COAGULATION
Sunil Badve, MD, MRCP
D-Dimer Measurements
Unhelpful for Ruling In DIC
Disseminated intravascular coagulation (DIC) is a
thrombohemorrhagic syndrome characterized by
diffuse intravascular activation of the coagulation
system. Diagnosis is difficult because the clinical
manifestations are not uniform and there is no
consensus regarding the appropriate tests for lab-
oratory diagnosis. Despite these drawbacks, most
clinicians rely on D-dimer test results to indicate
the presence or absence of DIC. This questionable
practice is the subject of our investigation. The
minimal criteria for the clinical diagnosis of DIC
include evidence of hemorrhage, thrombosis, or
both, occurring in the appropriate clinical settings.
These signs and symptoms may also be seen in
thrombotic thrombocytopenic purpura, hemolytic-
uremic syndrome, and other disorders. Physicians
use the following laboratory findings to differentiate
DIC from these conditions: (1) thrombocytopenia
or a rapidly falling platelet count; (2) prolongation
of the prothrombin time (PT), activated partial
thromboplastin time (aPTT), or both; (3) detection
of fibrin degradation products in plasma; and (4)
low levels of antithrombin III.1,2 This constellation
of abnormalities is also emblematic of other condi-
tions such as sepsis, liver disease, and vitamin K
deficiency. In practice, physicians rely on D-dimer
results to distinguish DIC from these conditions,
and a positive value is often considered diagnostic
of DIC. In this study, we evaluated the accuracy of
D-dimer as a marker of DIC in patients admitted
to medical or surgical intensive care units (ICUs).
In all patients, the values of common coagulation
parameters were within the reference ranges. We
correlated these data with Acute Physiological and
Chronic Health Evaluation (APACHE) II3 scores
(indices of disease severity) to determine whether
D-dimer levels are affected by the severity of
underlying disease.
Edward R. Burns, MD
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ABSTRACT Physicians often use D-dimer assay results to
corroborate the diagnosis of disseminated intravascular
coagulation (DIC). We determined whether the results of this
nonspecific assay helped to diagnose DIC in a group of patients
admitted to the intensive care unit (a setting in which patients
are often evaluated for this condition). We defined DIC in
accordance with the following findings: systemic bleeding,
prothrombin time (PT) more than 3 seconds above the reference
range (or both); a fibrinogen level less than 150 mg/dL (1.5 g/L);
and a platelet count less than 100 3 103/mL (100 3 109/L). For
each patient, we calculated the Acute Physiological and Chronic
Health Evaluation (APACHE) II score for illness and measured
the PT, fibrinogen level, platelet count, and (semiquantitative)
Scientific Communications
D-dimer level. The D-dimer result was positive in 31 of 50
patients (62%); for all 50 patients, the PT, fibrinogen level, and
platelet count were within the reference ranges. None of these
patients had clinical or laboratory evidence of DIC. We found no
correlation between D-dimer results and (1) clinically observed
deep venous thrombosis or pulmonary embolus; and (2) PT,
level of fibrinogen, or platelet count. The mean ± SD APACHE
II scores of D-dimer–negative patients were lower than those of
the D-dimer–positive patients (13.4 ± 1.4 vs 16.2 ± 1.1, P =
4
.006) but did not correlate with the degree of D-dimer positivity.
Section
The mean ± SD fibrinogen level of the D-dimer–negative group
(456 ± 295 mg/dL [4.6 ± 3.0 g/L]) was not significantly different
from that of the D-dimer–positive group (393 ± 187 mg/dL [3.9
± 1.9 g/L], P = .36). We conclude that D-dimer levels are
elevated in most critically ill patients irrespective of their
hemostatic or thrombotic symptoms. The D-dimer assay should
not be used to diagnose DIC in this patient population because it
adds no specificity; it should be used only to rule out DIC.
From the Departments of Pathology and Medicine, Albert Einstein College of
Medicine, Bronx, NY.
Reprint requests to Dr Burns, Department of Pathology, Albert Einstein College
Hospital, 1825 Eastchester Rd, Bronx, NY 10461-2377; or e-mail:
eburns@aecom.yu.edu
J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E 383
 Materials and Methods
We studied hemostatic parameters in 50 critically
ill patients in whom DIC was ruled out on the
basis of clinical and laboratory parameters (not
including D-dimer). We defined clinical DIC as a
condition characterized by systemic bleeding, pro-
longed PT, or both; low plasma fibrinogen level;
and low platelet count. The DIC was considered
subclinical when we found combined abnormali-
ties of the PT, fibrinogen level, and platelet count
(even without systemic bleeding). We collected
prospective clinical and laboratory data from
patients admitted to a medical-surgical ICU. For
each patient, the PT, aPTT, and platelet count fell
within the reference ranges. For this study, we
defined reference ranges for PT, aPTT, platelet
counts, and fibrinogen levels. We considered PT
and aPTT readings normal if they were within 3
seconds of the mean PT or aPTT levels of 50
healthy control subjects. For platelets, we consid-
ered counts higher than 100 3 103/mL (100 3
109/L) as normal; for fibrinogen, levels above 150
mg/dL (1.5 g/L) were considered normal.
To calculate the APACHE II score for each
patient, we collected clinical and laboratory data
within the first 24 hours of admission. We
excluded patients with clinical, laboratory, or
imaging data that suggested the presence of pul-
monary embolism, deep venous thrombosis, or
myocardial infarction. We included clinical his-
tory and physical examination data in the
APACHE II calculation.
In compliance with Committee on Clinical
Investigation policy, citrated blood samples taken
for routine coagulation monitoring within the
first 24 hours of admission were sequestered for
further analysis. We used the Electra 1600 (MLA
Laboratories, Mt Vernon, NY) to measure PT and
plasma fibrinogen levels and a Sysmex SE9000
(Sysmex, Long Grove, IL) to count platelets. Low
counts were confirmed by peripheral blood smear
review. We measured D-dimer levels with a mouse
monoclonal latex agglutination test (D-Di test,
Diagnostica Stago, France) and tested serial dilu-
tions of plasma to obtain semiquantitative levels
of D-dimer. The D-dimer level—expressed as
mg/L of D-dimer units—was the middle concen-
tration of the dilution that agglutinated the latex
beads. Levels exceeding 250 mg/L were considered
positive. Results are given as mean ± SD unless
otherwise stated.
384 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0
Results
D-dimer results were positive in 31 of 50 patients
(62%) who had no clinical evidence of DIC, sys-
temic bleeding, deep venous thrombosis, or pul-
monary embolus. D-dimer was not detected in
any of 10 healthy blood donors. In 3 of 31 D-
dimer–positive patients, levels exceeded 4,000
mg/L; among the other patients, D-dimer levels
were 3,000 (4 patients), 1,500 (10 patients), 750 (8
patients), and 375 mg/L (6 patients).
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We found no correlation between D-dimer
results and PTs, fibrinogen concentrations, or
platelet counts. The APACHE II scores of D-
dimer–negative patients were lower than those of
the D-dimer–positive patients (13.4 6 1.4 vs 16.2
6 1.1, P = .006), but the scores did not correlate
with the degree of D-dimer positivity. The fibrino-
gen level of the D-dimer–negative group (456 6
295 mg/dL [4.6 6 3.0 g/L]) did not differ signifi-
cantly from that of the D-dimer–positive group
(393 187 mg/dL [3.9 6 1.9 g/L], P = .36). There
was a significant positive correlation between the
D-dimer levels and patient age. The patients in this
series were 18 to 96 years old (mean, 66.5; median,
71). The average age of D-dimer–positive patients
(66.4 years) did not differ from that of D-
dimer–negative patients (66.7 years). The D-dimer
test result was positive, however, in 14 of the 20
patients older than 75 years (70%).
There was no clear-cut relationship between
the D-dimer assay results and the presenting clin-
ical diagnosis. The table gives some common diag-
noses and their D-dimer results.
Discussion
The APACHE II is widely used to assess the sever-
ity of patient conditions. In addition to assessing
neurologic, respiratory, cardiovascular, renal, and
hematologic systems, the score also considers age,
chronic ill health, and whether the patient was
admitted to ICU for elective or emergency surgery.
The score is an objective clinical parameter to cor-
relate these variables with laboratory findings.
Because conditions leading to ICU admission
predispose to DIC, DIC is common in the ICU
setting. Diagnosis of DIC requires a high degree of
clinical suspicion and is often imprecise. Alter-
ations in PT and aPTT, although typical of DIC,
have little specific diagnostic value, as do tests for
specific coagulation factors. Although platelet
counts are often low in DIC, they may also be
reduced in sepsis, the use of a host of medications,
and many other situations. If low, plasma fibrino-
gen levels may contribute to diagnosis but to a
limited extent because fibrinogen, as an acute
phase reactant, may exist at normal or even ele-
vated levels in DIC. Tests for fibrin degradation
products have also been used to diagnose DIC, but
their nonspecific reactivity produces many false-
positive results. For this reason, tests for fibrin
degradation products have been replaced by the
D-dimer assay.
The D-dimer assay was developed to detect a
specific type of degradation product formed by
cross-linking 2 “D” fragments of the fibrin mole-
cule. The assay, which uses a monoclonal antibody
to detect free circulating D-dimer, comes in both
enzyme-linked immunosorbent assay and latex
agglutination formats. Reliability depends on the
monoclonal antibody,4,5 and results are positive in
DIC and other fibrinolytic conditions. Thus, the
results are considered helpful in detecting pul-
monary embolism and deep venous thrombosis,6–8
a claim that has been challenged.9 D-dimer assay
results are also positive in patients with myocardial
infarction after thrombolytic therapy.
In this study, we tested the reliability of the D-
dimer assay as a single marker for diagnosing DIC.
For this reason, we excluded patients with
myocardial infarction, pulmonary embolism, and
deep venous thrombosis. We studied routine
hemostatic parameters in 50 critically ill patients
in whom we had ruled out DIC on the basis of
clinical and laboratory findings. The patients
showed no evidence of systemic bleeding or fibri-
nolysis, and their PTs, fibrinogen levels, and
platelet counts were within the reference ranges,
thereby excluding subclinical DIC. We measured
PT, fibrinogen levels, and semiquantitative D-
dimer levels (by latex agglutination) on the same
sample of citrated blood and obtained platelet
counts from blood samples taken at the same
time. Although the results of any one of these tests
may fall within the reference range in DIC, it is
unlikely that they all would. Thus, we could say
that none of the 50 patients had DIC, even though
most had elevated D-dimer levels.
In addition to DIC, deep venous thrombosis,
and pulmonary embolism, increased levels of cir-
culating D-dimers have been reported in cirrhosis,
sickle cell anemia, and certain cancers.10 D-dimer
levels generally rise during the first 2 to 3 days
after surgery,10 which is considered evidence for
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lytic activity directed against the fibrin formed as
a result of surgery. This partly explains the limited
postsurgical usefulness of the D-dimer test.
Elevated D-dimer levels have been reported in
a variety of tumors. For example, they have been
used as a preoperative prognostic indicator for
ovarian carcinoma because high D-dimer levels
correlate with higher stages of the disease.11,12 Ele-
vated levels are also found in other gynecologic
tumors,11-14 as well as carcinoma of the lung,15
breast,16 colon and rectum,17,18 prostate gland,19
and thyroid gland.20 Thirteen of our 50 patients
had a malignant neoplasm. Of these, 8 were
admitted to ICU for symptoms directly related to
the neoplasm. The incidence of D-dimer positivity
was 62% in these patients. Of the 20 patients in
the geriatric age group, 14 were positive for D-
dimer (70%). Elevated D-dimer levels have been
Scientific Communications
reported in a significant proportion of the healthy
geriatric population,21,22 the increase considered
to be the result of higher fibrinogen concentra-
tions in elderly people, a slower urinary excretion
of D-dimer, more frequent fibrin generation,
occult disease, risk factors, inflammatory disor-
ders, and degenerative vascular damage. D-dimers
are cleared by both macrophages and the kidney. A
low creatinine clearance correlates inversely with a
high concentration of D-dimer.21
4
Because D-dimer results without other coagu-
Section
lation and fibrinolytic findings are nonspecific,
they cannot be used alone to diagnose DIC.
Results are positive in conditions ranging from
advanced age and physical activity to surgery and
cancer. In addition, the commonly used latex agglu-
tination assay (used in this study and in others) to
diagnose or exclude pulmonary embolism is non-
specific owing to observer dependency.23 To diag-
nose DIC, we need tests without these drawbacks.
J U LY 2 0 0 0 VO L U M E 3 1 , N U M B E R 7 L A B O R ATO RY M E D I C I N E 385
 Prevalence of D-Dimer Levels With Different Diagnoses
Diagnosis No. of Positive Results/Total
Cancer 8/11
GI hemorrhage 5/7
CVA 2/4
Surgery 1/3
Sickle cell crisis 1/2
Sepsis 1/2
GI, gastrointestinal; CVA, cerebrovascular accident.
New tests based on endothelial cell markers24,25 or
neutrophil activation products26 may prove more
useful for DIC diagnosis and prognostication. In
the interim, we recommend using the semiquanti-
tative D-dimer assay (when results are negative)
only to rule out DIC, not to diagnose it.l
References
1. Bick R. Disseminated intravascular coagulation: objective
clinical and laboratory diagnosis, treatment, and assessment of
therapeutic response. Semin Thromb Hemost. 1996;22:69-88.
2. Levi M, Ten Cate H. Disseminated intravascular coagula-
tion. N Engl J Med. 1999;341:586-592.
3. Knaus W, Draper E, Wagner D, et al. APACHE II: a severity
of disease classification system. Crit Care Med. 1985;13:818-829.
4. Nieuwenhuizen WF. A reference material for harmonisa-
tion of D-dimer assays. Fibrinogen Subcommittee of the Sci-
entific and Standardization Committee of the International
Society of Thrombosis and Haemostasis. Thromb Haemost.
1997;77:1031-1033.
5. Eisenberg P, Rylatt D, Rusticali F, et al. The importance of anti-
body specificity in measuring the cross-linked fibrin degradation
products by ELISA. Blood Coagul Fibrinolysis. 1997;8:105-113.
6. Baker WF Jr. Diagnosis of deep venous thrombosis and
pulmonary embolism. Med Clin North Am. 1998;82:459-476.
7. Bounameaux H, Schneider P, Slosman D, et al. Plasma D-
dimer in suspected pulmonary embolism: a comparison with
pulmonary angiography and ventilation-perfusion scintigra-
phy. Blood Coagul Fibrinolysis. 1990;1:577-579.
8. Perrier A, Buswell L, Bounameaux H, et al. Cost-effective-
ness of non invasive diagnostic aids in suspected pulmonary
embolism. Arch Intern Med. 1997;157:2309-2316.
386 L A B O R ATO RY M E D I C I N E VO L U M E 3 1 , N U M B E R 7 J U LY 2 0 0 0
9. Heit JA, Minor TA, Andrews JC, et al. Determinants of
plasma fibrin D-dimer sensitivity for acute pulmonary
embolism as defined by pulmonary angiography. Arch Pathol
Lab Med. 1999;123:235-240.
10. Levy G. Interet et limite du doasge d’un produit de
degradation de la fibrine: le D-dimere. Semin Hosp Paris.
1987;25:2061-2064.
11. Gadducci A, Marrai R, Baicchi U, et al. Preoperative D-
dimer plasma assay is not a predictor of clinical outcome for
patients with advanced ovarian cancer. Gynecol Oncol.
1997;66:85-88.
12. Gadducci A, Baicchi U, Marrai R, et al. Preoperative evalua-
tion of D-dimer and CA-125 levels in differentiating benign form
Downloaded from https://academic.oup.com/labmed/article/31/7/383/2657117 by guest on 15 June 2021
malignant ovarian masses. Gynecol Oncol. 1996;60:197-202.
13. Gadducci A, Baicchi U, Del Bravo B, et al. Evaluation of
some hemostatic parameters in patients with cervical carci-
noma. Eur J Gynaecol Oncol. 1990;11:215-218.
14. Rella C, Coviello M, De Frenza N, et al. Plasma D-dimer
measurement as a marker of gynecologic tumors: comparison
with Ca 125. Tumori. 1993;79:347-351.
15. Taguchi O, Gabazza E, Yasui H, et al. Prognostic signifi-
cance of plasma D-dimer levels in patients with lung cancer.
Thorax. 1997;52:563-565.
16. Mitter C, Zielinski C. Plasma levels of D-dimer: a cross-
linked fibrin-degradation product in female breast cancer. J
Cancer Res Clin Oncol. 1991;117:259-262.
17. Edwards C, Warren J, Armstrong L, et al. D-dimer: a use-
ful marker of disease stage in surgery for colorectal cancer. Br J
Surg. 1993;80:1404-1405.
18. Oya M, Akiyama Y, Yanagida T, et al. Plasma D-dimer lev-
els in patients with colorectal cancer: its role as a tumor
marker. Surg Today. 1998;28:373-378.
19. Geenen R, Delaere K, van Wersch J. Coagulation and fib-
rinolysis activation markers in prostatic carcinoma patients.
Eur J Clin Chem Clin Biochem. 1997;35:69-72.
20. Sagripanti A, Carpi A, Bacchi U. The measurement of
plasma D-dimer in the follow-up after thyroidectomy for can-
cer: preliminary data. Thyroidology. 1991;3:31-35.
21. Hager K, Platt D. Fibrin degeneration product concentra-
tions (D-dimers) in the course of aging. Gerontology.
1995;41:159-165.
22. Kario K, Matsuo T, Koabyashi H. Which factors affect high
D-dimer levels in the elderly? Thromb Res. 1991;62:501-508.
23. de Monye W, Huisman MV, Pattynama PM. Observer
dependency of the SimpliRed D-dimer assay in 81 consecutive
patients with suspected pulmonary embolism. Thromb Res.
1999;96:293-298.
24. Shimura M, Wada H, Wakita Y, et al. Plasma tissue factor
and tissue factor inhibitor levels in patients with disseminated
intravascular coagulation. Am J Hematol. 1996;52:165-170.
25. Wada H, Minamikawa K, Wakita Y, et al. Increased vascu-
lar endothelial cell markers in patients with disseminated
intravascular coagulation. Am J Hematol. 1993;44:85-88.
26. Okajima K, Fujise R, Motosato Y, et al. Plasma levels of
granulocyte elastase-alpha1-proteinase inhibitor complex in
patients with disseminated intravascular coagulation: patho-
physiologic implications. Am J Hematol. 1994;47:82-88.