Laboratory Testing in Disseminated

Intravascular Coagulation
Emmanuel J. Favaloro, Ph.D., M.A.I.M.S.1

ABSTRACT

The diagnosis of disseminated intravascular coagulation (DIC) relies on clinical

signs and symptoms, identification of the underlying disease, the results of laboratory
testing, and differentiation from other pathologies. The clinical features mainly depend on
the underlying cause of the DIC. The laboratory diagnosis of DIC uses a combination of
tests because no single test result alone can firmly establish or rule out the diagnosis. Global

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tests of hemostasis may initially provide evidence of coagulation activation and later in the
process provide evidence of consumption of coagulation factors, but their individual
diagnostic efficiency is limited. Fibrinolytic markers, in particular D-dimer, are reflective
of activation of both coagulation and fibrinolysis, so that a normal finding can be useful for
ruling-out DIC. Decreased levels of the natural anticoagulants (in particular, antithrombin
and protein C) are frequently observed in patients with DIC, but their measurement is not
normally incorporated into standard diagnostic algorithms. New tests are being explored
for utility in DIC, and some additional tests may be useful on a case-by-case basis,
depending on the proposed cause of the DIC or their local availability. For example, clot
waveform analysis is useful but currently limited to a single instrument. Also, procalcitonin
is an inflammatory biomarker that may be useful within the context of septic DIC, and
activated factor X clotting time is an emerging test of procoagulant phospholipids that also
seems to hold promise in DIC.

KEYWORDS: Disseminated intravascular coagulation, DIC, diagnosis, hemostasis,

laboratory testing

D isseminated intravascular coagulation (DIC) is
a systemic life-threatening disease characterized by
largely uncontrolled activation of the coagulation sys-
tem, excess thrombin generation, activation of the fibri-
nolytic system, and consumption of coagulation factors
and platelets. The clinical features are therefore charac-
terized by the variable presence of both intravascular
coagulation and hemorrhage. The International Society
on Thrombosis and Haemostasis (ISTH) defines the
pathology of DIC as an ‘‘acquired syndrome character-
ized by intravascular activation of coagulation with loss
of localization, which can arise from different causes, can
originate from and cause damage to the microvasculature
and, when sufficiently severe, can produce organ dys-
function.’’.1 DIC is not a primary disease but reflects a
complication of one of several possible underlying ill-
nesses or conditions, as largely reflected in this issue of
Seminars in Thrombosis and Hemostasis. Accordingly,
DIC resulting from systemic and persistent activation
of blood coagulation may occur in patients consequent to

1
Department of Haematology, Institute of Clinical Pathology and
Medical Research (ICPMR), Westmead Hospital, NSW, Australia.
Address for correspondence and reprint requests: Dr. E.J. Favaloro,
Ph.D., M.A.I.M.S., Department of Haematology, Institute of
Clinical Pathology and Medical Research (ICPMR), Westmead
Hospital, WSAHS, Westmead, NSW 2145, Australia (e-mail:
emmanuel.favaloro@swahs.health.nsw.gov.au).
458
Disseminated Intravascular Coagulation; Guest Editor, Marcel Levi,
M.D., Ph.D.
Semin Thromb Hemost 2010;36:458–468. Copyright # 2010 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0030-1254055.
ISSN 0094-6176.
 LABORATORY TESTING FOR DISSEMINATED INTRAVASCULAR COAGULATION/FAVALORO
sepsis, severe infection, malignancy (solid tumors, mye-
loproliferative/lymphoproliferative malignancies), ob-
stetric complications (amniotic fluid embolism,
abruptio placentae, placenta previa, retained dead fetus
syndrome), vascular disorders (vascular aneurysms,
Kasabach-Merritt syndrome), severe organ injury
(e.g., acute pancreatitis, hepatic failure), massive trauma,
extensive burns, surgery, and severe toxic (snakebites,
drugs) or immunological reactions (hemolytic transfu-
sion reaction, transplant rejection).2–4
The clinical spectrum of DIC may be heteroge-
neous, with the balance between thrombosis (micro- or
macro-thrombosis) and bleeding (petechiae, ecchymo-
ses, mucosal, skin, and catheter hemorrhages) varying
according to the underlying cause and stage of DIC. The
clinical outcome also depends somewhat on the under-
lying cause. For example, sepsis reflects one of the main
causes of DIC, or put another way, DIC is a frequent
complication of sepsis, observed in up to 50% of septic
patients, and is a strong predictor of mortality.5,6 The
mechanisms involved in sepsis-induced DIC are more
extensively reviewed elsewhere,7–9 but in brief are likely
to involve the release of several cell membrane compo-
nents from microorganisms (lipopolysaccharide or en-
dotoxin) or bacterial exotoxins, such as staphylococcal
hemolysin, the induction of a generalized inflammatory
response through the activation of proinflammatory
cytokines, and coagulation activation and thrombin
generation via the tissue factor/factor VIIa pathway.
Additional mechanisms may involve the translocation
of cell membrane phospholipids from the inner to the
outer leaflet, or their release into the bloodstream as a
consequence of cellular breakdown. Likewise, other
underlying causes of DIC are also likely to act via similar
mechanisms involving cellular damage and the activation
of inflammatory pathways and coagulation activation
and thrombin generation via the tissue factor/factor
VIIa pathway. The severity of the effect may depend
partly on the organs involved. For example, head injuries
are those most often leading to trauma-related DIC,
reflecting in part the rich deposit of tissue factor and
phospholipids localized to the organ called the brain.10
In general, the pathogenesis of DIC is charac-
terized by simultaneous and ongoing activation of both
hemostasis and fibrinolysis, resulting in extensive and
persistent generation of thrombin and plasmin,11 as
well as progressive consumption of coagulation factors
and platelets, production of fibrin, and consequent
fibrin(ogen) degradation products (FDPs). Levels of
plasminogen activator inhibitor type 1 may also be
elevated, suggesting some imbalance between the pro-
coagulant and fibrinolytic process.12 A reduction in
antithrombin levels, a depression of the protein C
pathway, and inhibition of the tissue factor pathway
inhibitor may also occur and aggravate the clinical
course.13 The proinflammatory process can also con-
459
tinually induce coagulation, and the elevated thrombin
may act to boost the inflammatory process, thus leading
a cycle of activation that largely fails to be dampened by
the natural anticoagulant system.
LABORATORY DIAGNOSTICS IN
DISSEMINATED INTRAVASCAULR
COAGULATION
The diagnosis of DIC mostly relies on clinical signs and
is further assisted by using a combination of various
laboratory tests. It is important to diagnose DIC as early
as possible in the process to minimize the pathological
consequences and then to monitor the progress contin-
ually using laboratory testing. Clearly, the availability of
tests in urgent clinical settings mandate that the most
useful test panel would be one that is widely (i.e.,
routinely) available.1,14 In the initial stages of inflam-
mation or coagulation activation, including DIC, some
hemostasis tests will potentially show elevation in test
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parameters (e.g., fibrinogen, FVIII), and hence routine
coagulation tests in part reflective of these parameters
may be normal and in some cases even shortened (e.g., in
sepsis). However, because most patients with DIC are
tested at some stage following the initiation of this
pathogenic process, they more typically show a low or
rapidly decreasing platelet count, prolonged coagulation
tests, low plasma levels of coagulation factors (including
fibrinogen) and natural anticoagulants (i.e., protein C,
antithrombin), and increased levels of fibrin formation
(e.g., fibrin monomers) and/or degradation (i.e., FDPs
including D-dimer) (Table 1). Some of these tests would
likely be more readily available in all laboratories as
urgent, or stat, tests (e.g., platelet count, routine coag-
ulation tests, fibrinogen, D-dimer) than others (e.g.,
fibrin monomers, protein C, antithrombin). Therefore,
the most commonly recommended approaches to the
diagnosis of DIC are the use of simple scoring systems
based on a combination of routinely available coagula-
tion tests, as discussed in the section ‘‘Scoring Systems
for Disseminated Intravascular Coagulation.’’
Global Tests of Hemostasis Used in
Disseminated Intravascular Coagulation
Diagnostics
The prothrombin time (PT) is a simple, rapid, and
relatively inexpensive test that assesses the tissue factor
(‘‘extrinsic’’ and common) pathway of blood coagula-
tion.15 Although the PT is generally prolonged in most
patients with DIC, elevation often occurs in later stages
of the disease, by which time the patient outcome may
already be compromised.16 The activated partial throm-
boplastin time (APTT) is anther simple, rapid, and
relatively inexpensive test. As a global hemostasis assay,
the APTT is sensitive to several plasma inhibitors and
460 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4 2010

Table 1 Laboratory Tests Available for Assisting the Diagnosis of Disseminated Intravascular Coagulation
Test Category Test Name and Expected Patterns Comments

Global hemostatic tests
Prolongation of prothrombin time (PT),
activated partial thromboplastin time
(APTT), and thrombin time (TT)
Low or dropping level of fibrinogen
Low or dropping platelet count
Elevated FDPs including D-dimer
Abnormalities on the peripheral smear
(schistocytes, large platelets)
Presence of biphasic waveform
A normal value for these tests will not
exclude DIC (early DIC may show
activation events and elevation in
acute-phase proteins including FVIII
and fibrinogen, and a shortened APTT).
A normal value will not exclude DIC
(fibrinogen is an acute-phase protein and
may be elevated in early DIC).
Wide range of normal platelet count; additional
value in monitoring change in platelet
count over time.
A normal D-dimer can effectively rule out DIC,
but a positive D-dimer is not specific for DIC.
Need to consider local cutoff values.
Not specific for DIC
High sensitivity for DIC in sepsis, but instrument

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specific and only available in some laboratories.
Specific tests suggestive of Elevated: prothrombin fragment 1 þ 2 (F1 þ 2); These tests are not widely available or may not be
hypercoagulability fibrinopeptide A (FPA) and B (FPB); available as an urgent test procedure.
thrombin-antithrombin complexes (TAT); Not specific for DIC.
soluble fibrin monomer (sFM).
Specific tests suggestive of Decreased: antithrombin; protein C; protein S Not incorporated into common algorithms; may not
consumption of natural be available as an urgent test procedure;
inhibitors not specific for DIC.
Decreased antiplasmin Not widely available; not specific for DIC.
Elevated plasmin-antiplasmin complexes (PAP) Not widely available; not specific for DIC.
Inflammatory biomarkers Elevated: C-reactive protein (CRP); procalcitonin; Limited utility depending on setting; limited
interleukins 1, 6, and 8; tumor necrosis factor evidence base. Procalcitonin potentially
(TNF)-a; LPS-binding protein (LBP) most useful in setting of septic DIC.
White blood cell and differential counting Not specific for DIC.
Other ‘new’ tests Elevated procoagulant phospholipid Not specific for DIC.
Presence of Immature platelets (reticulocytes) Not specific for DIC.
Note: There is additional value in longitudinal monitoring of many of these tests over time, in particular the routine coagulation tests, as
discussed in the text and noted by some of the DIC scoring systems. Adapted from Lippi and Guidi.8
DIC, disseminated intravascular coagulation; FDP, fibrin(ogen) degradation product.

acquired or inherited deficiencies of coagulation factors
of the contact (‘‘intrinsic’’ and common) pathway.17
Prolonged APTTs are often seen in many patients
with DIC, but APTTs can alternatively be normal or
even shortened (e.g., mirroring the initial acute-phase–
induced activation events and increases in fibrinogen and
FVIII). Because significant prolongations often occur at
a late stage in DIC, this also compromises the overall
efficiency of this test for an early diagnosis. Moreover,
both PTs and APTTs can be prolonged in patients being
evaluated for reasons other than DIC. For example,
trauma or other hemorrhage can lead to loss of blood
and plasma components, so that prolonged coagulation
tests may simply reflect this phenomenon rather than a
pathological DIC process. Prolonged coagulation tests
can also occur with hematologic malignancies unrelated
to DIC. Accordingly, the overall clinical usefulness of
both the PT and the APTT is limited in the diagnostics
of DIC, and the results of these tests need to be
considered in the clinical context. Moreover, abnormal
values may reflect pathology other than DIC,17 and
normal values cannot be used to rule out the diagnosis.16
Fibrinogen levels often decline in patients with
DIC, due to ongoing consumption of the protein as well
as entrapment within the thrombi. However, the overall
sensitivity of plasma fibrinogen levels for the diagnosis of
DIC is also low because the protein is a well-recognized
acute-phase reactant, and levels may therefore be normal
(particularly in the early developing phase of DIC and in
patients with sepsis). Thus hypofibrinogenemia is fre-
quently detected only in very severe cases of DIC or in the
advanced stages of the disease.2,16 Again, like routine
coagulation test times, depending on the clinical context,
low fibrinogen levels can also reflect inherited or acquired
 LABORATORY TESTING FOR DISSEMINATED INTRAVASCULAR COAGULATION/FAVALORO
pathologies other than DIC (e.g., afibrinogenemia, liver
failure). More important than the absolute level of
fibrinogen in DIC, then, are longitudinal comparisons
of values over time because a sudden or dramatic drop
may reflect massive consumption, classically characteristic
of DIC.
The platelet count is considered a useful test in
the diagnosis of DIC because it strongly correlates with
markers of thrombin generation and because thrombin-
induced platelet aggregation advances platelet consump-
tion. Moreover, the platelet count is not influenced by
the acute-phase response. However, because the normal
platelet count varies considerably among individuals
(
150 to 450  109/L), a single determination might
not reliably identify DIC, and like the case for fibrino-
gen, a longitudinal assessment of data will provide more
value in DIC diagnostics. Also, like the case for fibri-
nogen and routine coagulation tests, many of the under-
lying conditions associated with DIC (e.g., infections,
malignancy, or anticancer therapy) as well as other life-
threatening pathologies (e.g., heparin-induced throm-
bocytopenia) can cause a low platelet count in the
absence of DIC.18–20 Accordingly, ongoing reduction
in the platelet count, determined at intervals between 1
and 4 hours, may better identify intravascular platelet
aggregation through increasing thrombin generation.
Conversely, a stable platelet count suggests that intra-
vascular platelet aggregation (and thrombin formation)
is not occurring or has ceased.2,16
Markers of Fibrin Production and Breakdown
Elevated fibrin or FDPs (including D-dimer) and ele-
vated soluble fibrin monomers are known to be highly
sensitive for the diagnosis of DIC, and elevations of their
values often precede overt DIC by several days, but these
tests are not specific for DIC.21,22 The sensitivity of
these tests range from
90 to 100%, depending on the
assay and the relative cutoff chosen to distinguish normal
and abnormal levels.11 Except for some geographic
localities (notably Japan22), total FDPs and fibrin mono-
mer testing is no longer readily available, and currently,
D-dimer testing has largely replaced most other markers
of fibrinolysis in general clinical and laboratory practice,
for both DIC and the diagnosis of thrombotic disor-
ders.23 In the 2003 meeting of the ISTH Scientific and
Standardization Committee (SSC) on DIC, D-dimer
was also proposed as the ideal fibrin marker among the
diagnostic algorithm for DIC.24 As for the other labo-
ratory tests, however, the utility of D-dimer testing alone
is limited. Although this test has a high negative
predictive value, the positive predictive value is poor
because a positive D-dimer can occur in patients for a
variety of reasons other than DIC. Moreover, due to
poor standardization and harmonization among the
different commercial assays available on the market,
461
the choice of the most predictive threshold for the
diagnosis of DIC is crucial but sometimes unavailable.
Different assays may use different cutoffs, and these are
not interchangeable.23 Moreover, D-dimer thresholds
may be locality dependent, and for example, normal
Japanese people appear to show values of D-dimer that
are twice those comparable in European test centers,22
mandating local revision of cutoff values in that locality.
Nevertheless, D-dimer testing can be used within a rule-
out strategy that incorporates several other pieces of
clinical and laboratory evidence and takes these variables
into consideration.
Consumption of Natural Inhibitors in
Disseminated Intravascular Coagulation
The natural anticoagulants, especially antithrombin and
protein C, are frequently reduced in patients with DIC,
and these reductions may also have prognostic signifi-
cance.13,25,26 For example, a decrease in plasma antith-
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rombin levels <50% of normal is strongly associated
with increased mortality in patients with DIC due to
sepsis,27 and in surgical patients with sepsis antithrom-
bin levels <70% and 65%, they are associated with a 90%
and 100% mortality, respectively.28 Moreover, lower
initial antithrombin levels in neonatal sepsis are asso-
ciated with a severe disease and increased mortality,29
antithrombin levels were found to provide the best
prognostic value for prediction of subsequent death in
patients affected by septic shock,30 and protein C
concentrations in neutropenic patients affected by sep-
tic shock has also been reported to provide a significant
prognostic value.31
Although a significant decrease in the level of
these natural inhibitors may provide valuable informa-
tion for establishing a diagnosis of DIC and monitoring
the clinical course of the disease, these tests (unlike the
routine tests previously noted) are not commonly avail-
able in all laboratories, nor are they always available as an
urgent test procedure. Moreover, the ISTH SSC on
DIC recently concluded there was no added value in
including their estimation within the conventional four-
test-parameters scoring system (see next section).32
Nevertheless, their measurement might be helpful in
selected situations, in assessing for non-overt DIC or the
severity of DIC, in monitoring of therapy, and in an
assessment of the prognosis.33
SCORING SYSTEMS FOR DISSEMINATED
INTRAVASCULAR COAGULATION
A scoring system for DIC was established by the Japanese
Ministry of Health and Welfare (JMHW) in 1987.34
These diagnostic criteria were based on the presence of
underlying disease, bleeding, organ failure, and the results
of global coagulation tests (Table 2). The ISTH SSC on
 462

Table 2 Summary of Disseminated Intravascular Coagulation Scoring Systems

ISTH SSC Scoring ISTH SSC Scoring
Scoring System System for ‘‘Overt’’ System for ‘‘Non-Overt’’ JMHW Scoring JAAM Scoring KSTH Scoring
(footnotes/references): DICa,c1,32 DICb,c1,32 System for DICd34,36 System for DICe37,38 System for DICf41

Parameter Parameter Value

or Range ¼ Score
Platelet count (109/L) >100 ¼ 0 >100 ¼ 0 HPT patients only: 120 ¼ 0 <100 ¼ 1
<100 ¼ 1 <100 ¼ 1 120 ¼ 1  80 and <120 or >30% fall in 24 h ¼ 1
<50 ¼ 2 Rising ¼  1 80 ¼ 2 <80 or >50% fall in 24 h ¼ 3
Stable ¼ 0 50 ¼ 3
Falling ¼ 1
(Elevated) fibrin related No increase ¼ 0 Normal ¼ 0 FDPs (mg/mL): FDPs (mg/L): D-dimer: Increased ¼ 1
markers (e.g., FDPs, D-dimer)
Moderate increase ¼ 2 Raised ¼ 1 10 ¼ 1 <10 ¼ 0
Strong increase ¼ 3 Falling ¼ -1 20 ¼ 2 10 and <25 ¼ 1
Stable ¼ 0 40 ¼ 3 25 ¼ 3
Rising ¼ 1
(Prolonged) <3 s ¼ 0 <3 s ¼ 0 PT ratio: PT ratio: >3 s (or prolongation
prothrombin time (PT) of APTT >5 s) ¼ 1
>3 but <6 s ¼ 1 >3 s ¼ 1 1.25 ¼ 1 <1.2 ¼ 0
SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4

>6 s ¼ 2 Falling ¼ 1 1.67 ¼ 2 1.2 ¼ 1

Stable ¼ 0
2010

Rising ¼ 1
Fibrinogen >100 ¼ 0 Not included 150 ¼ 1 350 ¼ 0 <150 ¼ 1
level (mg/dL)
<100 ¼ 1 100 ¼ 2 <350 ¼ 1
(not included in revised criteria)
Additional tests/scoring No Yes (see notes) Yes (see notes) Yes (see notes) No
a
ISTH SSC scoring system for ‘‘Overt’’ DIC: (1) Requires prior risk assessment to confirm that the patient has an underlying disorder known to be associated with overt DIC; (2) An overall cumulative score
of 5 is compatible with overt DIC. A score <5 may be indicative (but not affirmative) of non-overt DIC.
b
ISTH SSC scoring system for ‘‘non-overt’’ DIC: (1) Requires prior risk assessment to identify if the patient has an underlying disorder known to be associated with DIC, with this adding to score (yes ¼ 2;
no ¼ 0); (2) Includes ‘‘specific’’ criteria with this adding to score using antithrombin, protein C, TAT-complexes (etc.) that each score add 1 if low, and subtract 1 if normal; (3) includes scoring for changing
values of routine tests over time; (4) in the original publication1 the authors did not provide guidance on the likelihood of DIC according to the score and instead indicated that ‘‘prospective validation of a
given score is needed’’; some data on validation were provided in the subsequent publication, and a score of 5 was considered as permitting the diagnosis of non-overt DIC.32
c
For both ISTH SSC scoring systems: (1) PT ¼ seconds above upper limit of reference range; (2) Degree of elevation in fibrin-related markers to be locally defined.
d
JMHW (Japanese Ministry of Health and Welfare) scoring system for DIC: (1) Underlying disease adds 1 point; (2) organ failure due to thrombosis adds 1 point; (3) differentiates between patients with
(HPTþ) and without (HPT) hematopoietic malignancies, such that bleeding symptoms in HPT add 1 point and platelet count changes do not score in HPTþ; (4) DIC is diagnosed when the cumulative score
is 4 in HPTþ or 7 or more in HPT.
e
JAAM (Japanese Association for Acute Medicine) scoring system for DIC: (1) Underlying disease taken into account, so that the presence of 3 ‘‘systemic inflammatory response syndrome criteria’’ add 1
point to score; (2) DIC is diagnosed when the cumulative score is 5; (3) the revised JAAM criteria removed fibrinogen from the scoring system, in which case DIC is diagnosed when the cumulative score
is 4.
f
KSTH scoring system for DIC: (1) This is the simplest of the scoring systems but is the least validated; (2) a score of 3 identifies overt DIC.
HPT, hematopoietic tumor; FDP, fibrin(ogen) degradation product; APTT, activated partial thromboplastin time.

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 LABORATORY TESTING FOR DISSEMINATED INTRAVASCULAR COAGULATION/FAVALORO
DIC developed scoring systems for both ‘‘overt’’ and
‘‘non-overt’’ DIC in 2001 (Table 2).1 These two separate
scoring systems have been evaluated and compared in
several published studies,35–41 including one by the Jap-
anese Association for Acute Medicine (JAAM) DIC
Study Group in 2006, who also reported their own
DIC diagnostic criteria for critically ill patients
(Table 2).37 Although there are some similarities between
the different scoring systems, there are also several
notable differences.
In one Japanese study involving 1284 people
with DIC, the rate of agreement in the diagnosis of
DIC by the ISTH SSC overt-DIC and JMHW DIC
criteria was 67%, and only 2% of non-DIC patients by
JMHW criteria were diagnosed with overt DIC by
ISTH criteria.36 Better concordance was obtained in
select clinical groups, namely those with trauma or
acute promyelocytic leukemia. An abnormal PT scoring
>1 by these criteria was observed in 70% of patients
with DIC or overt DIC, but 50% of these scored 0
points for fibrinogen. Abnormal FDPs and platelet
counts were seen in >88% of patients with DIC or
overt DIC, but were also seen in >50% of non-DIC
patients, consistent with the high sensitivity but poor
specificity otherwise reported for these tests. This study
concluded that these scoring systems could be improved
by tweaking the cutoff values for the global hemostasis
tests.
The JAAM DIC, ISTH SSC overt DIC, and
JMHW DIC scoring algorithms were also prospec-
tively evaluated in 273 patients with platelet counts
<150  109/L.37 The JAAM DIC system was found
to be the most sensitive for early diagnosis. Two
subsequent prospective surveys demonstrated the nat-
ural history of DIC patients diagnosed by the JAAM
DIC diagnostic criteria in a critical care setting,
highlighting a progression from the JAAM DIC to
the ISTH SSC overt DIC,38 especially in patients
with sepsis,39 and thus enabling these patients to
receive early treatment when using the JAAM DIC
criteria. Another recent study by the JAAM
DIC Study Group showed that >50% of the JAAM
DIC patients with sepsis who died within 28 days
would be missed using ISTH DIC criteria during the
initial 3 days.40
The Korean Society on Thrombosis and Hemo-
stasis (KSTH) has also evaluated the ISTH SSC
criteria for overt DIC against criteria it reported had
been established in 1993 (Table 2).41 Using 131 admit-
ted patients clinically diagnosed with DIC, 79 were
identified by the ISTH SSC criteria, and 63 by the
KSTH, with a concordance rate of 84.7%. Better
concordance was obtained by tweaking the cutoff values
for fibrinogen. Interestingly, fibrinogen has been re-
moved from the revised JAAM DIC scoring system
(Table 2).
463
A 5-year overview by the ISTH SSC on DIC has
recently confirmed that a score of 5 using the ISTH
SSC overt DIC criteria can reliably identify overt DIC,
with a sensitivity of 91% and a specificity of 97%.32 It
was also shown that patients with overt DIC diagnosed
according to the ISTH overt DIC score had a signifi-
cantly higher risk of death and of developing septic
shock. However, the utility of individual markers to
this process was highly dependent on the underlying
cause of the DIC. For example, >95% of septic patients
will have elevated fibrin-related markers, and so the DIC
score would be strongly dependent on prolongation of
the PT and reduction in the platelet count.35 A similar
limitation in utility of fibrin-related markers will in fact
also be obvious for many other causes of DIC. The
ISTH SSC overview also reflected on the variation in
reporting of laboratory results in different studies for PT
and in the cutoff values or definitions of moderate or
strong increases for D-dimer.
Finally, the British Committee for Standards in
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Haematology recently released their guidelines for the
diagnosis and management of DIC,26 identifying that
the ISTH DIC scoring system provides objective meas-
urement of DIC, and further, that the scoring system
correlates with key clinical observations and outcomes
where DIC is present.
There are several take-home messages here.
First, despite the general utility of all the noted diag-
nostic scoring systems for DIC, it is unlikely that any
will prove 100% sensitive, and none will be specific for
DIC. Accordingly, a clinical perspective, encompassing
the identification of the underlying disease and the
differentiation of presumptive DIC with other pathol-
ogies, is critical to the diagnosis of DIC and also
generally recognized within the scoring systems. Sec-
ond, the ISTH SSC overt-DIC criteria are intended to
identify overt DIC and may fail to identify non-overt or
early-stage DIC. The ISTH SSC non-overt DIC
criteria are more likely able to identify non-overt DIC
than the overt DIC criteria, but they are less well
investigated than the overt DIC criteria, and they also
rely on tests that may not be readily available in all test
centers or else not available as an urgent test procedure.
Third, although the Japanese DIC criteria have been
reported to better identify the early stages of DIC than
the ISTH SSC overt DIC criteria, they incorporate the
measurement of total FDPs (i.e., fibrin and FDPs), and
this test is no longer generally available in many geo-
graphic localities, being replaced by the D-dimer test in
most centers. Fourth, the utility of some of these
scoring systems (notably ISTH and KSTH) depends
in part on local establishment of cutoff values for
recognizing an elevation in fibrin-related markers.
Similarly, the cutoff values used for FDPs in the
Japanese scoring systems may not reflect appropriate
cutoff values in other localities.
464 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
ADDITIONAL INVESTIGATIONS FOR
DISSEMINATED INTRAVASCULAR
COAGULATION
Differential Diagnosis of Disseminated
Intravascular Coagulation versus Other Causes
of Laboratory Test Abnormalities
In part, the process of diagnosing DIC requires a clinical
and laboratory assessment of differentiating the pathology
of DIC from alternative pathologies. Many disorders of
hemostasis can be reflected in abnormalities in the pre-
viously outlined hemostasis assays. Thus elevations in the
PT and APTT may simply reflect the effects of anti-
coagulants (e.g., heparin used to flush a central line), liver
disease, myeloproliferative disease, lupus anticoagulants,
and specific factor inhibitors.15,17,42 The modern hemo-
stasis laboratory possesses various tools to help differ-
entiate at least some of these processes and thus assist the
clinician in affirming or excluding the diagnosis of DIC.
As some additional specific examples, the fol-
lowing can be considered. In critically ill patients,
thrombocytopenia is commonly observed. However,
DIC-associated thrombocytopenia may account for
only about a quarter of cases, with sepsis, blood loss,
and drug-induced causes explaining most cases.43 Sev-
eral diagnostic clues are available to differentiate these
possibilities, such as blood cultures (sepsis), low hemo-
globin (blood loss), and so on, as largely detailed else-
where.43 Similarly, although low levels of antithrombin
and/or protein C can be associated with DIC, low levels
could also be related to liver disease or other acquired
causes. To complicate matters, people with hepatic
failure may also develop DIC.44
Additional Laboratory Investigations
The APTT may hold additional promise within the
context of DIC than its traditional use, as previously
noted. The APTT is the second most common test of
hemostasis performed in clinical laboratories after the
PT.15,17 Clinicians and laboratories conventionally at-
tempt the identification of abnormalities in the end
point of this test (i.e., prolongation of the clotting
time) to identify quantitative and qualitative deficiencies
in the contact pathway of coagulation, including DIC.
The APTT is also used for monitoring anticoagulant
therapy with unfractionated heparin and for detecting
inhibitors of blood coagulation. However, other aspects
of the APTT have recently been explored, and this has
relevance to the investigation of DIC, as explained next.
Waveform Analysis
During the APTT clotting process, fibrinogen is con-
verted to fibrin, which causes a change in the opacity (or
turbidity) of the plasma and reagent mixture. This
2010
change in turbidity can be detected by automated instru-
ments as a change in light transmission or absorbance. In
some instruments, the entire process of clot formation
can be visualized and thus assessed. Interestingly, an
atypical profile of clot formation has been observed in
some patients with hemostatic dysfunction. In early
studies using an MDA-180 automated coagulation ana-
lyzer, a ‘‘biphasic waveform’’ was identified when a
decrease in plasma light transmittance before clot for-
mation was observed, and this was later shown to be a
hallmark of critically ill patients with DIC.45,46 Thus,
although the normal sigmoidal waveform pattern is
characterized by an initial 100% light transmittance
phase before clot formation, the biphasic patterns ob-
served in these studies identified an immediate, pro-
gressive decrease in light transmittance that occurred
even in the preclotting phase. The mechanisms under-
lying the biphasic waveform have not been definitely
elucidated, although C-reactive protein (CRP), whose
levels are persistently elevated in sepsis, and very low
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density lipoproteins or intermediate density lipoproteins
have been implicated to form macroscopic precipitates
upon recalcification of plasma.47
Further evidence of the potential value of APTT
waveform analysis in identifying both the presence and
overall mortality in patients with DIC continues to be
reported.48,49 For example, the prevalence of the biphasic
waveform is as high as 87% (odds ratio: 29.9) and 75%
(odds ratio: 19.0) in patients with septic DIC diagnosed
by the ISTH and the JMHW scores, respectively.49 Thus
the biphasic waveform has modest sensitivity (59.2% for
the ISTH score; 47.9% for the JMWH score) but high
specificity (95.4% for both scores) for DIC.49 Similar
findings were reported by Bakhtiari et al, where the
biphasic waveform was observed in only a third of
patients with a clinical suspicion of DIC but actually
correlated well with the presence of disease (sensitivity
88%, specificity 97%).50 The APTT biphasic waveform-
based diagnosis of DIC also preceded that based on the
traditional ISTH scoring system in nearly 20% of the
patients assessed. More extensive reviews of the value of
waveform analysis are provided elsewhere.8,17,51,52
However, although APTT waveform analysis
might be a promising, inexpensive, and rapid test in
the diagnosis of DIC in some settings such as severe
sepsis (with both sensitivity and negative predictive value
>90%), as well as for the prognosis of these patients, and
perhaps providing data much earlier than traditional
score systems permit,53 this facility is currently only
provided by a single instrument, the MDA-180, and
so it would not be available in most test laboratories.
Procoagulant Phospholipids
Conventional clotting tests such as the PT or APTT
normally contain relatively high levels of phospholipid,
 LABORATORY TESTING FOR DISSEMINATED INTRAVASCULAR COAGULATION/FAVALORO
and so they tend to be undersensitive to any excess
procoagulant phospholipids (PPL) present in test sam-
ples. The exception here may be the APTT, depending
on the test reagent used, and the level of phospholipid
included (which will differ between reagents). Also, as
previously noted, the APTT may be short in some
patients with early DIC. It has always been assumed
that this shortening reflects activation events and ele-
vation of acute-phase proteins (notably fibrinogen and
FVIII). However, in a recent general investigation into
short APTTs unrelated to DIC, my research group
observed that short APTTs were associated with a
wide variety of altered hemostasis, including the pres-
ence of additional PPL, as detected by a novel test called
activated factor X-activated clotting time (XACT).54 In
contrast to the PT and the APTT, the XACT assay has
been purposely designed to be sensitive to test plasma
provided PPL.55 In vivo, PPL is likely provided mainly
by platelets localized to, and activated at, a site of injury.
Activated platelets usually aggregate but can also release
PPL-rich microparticles of various size that are other-
wise detectable in circulation using various other meth-
ods including enzyme-linked immunosorbent assay or
flow cytometry.56,57 The XACT test is a functional assay
sensitive to these presentations of PPL, and hence the
elevation of PPL within short APTT test samples would
suggest heightened PPL availability, with potential
hypercoagulable status. The XACT test has also recently
been evaluated in several other settings, where it has
been shown to be effective in identifying the elevation of
PPL in specific potential prothrombotic settings such as
diabetes mellitus, sickle cell disease, and thyroid can-
cer.58–60 Of more relevance to the current review, the
XACT assay has recently been identified as a potentially
useful diagnostic and prognostic marker for DIC. Most
notably, among various potential markers (including the
endogenous thrombin potential (ETP) and the throm-
bin-antithrombin complex, or TAT), the XACT served
as a good predictor of the 28-day mortality in patients
suspected of having DIC.60 Moreover, higher XACT
and TAT values were obtained in overt DIC nonsurvi-
vors than from survivors. The odds ratio of XACT for
the relative risk (and 95% confidence interval) of 28-day
mortality was 9.60 (3.53 to 26.11), that of TAT was 5.18
(2.11 to 12.72), and that of ETP 7.66 (1.67 to 35.17).
For the diagnosis of overt DIC, the odds ratio of XACT,
TAT, and ETP were 37.35 (4.86 to 286.89), 4.89 (1.93
to 12.43), and 4.89 (1.98 to 12.09), respectively. There
was a negative correlation between the TAT and ETP
(r ¼ 0.223; p ¼ 0.012) and a positive correlation be-
tween the TAT and XACT (r ¼ 0.251; p ¼ 0.004).
Additional Platelet-Related Parameters
The platelet count has already been discussed within the
context of DIC investigation. There are additional
465
platelet-derived parameters that may in time emerge to
better assist in the diagnosis of DIC. For example, the
presence of reticulated platelets, measured as an imma-
ture platelet fraction, and plasma thrombopoietin are
markers of platelet production, and measurement of
these may improve the identification of DIC. In one
recent study, both were significantly increased in overt
DIC as well as correlating with the DIC score using the
ISTH overt DIC criteria.61 Moreover, the presence of
reticulated platelets correlated with FDPs, and both the
immature platelet fraction and plasma thrombopoietin
showed better mortality prediction than platelet count.
Inflammatory Biomarkers
DIC is often associated with, or consequent to, a process
of inflammation. Thus, for a comprehensive investigation
of DIC in certain clinical settings, for example sepsis, the
evaluation of several inflammatory biomarkers might be
of additional value, and these might also be available in
Downloaded by: Universite Laval. Copyrighted material.
some laboratories for routine or urgent diagnostics. This
would include CRP, differential blood counting, the
cytokines interleukin (IL)-6, IL-8, tumor necrosis fac-
tor-a, procalcitonin and the lipoprotein-binding protein
(LBP).62 However, these will have differential utility,
some will have limited utility, and only a few will
ultimately make a real impact in the managed care of
patients with DIC, as largely reviewed elsewhere.8,63
CONCLUSIONS
Although the diagnosis of DIC benefits from the con-
tribution of laboratory diagnostics, no single test result
alone can definitely establish or rule out the disease.
When approaching patients with suspected DIC, it is
therefore essential to consider a constellation of param-
eters relevant to the specific context being investigated,
including clinical signs and symptoms, the identification
of the potential underlying disease, the differentiation of
DIC from alternative possible pathologies, and, last but
not least, the results of laboratory testing in this inves-
tigation.
There are a battery of tests available, but some tests
are more useful than others. It is important to investigate
early in the condition, and then to undertake regular
monitoring, choosing the tests most readily available and
most likely to provide useful information within this
process. Global tests of hemostasis such as PT, APTT,
fibrinogen, and platelet count provide important evidence
of activation of blood coagulation and eventually con-
sumption of coagulation factors, but their diagnostic
efficiency is incomplete because normal values cannot
be used to rule out DIC, and abnormal values may reflect
a disease process unrelated to DIC. Fibrinolytic markers
(namely D-dimer) reliably reflect the extent of activation
of both coagulation and fibrinolysis, so that normal values
466 SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 36, NUMBER 4
can reliably rule out the disease, but elevation may or may
not reflect DIC.
Other tests of hemostasis, such as antithrombin
and protein C, may have value in select cases because
decreased levels may identify a consumptive coagulop-
athy and are frequently observed in patients with septic
DIC, but these tests may not be routinely available,
levels may reflect alternative pathologies, and they are
not currently incorporated in any of the widely used
diagnostic algorithms (except for the ISTH SSC non-
overt DIC scoring system). The evaluation of inflam-
matory biomarkers such as procalcitonin may also be of
value in select investigations, in particular septic DIC.
Finally, additional laboratory investigations may also be
of value such as an assessment of procoagulant phos-
pholipids as well as waveform analysis should these tests
and instrumentation be readily available.
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