Received: 15 December 2018 Revised: 26 March 2019 Accepted: 1 April 2019

DOI: 10.1002/ajh.25482

TEST OF THE MONTH

The D-dimer assay

Eric D. Johnson1 | John C. Schell2 | George M. Rodgers1

1
Division of Hematology and Hematologic
Malignancies, University of Utah Health
Sciences Center, Salt Lake City, Utah
2
Department of Internal Medicine, University
of Utah School of Medicine, Salt Lake
City, Utah
Correspondence
Eric D. Johnson, MD, Division of Hematology
and Hematologic Malignancies, Huntsman
Cancer Institute, University of Utah,
Salt Lake City, UT 84132.
Email: eric.johnson@hci.utah.edu
Abstract
D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits
unique properties as a biological marker of hemostatic abnormalities as well as an
indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product
that results from the systematic degradation of vascular thrombi through the fibrino-
lytic mechanism. Because of this, the D-dimer serves as a valuable marker of activa-
tion of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly,
D-dimer has been extensively investigated for excluding the diagnosis of venous
thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer
has been evaluated for determining the optimal duration of anticoagulation in VTE
patients, for diagnosing and monitoring disseminated intravascular coagulation, and
for monitoring other conditions in which the patient is at high risk of bleeding or
thrombosis. Limitations of the assay include D-dimer elevation in a constellation of
clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization.

1 | B A C KG RO U N D fibrinolytic systems, and function as an indirect marker of thrombotic

D-dimer molecules are generated through the degradation of cross-
linked fibrin during fibrinolysis. D-dimer generation requires the activ-
ity of three enzymes: thrombin, activated factor XIII (factor XIIIa), and
plasmin. The process starts when thrombin generated by the coagula-
tion system converts soluble fibrinogen to fibrin monomers. These
monomers then form fibrin polymers through noncovalent interac-
tions based on allosteric changes within the protein as a result of
thrombin cleavage of fibrinopeptides from the N-terminal domain
(Figure 1). Fibrin is strengthened through interactions with factor XIII,
which, after activation by thrombin, cross-links the D domains of adja-
cent fibrin monomers. Plasmin digestion of the fibrin clot results in
the D-dimer molecule.1
D-dimer measurements are done usually by central laboratory
assays as well as by point-of-care assays with various cutoffs designed
2
for both quantitative and qualitative measurements. The presence of
D-dimer molecules is suggestive of intravascular coagulation because
it can only be generated after thrombin formation and subsequent
degradation of cross-linked fibrin. Because of this, D-dimer measure-
ments serve as a global marker of activation of the coagulation and
and subsequent thrombolytic activity.2
There are a variety of uses for the presence or absence of D-dimer
molecules under different pathologic conditions. The analysis of
D-dimer is critical for the modern triage and diagnosis of deep vein
thrombosis (DVT),3–5 pulmonary embolism (PE),6–8 aortic dissection,9
and disseminated intravascular coagulation (DIC).10–13 Measuring
D-dimer is mostly useful in situations where the likelihood of throm-
boembolism is low with a negative test effectively excluding thrombo-
sis, and a positive test being suggestive, but not conclusive of
thrombosis.3–5 Additional complexity results from pretest probability
that influences the accuracy of diagnosis of thromboembolism.3–6
There has been extensive work on assessing the usefulness of the
D-dimer test in the diagnosis of coagulation disorders with a number
of PubMed articles on this subject rising steadily since the 1980s. This
work includes testing D-dimer in conjunction with clinical information
as part of a diagnostic model/paradigm, for example, in exclusion of
VTE and in determining duration of anticoagulation.13,14 Despite this
volume of data, its clinical value and significance for many indications
remain controversial.15 Many attempts have been made to increase
clinical utility of the D-dimer test in a variety of other medical

Am J Hematol. 2019;94:833–839. wileyonlinelibrary.com/journal/ajh © 2019 Wiley Periodicals, Inc. 833

834 JOHNSON ET AL.

F I G U R E 1 Generation of D-dimer following

thrombin generation and fibrinolysis. A, Thrombin
cleaves fibrinopeptides from the E-domain of
fibrinogen, producing fibrin monomers. B, Fibrin
monomers aggregate, and C, they are cross-linked
by the action of factor XIIIa to form a fibrin clot.
The degradation of cross-linked polymers by
plasmin leads to the liberation of fibrin
degradation products, including D-dimer, D

conditions, including combining D-dimer with other laboratory tests
17–20
and clinical algorithms.
2 | ASSAY METHODS AND TECHNICAL
ASPECTS
D-dimer is detected and quantified in whole blood, plasma, or serum
using monoclonal antibodies that recognize a specific epitope on
cross-linked D-dimer molecules that are otherwise absent on the
D-domain of fibrinogen and fibrin monomers that are noncross-linked.2
At least 30 commercial D-dimer assays are available,21 but there are
three general types: enzyme-linked immunosorbent assays (ELISA),
immunofluorescent assays, and latex agglutination assays.2,22–24 Each
of these test methods has its own specific considerations and
limitations, which has been thoroughly reviewed elsewhere.2,22–24
The Vidas D-dimer assay, a widely used method, reportedly shows no
interference from heparin, bilirubin, hemoglobin, fibrin degradation
products, or plasma turbidity.25 Tables 1 and 2 provide a summary of
specific D-dimer assays that have been frequently used in clinical tri-
als for VTE exclusion, including their respective cutoff values, sensitiv-
ities, and specificities. A summary table (Appendix) is included for
additional details regarding the D-dimer test.
3 | L A C K O F A RE F E R EN C E S T A N D A R D
As most laboratory assays are validated against a reference standard,
lack of such a standard for D-dimer assays makes a direct comparison
of different assays impossible.21 Despite its use as a biomarker, the

TABLE 1 Central laboratory D-dimer assays frequently used in VTE clinical trials

Assay Manufacturer’s cutoff for detectiona DVT sensitivity DVT specificity

Asserachrom D-dimer 500 ng/mL FEU 98% (91-100%) 47% (29-65%)
Clearview Simplify D-dimer 500 ng/mL DDU 100% (92-100%) 48% (43-53%)
Hemosil D-dimer HS 500 500 ng/mL DDU 100% (85-99%) 45% (41-49%)
Innovance D-dimer 500 ng/mL FEU 99% (97-99%) 40% (38-40%)
MiniQuant D-dimer 200 ng/mL DDU 96% (95-98%) 44% (40-47%)
STA-Liatest D-dimer 500 ng/mL FEU 96% (90-100%) 47% (33-76%)
TinaQuant D-dimer 500 ng/mL FEU 99% (90-100%) 46% (39-72%)
Vidas D-dimer 500 ng/mL FEU 100% (82-100%) 42% (37-46%)

Abbreviations: DDU, D-dimer units; DVT, deep vein thrombosis; FEU, fibrinogen equivalent units.
a
Values as per Manufacturer Package Insert, FDA Memorandum, and Independent expert comparison. References: 5,26–37. Other studies might report
other sensitivities/specificities. Reported ranges represent 95% CI.
JOHNSON ET AL. 835

TABLE 2 Point-of-care D-dimer assays frequently used in VTE clinical trials

Assays Manufacturer’s cutoff for detectiona DVT sensitivity DVT specificity

LABGEO 450 ng/mL FEU 99% (93-100%) 53% (38-68%)
Roche Cardiac D-dimer 500 ng/mL FEU 95% (88-99%) 62% (58-67%)
PATHFAST D-dimer 570 ng/mL FEU 98% (94-100%) 40% (35-44%)
SimpliRED D-dimer 400 ng/mL FEU 94% (84-95%) 67% (56-84%)
TRIAGE 200 ng/mL DDU 97% (93-100%) 48% (44-53%)

Abbreviations: DDU, D-dimer units; DVT, deep vein thrombosis; FEU, fibrinogen equivalent units.
a
Values as per Manufacturer Package Insert, FDA Memorandum, and Independent expert comparison. References: 5,26–37. Other studies might report
other sensitivities/specificities. Reported ranges represent 95% CI.

development of a reference standard has been difficult, and studies VTE exclusion. Clinicians and laboratory professionals must be aware
comparing different D-dimer assays confirm that they are not inter- of the specific cutoffs assigned for the assay that they are using.
38
changable. The use of proprietary antibodies that recognize differ-
ent epitopes with varying kinetics makes development of a universal
reference for calibration and standardization unlikely. 4.2 | D-dimer in assessing the duration of
Another standardization issue with the D-dimer assay is the defi- anticoagulation
nition of the reported result. There are two such definitions of
Assessing the length of oral anticoagulation in a patient with
D-dimer units: fibrinogen equivalent units (FEUs) that relate the mass
unprovoked VTE is controversial. Longer durations of anticoagulation
of D-dimer to the mass of fibrinogen; and D-dimer units (DDU) that
carry the risk of bleeding, while shorter durations of anticoagulation
relate to the mass of D-dimer alone.2 The calibrator used for FEU
may increase the risk of recurrent VTE. Palareti et al reported that
assays compares the D-dimer mass to a related molecular weight of
340 kDa, while the calibrator for DDU assays compares the D-dimer
mass to 195 kDa. Therefore, testing a sample for D-dimer with both
FEU and DDU assays would lead to a 1.75-fold difference in the
result.2 In addition, different assay manufacturers use different magni-
tude of units (eg, ng/mL, mcg/mL). Each assay manufacturer recom-
mends a unit definition for their assays; however, laboratory
proficiency testing data suggest that 33% of laboratories report the
results in different units than those recommended by the assay manu-
facturer.2 Such reporting values could result in an inaccurate classifi-
cation of normal versus abnormal results.

4 | C O M M O N U S E S OF D - D I M E R A S S A Y S

4.1 | VTE exclusion

The original clinical scoring system using a D-dimer assay was
reported in 2000, with numerous subsequent trials confirming the
utility of this approach.3–5 The most commonly used D-dimer assays
in these trials were Asserachrom D-dimer, VIDAS D-Dimer, STA-
Liatest D-Dimer (Stago), Hemosil HS 500 D-dimer, and Innovance
D-Dimer assays. Figure 2 shows a clinical algorithm utilizing D-dimer
testing to diagnose VTE. Not all commercially available assays have
F I G U R E 2 Algorithmic approach to evaluate thromboembolism
sufficient sensitivity to be used to exclude VTE.39 According to the
and utility of the D-dimer assay.3 Beginning with a case of possible
Clinical and Laboratory Standards Institute, assays should have ≥98% thromboembolism, it is necessary to quantify the clinical probability of
negative predictive value (NPV) and ≥97% sensitivity to be used for such an event using a tool such as the Wells score. Following this,
VTE exclusion.39 For some assays, the cutoff between normal and patients with high probability scores are evaluated with imaging and
treated accordingly. Those patients with low-to-intermediate
abnormal results is the same as the cutoff for VTE exclusion. How-
probability are assessed via D-dimer assay and those below threshold
ever, it is important to note that for other D-dimer assays, the cutoff are effectively ruled out, while those above the threshold are
between normal and abnormal results is different from the cut-off for subjected to imaging and treated appropriately
836 JOHNSON ET AL.

measuring D-dimer in patients with unprovoked VTE for 1 month TABLE 4 ISTH DIC scoring systema
after completion of oral anticoagulant therapy predicted recurrent
Test Score
VTE.40 These results were confirmed in a larger study,14 and an addi-
Platelet count >100 000 = 0
tional trial reported that serial D-dimer testing of patients with an initial
50 000-100 000 = 1
normal result after stopping anticoagulation could identify patients at a
<50 000 = 2
higher risk of late recurrent VTE.41 These investigators used the Vidas
D-Dimer No increase = 0
D-dimer ELISA and Clearview Simplify D-dimer assays. In contrast to
Moderate increase = 1
the results of the abovementioned three European trials, another trial
Strong increase = 2
found that negative D-dimer results in female patients could justify dis-
continuing anticoagulation, but not in male patients.15 These latter Prolongation of PT <3 s = 0

investigators used the Clearview Simplify assay. >3 but < 6 s = 1

>6 s = 2
Fibrinogen mg/dL >100 mg/dL = 0
4.3 | D-dimer utility in DIC
<100 mg/dL = 1
D-dimer testing is particularly useful in evaluating patients with possible Score ≥5 = overt DIC
DIC, those with unknown coagulopathy (prolonged prothrombin time
Abbreviations: DIC, disseminated intravascular coagulation; ISTH,
(PT) and partial thromboplastin time (PTT) values), or patients with International Society of Thrombosis and Haemostasis; PT,
thrombocytopenia. One concern with using D-dimer assays in evaluat- prothrombin time.
a
ing DIC is identifying a D-dimer level that is consistent with a diagnosis Information in this table is taken from Reference 42.

of DIC. For example, while a D-dimer level of 1.1 mcg/mL FEU is above
in the scoring system include a relevant clinical diagnosis and other
the normal reference interval, such levels are frequently seen in
laboratory tests—PT, platelet count, and fibrinogen42 (Table 4). The
patients without DIC, including outpatients and inpatients without seri-
cutoff values for D-dimer have been evaluated in this model; ROC
ous illness.16 One study used a quantitative D-dimer assay and receiver
analysis indicated that cutoff values for diagnosing DIC varied
operating characteristic (ROC) curve analysis in a cohort of patients
depending on the D-dimer assay used.43 The data did suggest that
thought to have DIC. A D-dimer cutoff of 8.2 mcg/mL FEU provided
D-dimer levels of 3-7 mcg/mL might be sensitive for diagnosing DIC
excellent sensitivity and NPV for the diagnosis of DIC.13 Serial monitor-
with all D-dimer assays evaluated (FEU or DDU not specified).43
ing of D-dimer in DIC patients also provides clinical evidence as to
whether the underlying disease process is being successfully treated.13
The utility of D-dimer testing in diagnosing DIC has been 4.4 | Clinical aspects and limitations
addressed by the Scientific and Standardization Committee on DIC of
Circulating D-dimer is also elevated in patients with liver disease,18 cor-
the International Society of Thrombosis and Haemostasis (ISTH). Their
onary artery disease20,44 and other cardiovascular diseases,9 cancer,45
recommendation is to use a scoring system to diagnose DIC that
trauma,17 pregnancy,23 infections,19 inflammatory diseases,46 severe
includes fibrin-related markers such as D-dimer.42 Other parameters
renal disease,47 recent surgical procedures,48 and advanced age23,49 as
summarized in Table 3. However, the D-dimer elevation in these condi-
T A B L E 3 Clinical disorders associated with elevated
measurement/positive D-dimer results tions is less specific than for DVT/PE. Although reporting age-adjusted
values have been proposed to account for a relative increase in circulat-
Venous/arterial thrombosis3–8
ing D-dimers with aging,50 there is currently insufficient evidence to
Inflammation46
recommend the widespread use of age-adjusted reference intervals.51
DIC10–13
D-dimer has been falsely positive/elevated in certain assays, in which
Age49,50
the rheumatoid factor causes cross reactivity with human anti-mouse
Surgery48
antibodies.52 Because the preparation of antibodies used in D-dimer
Trauma/burns17
testing is routinely done in mice, those patients who have received
Aortic dissection9 mouse monoclonal antibody therapy may also have falsely elevated
Cancer/malignancy2,45 values. This limitation can be overcome by using alternative assays such
Infection/sepsis19 as fibrin monomer if an unexpected positive result occurs, but concerns
Pregnancy2 for underlying active thrombosis/fibrinolysis remain low.
Liver disease18
Thrombolytic therapy2
5 | C O N CL U S I O N
Renal disease47
Cardiovascular disease20,44
The D-dimer test is clinically useful as a biological marker of hemostasis
Abbreviation: DIC, disseminated intravascular coagulation. and hemostatic abnormalities, especially as an indicator of intravascular
JOHNSON ET AL.
thrombosis. Despite limitations, including lack of standardization,
D-dimer is used routinely to exclude VTE and diagnosing and monitor-
ing DIC; the test may also be useful in determining the duration of
anticoagulation.
CONF LICT OF IN TE RE ST
The authors have no conflicts of interest to disclose.
ORCID
Eric D. Johnson https://orcid.org/0000-0003-0958-5992
George M. Rodgers https://orcid.org/0000-0003-1234-0128
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How to cite this article: Johnson ED, Schell JC, Rodgers GM.
The D-dimer assay. Am J Hematol. 2019;94:833–839. https://
doi.org/10.1002/ajh.25482
JOHNSON ET AL. 839

APPENDIX

What is the test?

D-dimer assay measures activation of coagulation since it reflects thrombin activity. As such, it is commonly used as a biomarker of bleeding or
thrombosis. D-dimer is quantified through analysis of whole blood, serum, or plasma; monoclonal antibodies can detect its presence and
concentration within the measured sample. The test utilizes monoclonal antibodies that recognize a specific epitope on cross-linked D-dimer/fibrin
degradation products that are otherwise absent on the D-domain of fibrinogen and fibrin monomers that are noncross-linked. D-dimer is generated
when the cross-linked fibrin network undergoes plasmin-mediated degradation.
How is D-Dimer measured?
There are various methods that can be used to measure D-dimer levels. These include whole-blood agglutination assays, enzyme-linked
immunosorbent assays (ELISA), and latex agglutination assays. Whole-blood agglutination assays use a bispecific antibody conjugate with binding
sites for both D-dimer and a red blood cell membrane antigen such that red blood cell agglutination occurs when D-dimer levels are elevated.
Whole-blood agglutination assays are semiquantitative and yield positive or negative results. By contrast, plasma D-dimer levels can be quantified
using ELISA or latex agglutination assays.
What are the normal reference range values?
Many assays confer a positive result when greater than 500 ng/mL FEU, but this varies among different methods. For example, another method has a
normal cutoff of 120 ng/mL D-dimer units. There is further subinterpretation of a positive result, which would be the quantity of the calculated
D-dimer value with respect to the underlying condition/pathology. For example, a D-dimer of 525 ng/mL FEU would be abnormal, but would not
usually be consistent with disseminated intravascular coagulation (DIC). Not all commercially available assays have sufficient sensitivities to be used
to exclude VTE. The Clinical and Laboratory Standards Institute recommends that D-dimer assays should have ≥98% negative predictive value and
≥97% sensitivity to be used for VTE exclusion.
Conditions where D-dimer assays are useful.
D-dimer levels are mostly useful in excluding a diagnosis of venous or arterial thrombosis, diagnosing and monitoring DIC, and determining the
duration of anticoagulation. D-dimer also has limited utility under situational acute conditions such as vascular disease, coronary artery disease,
stroke, cancer/malignancy, infections, rheumatologic conditions, renal disease, and liver disease.
Additional tests that give a complete picture?
Given that numerous clinical conditions are associated with an elevated D-dimer level, there are guidelines and empirically directed studies to better
identify suspected etiology. With regard to thrombosis, D-dimer assay is usually used in low/moderate risk individuals, as per Wells' criteria and/or
clinical suspicion, in order to rule out arterial or venous thrombosis. This is done to avoid more invasive testing, but additional tests that give a
complete picture would be vascular ultrasound, computed tomography (CT) scans—particularly CT pulmonary angiogram, and ventilation-perfusion
scans. Some conditions utilize echocardiogram or other cardiac-related studies.
What tests provide similar information?
Imaging studies, such as CT scans, ultrasound, and angiograms, as well as ventilation-perfusion studies can provide evidence of intravascular
thrombosis. Coagulation factor-level alteration, specifically depletion, can suggest increased consumption of intravascular coagulation factors, which
would be compatible with an elevated/positive D-dimer. Fibrin degradation products and fibrin monomer tests also measure activation of
coagulation and fibrinolysis.
Tests that can be avoided/eliminated?
Unnecessary laboratory tests include fibrin degradation products, fibrin monomers, imaging studies for venous thromboembolism, and many tests for
pulmonary embolism (PE); such tests include vascular ultrasound, CT pulmonary angiogram, and ventilation-perfusion scans. Some instances can
avoid echocardiogram or other cardiac-related studies.
How does the use of D-dimer assays impact treatment?
The D-dimer assay is involved in the investigation process for a number of diseases or disease states. One of the most common uses is in the
investigation of deep vein thrombosis (DVT)/PE in low-to-moderate probability patients per Wells' criteria. D-dimer is considered part of the
noninvasive algorithm for investigation, specifically in the decision to escalate investigation to more invasive techniques. D-dimer assays can also be
used to evaluate a coagulopathy (prolonged prothrombin time and partial thromboplastin time values) and thrombocytopenia as due to DIC.
Monitoring serial D-dimer values in DIC patients informs clinicians whether the underlying condition causing DIC is being successfully treated
or not.