In conclusion, we demonstrate the following conclusions. Both plasmin- and neutrophil-mediated
fibrinolytic pathways, but not TAFI, are involved in
the pathogenesis of DIC with the fibrinolytic phenotype at an early phase of trauma. Consumption
coagulopathy and excessive fibrinolysis in this type
of DIC increase the requirement of blood transfusions, and if simultaneously associated with ISTH
overt DIC, then the DIC contributes to a poor
patient outcome. Numerous DIC patients remain
in DIC at a late phase of trauma independent from
sepsis complication. Although hypoperfusion
may strengthen the changes in coagulation and
fibrinolysis of DIC, DIC develops without hypoperfusion. The neutrophil-mediated alternative fibrinolytic pathway may compensate for insufficient
plasmin-mediated fibrinolysis.
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