Disseminated Intravascular Coagulation

in Trauma Patients
Satoshi Gando, M.D., Ph.D.1

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ABSTRACT

Disseminated intravascular coagulation (DIC) is characterized by the in vivo activation of the coagulation system, which results in the intravascular deposition of fibrin
and consumption bleeding. DIC is a serious hemostatic complication of trauma. It can be
clearly distinguished from physiological hemostatic response to trauma by using sensitive
coagulofibrinolytic molecular markers. Physiological hemostasis to injuries is similar in
all kinds of trauma without exception. There is an increase in circulating proinflammatory
cytokines in DIC patients after trauma. Elevated cytokines induce tissue factormediated
activation of coagulation, suppression of the anticoagulant pathway, and plasminogen activator inhibitor-1 (PAI-1)mediated inhibition of fibrinolysis followed by disseminated
fibrin deposition in the microvasculature. In addition to the occlusive microvascular
thrombosis and hypoxia, sustained systemic inflammatory response characterized by neutrophil activation and endothelial damage plays a pivotal role in the development of multiple organ dysfunction syndrome (MODS) in posttrauma DIC patients. DIC associated
with sustained systemic inflammatory response syndrome (SIRS) after trauma leads to
the development of MODS, which is the main determinant of patients outcome after
trauma.
KEYWORDS: Disseminated intravascular coagulation (DIC), trauma, multiple organ

dysfunction syndrome (MODS), systemic inflammatory response syndrome (SIRS),

inflammation

Objectives: Upon completion of this article, the reader should be able to (1) recognize the differences between physiological and
pathological hemostatic responses to trauma and (2) appreciate the close relationship between DIC, SIRS and MODS in trauma patients.
Accreditation: Tufts University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians. TUSM takes full responsibility for the content, quality, and scientific integrity of
this continuing education activity.
Credit: Tufts University School of Medicine designates this education activity for a maximum of 1.0 hours credit toward the AMA
Physicians Recognition Award in category one. Each physician should claim only those hours that he/she actually spent in the educational activity.

Seminars in Thrombosis and Hemostasis, volume 27, number 6, 2001. Address for correspondence and reprint requests: Satoshi Gando, M.D., N15,
W7, Kita-ku, Sapporo 060 Japan. E-mail: sgando@med.hokudai.ac.jp. 1Division of Acute and Critical Care Medicine, Department of
Anesthesiology and Critical Care Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Copyright 2001 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0094-6176,p;2001,27,06,585,592,
ftx,en;sth00762x.

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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001

he trauma patients survival depends on the

ability to control hemorrhage and support vital organs
by preventing MODS after DIC. DIC is a serious hemostatic problem in critically ill patients and is often
seen in trauma patients. It is characterized by an activation of the coagulation cascade and, thereby, accelerated
consumption of numerous coagulation factors and
platelets. The consumption and subsequent exhaustion
of coagulation proteins and platelets induce severe
bleeding complications in trauma patients. Suppression
of the physiological anticoagulant pathway and impaired fibrinolysis as well as activation of coagulation
can be seen in DIC after trauma. The extensive activation of blood coagulation with impaired fibrinolysis results in the generation and deposition of fibrin, leading
to microvascular thrombi in various organs and contributing to the development of MODS.1 Recent observations suggest that, in addition to ischemic organ failure because of disseminated fibrin deposition, DIC
causes inflammatory organ failure through the interaction between coagulation and the inflammatory pathway.2 In trauma patients, DIC has an important role in
the pathogenesis of MODS. Accordingly, DIC strongly
influences trauma patients morbidity and mortality
through serious hemorrhage and organ dysfunction.
To understand the pathophysiology of DIC in
injured patients, we have to know the physiological hemostasis after trauma. In this article, the physiological

hemostatic responses to trauma are discussed and then

the coagulofibrinolytic changes in posttrauma DIC are
mentioned. After the overview of these hemostatic responses to trauma, the mechanisms of organ dysfunction in DIC are shown. Finally, the relationship among
DIC, MODS, and SIRS3 in trauma patients will be
discussed.

PHYSIOLOGICAL HEMOSTATIC
RESPONSES TO TRAUMA
As presented in Figure 1, platelet counts of non-DIC
patients were reduced significantly on day 1 as compared with those on day 0 and then gradually increased
almost to the initial values. However, platelet counts of
DIC patients showed continuously low levels during
the study period. The lowest values of prothrombin
time and fibrinogen levels were observed on the day of
trauma. The prothrombin time returned to normal, and
the levels of fibrinogen reached the highest values on
day 4, as an acute phase-reactant protein. Fibrin/fibrinogen degradation product (FDP) levels were minimally
elevated during the study period in patients without
DIC; this was different from what was seen in the DIC
patients. Careful observation of the changes in FDP
levels indicates a depression of fibrinolysis and its reactivation (see later). Except for platelet counts and FDP
levels, the differences in the levels of global parameters

Figure 1 Global measurements of coagulation and fibrinolytic activity in trauma patients with (stippled bars) and without (open
bars) DIC. *Denotes p values from 0.05 to 0.0001.

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586

were minor, but one can obviously distinguish DIC patients from non-DIC patients.
The immediate function of the hemostatic
mechanisms after trauma is the termination of bleeding
from the intravascular space by vascular contraction and
platelet plug formation. The next step is the provision of
a fibrin framework at the injured site by activation of
thrombin and impairment of fibrinolysis. A further
function is the removal of the fibrin by secondary fibrinolysis when repair of injured blood vessels or the tissue
is sufficiently advanced. Global measurements of coagulation and fibrinolysis mentioned earlier hardly detect
these changes. However, using sensitive assay methods,
we can assess thrombin and plasmin activation (fibrinopeptide A [FPA] and fibrinopeptide B1542 [FPB1542]),
fibrin formation and its degradation (D-dimer), and inhibition of fibrinolysis by PAI-1.4,5 Figure 2 (left)
shows the immediate increase in thrombin activity after
trauma followed by plasmin activity to protect intravascular thrombi caused by extra fibrin formation. As a result of the secondary fibrinolysis by plasmin, a steep increase in D-dimer levels is noted. To prevent rebleeding
by excessive fibrinolysis, PAI-1 increases a few hours
after the trauma, which brings about a decrease of both
FPB1542 and D-dimer levels. Several days after trauma,
PAI-1 increase comes to an end, indicating repair of injured blood vessels and wound healing. Then we can detect removal of unused fibrin by reactivating plasmin
and reelevation of D-dimer. These scenarios have been
constructed in several of our studies on hemostatic
changes after trauma.
These hemostatic responses, detected by using
sensitive molecular markers, have long been incorrectly

called hypercoagulability, fibrinolytic shutdown, and

its reactivation.69 The coagulofibrinolytic changes observed in trauma patients without DIC are not a disease
process but a physiological process for hemostasis and
wound healing. The poorly defined term hypercoagulability or fibrinolytic shutdown should not be used
for the normal physiological hemostatic response to
trauma. The use of those terms should be restricted to
abnormal hemostatic changes such as DIC.
For the past two decades, the hypothesis that
head injury strongly activates the coagulation cascade
and that the subsequent coagulopathy predicts the outcome of these patients has been widely accepted.1012
We recently demonstrated that, after systematic elucidation of the time course of coagulation and fibrinolysis
following isolated head injury, changes in the coagulofibrinolytic and antifibrinolytic systems in patients
with head injuries are not different from those in
trauma patients without head injury.4,13 These results
suggest that the physiological homeostatic response to
injury is similar in all kinds of trauma patients, without
exceptions.

PATHOLOGICAL HEMOSTATIC
RESPONSES TO TRAUMA
An abnormal pathological hemostatic response to
trauma is called DIC. Although identification of normal systemic activation of coagulation and fibrinolysis is
possible using sensitive molecular markers, hemostatic
activity is basically confined to the area of the injury.
Occasionally, control mechanisms fail to restrict the hemostatic processes to the area of tissue damage, and

Figure 2 Schematic variation of thrombin activity (FPA), plasmin activity (FPB1542), fibrin formation and secondary fibrinolysis (Ddimer), and inhibition of fibrinolysis (PAI-1) after trauma. Patients without DIC (left) and with DIC (right). A vertical axis shows increases from normal values (times). A, FPA; B, FPB1542; C, D-dimer; D, PAI-1.

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Table 1 Criteria for the Diagnosis of DIC by the

Japanese Ministry of Health and Welfare
Score
Etiology of DIC
Yes
No
Clinical symptoms
Bleeding symptom
Yes
No
Organ dysfunction
Yes
No
Laboratory tests
FDP (g/mL)
 40
 20, < 40
 10, < 20
< 10
Platelet Counts (104/mL)
5
 8, > 5
 12, >8
> 12
Fibrinogen (mg/dL)
 100
 150, > 100
> 150
Prothrombin time (value of patient/normal value)
 1.67
 1.25, < 1.67
< 1.25
Diagnosis
 7 points

1
0

1
0
1
0

3
2
1
0
3
2
1
0
2
1
0
2
1
0
DIC

they become disseminated throughout the systemic circulation, which causes DIC. The DIC diagnosis can be
performed accurately on the basis of the DIC Diagnosis
Standard published in 1988 by the Japanese Ministry of
Health and Welfare (Table 1). The basic disorder, the
clinical condition, and the results of examination for
global coagulation and fibrinolytic tests are quantified
on a score basis (maximum = 13; minimum = 0). If the
number is 7, DIC can be assumed.

Tissue FactorMediated Activation

of Coagulation and PAI-1Mediated
Inhibition of Fibrinolysis
The intrinsic pathway of coagulation does not appear to
play an important role for the activation of coagulation
in DIC.14 The consensus is that the function of the contact system is to generate bradykinin, a potent inducer

of local edema and systemic hypotension.1,14 Several

lines of evidence point to the pivotal role of the tissue
factordependent pathway in the initiation of thrombin
generation. This concept is true for DIC patients after
trauma. Continuously higher tissue factor levels were
observed in DIC patients compared with non-DIC patients on the day of trauma and on days 1 through 4
after admission.15 The results suggest extensive activation of the extrinsic coagulation pathway in posttrauma
DIC. Massive activation of thrombin and plasmin,
measured by FPA and FPB1542, respectively, were
noted after tissue factor production.4 The levels of
these activation products showed significantly higher
values than those seen for non-DIC patients. As a consequence, cross-linked fibrin degradation products,
D-dimer also increased to markedly higher levels than
those seen in non-DIC patients. Both PAI-1 activity
and its antigen levels in non-DIC patients decreased to
normal concentrations on day 5 after trauma. On the
contrary, PAI-1 levels in the DIC patients, especially
values in nonsurvivors, continued to be markedly higher
up to day 5 after trauma.5 The high PAI-1 activity suggests that elevated D-dimer levels are not balanced with
the massive fibrin formation observed in DIC patients
after trauma. The PAI-1mediated inhibition of fibrinolysis results in inadequate fibrin removal from the
vasculature.

Suppression of Physiological
Anticoagulant Pathways
An impaired function of the natural regulating pathways of coagulation activation contributes to fibrin formation. Tissue factor pathway inhibitor (TFPI), protein
C, and antithrombinthree major physiological anticoagulantsare greatly affected in posttrauma DIC.
Recently, we systematically elucidated the relationship
between tissue factor and TFPI in posttrauma patients.
We found that an activated tissue factordependent
pathway is not sufficiently prevented by the normal
TFPI levels in patients with DIC.15
The serial changes of the protein C system after
trauma were further investigated.16 When trauma patients were complicated with DIC, the protein C activity and the antigen levels showed significantly lower
values than those for the non-DIC patients. When classified into subgroups of survivors and nonsurvivors, the
protein C activity and antigen levels decreased significantly in the nonsurvivors compared with those in the
survivors. Antithrombin, the last endogenous physiological anticoagulant, was also significantly reduced in
posttrauma patients.17 The reduction of the protein C
system and antithrombin may be caused by consumption, degradation, impaired synthesis, and downregulation of thrombomodulin.1 Markedly elevated levels of
soluble thrombomodulin and elastase released from ac-

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588

tivated neutrophils until the fifth day of trauma in DIC

patients partly confirms the hypothesis.18
These studies clearly demonstrate tissue factor
mediated activation of coagulation, depression of anticoagulant system, and impaired fibrinolysis in DIC
patients after trauma. Based on these results, we can
construct Figure 2 (right), reflecting the pathological
hemostatic response to trauma. This can be obviously
distinguished from the physiological hemostatic
changes also presented in Figure 2 (left).

CLOSE RELATIONSHIP BETWEEN

DIC AND MODS
In the 1990s, our understanding of the underlying
mechanisms in organ dysfunction after trauma increased dramatically.3,1921 Multiple alterations in the
hemostatic, inflammatory, and immunologic functions
have been demonstrated in clinical and experimental
situations after trauma. In particular, it is now apparent
that acute respiratory distress syndrome (ARDS) and
MODS have their genesis in the development of DIC
following trauma.22
DIC patients showing higher thrombin activity
exhibited by FPA have had poor outcomes.4 Inhibition
of fibrinolysis using the differences of tissue plasminogen activator activity and its antigen levels in DIC patients has been indirectly implied.4 Gando et al5 described 58 trauma patients, 22 with DIC. The DIC
patients had a higher mortality rate, 59% versus 14%.
Tumor necrosis factor- (TNF-), interleukin-1
(IL-1), and PAI-1 increases were most consistently associated with fatal outcome, whereas DIC was a predictor of ARDS and MODS.5 Neutrophil elastase released
from activated neutrophils causes damage to vascular
endothelial cells, and this endothelial cell injury was
demonstrated to be deeply involved with ARDS and
MODS in patients with DIC after trauma.18 The activation of the tissue factordependent coagulation pathway and impaired fibrinolysis, as well as neutrophil activation, plays an important role in the pathogenesis of
posttraumatic ARDS.23,24 The ARDS patients had a
higher incidence of DIC (74 to 100%) and showed
poorer outcomes.23,24 These studies clearly suggest that
a frequent complication of DIC in trauma gives rise to
the development of ARDS and MODS.

PATHOLOGICAL MECHANISMS OF DIC

IN THE DEVELOPMENT OF MODS
Extensive thrombin generation, serious defects in coagulation inhibitors, and impaired fibrinolysis, observed in
DIC, result in ongoing massive fibrin deposition in the
vasculature. Several lines of evidence indicate that hypoxic occlusive thrombosis caused by disseminated fibrin formation gives rise to MODS and mortality in

DIC patients.1 It is not certain, however, to what extent

intravascular fibrin deposition alone contributes to
MODS and mortality. Taylor et al25 demonstrated that
effective inhibition of the hemostatic response by DIC
with active siteinhibited factor Xa did not protect the
animals from organ failure and death. The results suggest that fibrin formation per se does not influence the
outcome in DIC animals.
Recent experimental evidence has suggested
that, in addition to their role in hemostasis, proteases of
the clotting and fibrinolytic cascades transduce intracellular signals and modulate immunoinflammatory responses through both protease and protease-activated
receptors.2 Cross-talk between coagulation and inflammation amplifies mutual cascades, contributing to the
pathogenesis of tissue injury and organ dysfunction.26,27
In particular, the thrombin/protease activated receptor-1
(PAR-1) system plays an important role in inflammatory endothelial damage by inducing proinflammatory
cytokines and adhesion molecule expression after activation of neutrophils and endothelium.2 These studies
suggest that amplification and perpetuation of inflammatory response through interactions between inflammatory and coagulation pathways, as well as to the
occlusive microvascular thrombosis and hypoxia, are
critical to the development of MODS in DIC patients
after trauma.

CLINICAL EVIDENCE OF THE CROSS-TALK

BETWEEN DIC AND INFLAMMATION
The derangement of coagulation and fibrinolysis in
DIC is mediated by several proinflammatory cytokines
and neutrophil activation associated with endothelial
injury, which is greatly involved in the development of
MODS in posttrauma DIC patients.5,18 A report by
Nast-Kolb et al28 reinforces these results. They demonstrated low antithrombin levels, elevated neutrophil
elastase, and proinflammatory cytokines (IL-6 and
IL-8) in trauma patients who died from MODS. The
data show that the degree of coagulation and inflammatory responses corresponds with posttraumatic MODS.
That DIC and inflammation synergistically contribute
to the development of MODS and poor outcome in
trauma patients was confirmed by two other investigations.29,30 The inflammatory response has been found to
be amplified and perpetuated through a thrombin/
receptor interaction in a positive feedback manner.
There is a possibility that activation of the coagulation
pathway can participate in sustaining and amplifying an
inflammatory response in addition to producing hypoxia through the production of microvascular thrombosis by fibrin. Thus, sustained SIRS originating from
DIC is the main determinant for ARDS, MODS, and
poor outcome in patients with DIC after trauma.29
After this study, the accuracy of DIC and sustained

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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 27, NUMBER 6 2001

Figure 3 Schematic representation of mechanisms in the pathogenesis of MODS after trauma.

Figure 4 Relationship among DIC, sustained SIRS, and MODS after trauma. 1st insult, trauma; 2nd insult, DIC; 3rd insult, sepsis.

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590

SIRS in predicting MODS after trauma was determined by application of clinical decision analysis. Likelihood ratios of DIC and SIRS for >3 days for predicting posttrauma MODS were 11.6 and 6.25,
respectively.30 Platelet counts could be used as a simple
laboratory test for predicting MODS. These studies
clearly demonstrate the important link among, DIC,
SIRS, and MODS after trauma. Figure 3 shows the
schematic representation of mechanisms in the pathogenesis of MODS after trauma.

CONCLUSION
Figure 4 shows our scenario on the relationship among
DIC, sustained SIRS, and MODS after trauma.
Trauma is the first insult, followed by initial SIRS. Severe insult per se causes primary MODS and death.
Mild to moderate SIRS comes to an end within a few
days after trauma, which is thought to be a physiological
response to the insult, but severe SIRS persists for
>3 days after the onset of trauma. The DIC associated
with massive thrombin generation, excessive systemic
mediator release (e.g., proinflammatory cytokines and
neutrophil elastase), and endothelial injury alters the
SIRS reaction. Finally, the persistent alterations ultimately lead to sustained SIRS, producing secondary
MODS and death. Sometimes a complicating sepsis
about a week later acts as a third insult and modifies
sustained SIRS after trauma.
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