JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 70, NO.

19, 2017

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REVIEW TOPIC OF THE WEEK

A Test in Context: D-Dimer

Jeffrey I. Weitz, MD,a,b,c James C. Fredenburgh, PHD,a,c John W. Eikelboom, MBBSa,c

ABSTRACT

D-dimer is a soluble brin degradation product that results from ordered breakdown of thrombi by the brinolytic system.
Numerous studies have shown that D-dimer serves as a valuable marker of activation of coagulation and brinolysis.
Consequently, D-dimer has been extensively investigated for 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 anticoa-
gulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and as an aid in the identi-
cation of medical patients at high risk for VTE. Thus, quantication of D-dimer levels serves an important role in guiding
therapy. This review: 1) describes how D-dimer is generated; 2) reviews the assays used for its detection; and 3) discusses the
role of D-dimer determination in these various conditions. (J Am Coll Cardiol 2017;70:241120) Crown Copyright 2017
Published by Elsevier on behalf of the American College of Cardiology Foundation. All rights reserved.

D -dimer is a biomarker of brin formation

and degradation that can be measured in
whole blood or in plasma. Healthy individ-
uals have low levels of circulating D-dimer, whereas
and 3) discuss the role of D-dimer determination in
these various conditions.

elevated levels are found in conditions associated
with thrombosis. D-dimer has been extensively inves-
tigated for the diagnosis of venous thromboembolism
(VTE) and is used routinely for this indication.
D-dimer also has been evaluated for determining the
optimal duration of anticoagulation in VTE patients,
for diagnosing and monitoring disseminated intra-
vascular coagulation (DIC), and for
medical patients at high risk for VTE. The role of
D-dimer in patients with other conditions such as
predicting the risk of stroke in atrial brillation,
identifying patients with coronary artery disease or
human immunodeciency virus (HIV) infection at
risk for cardiovascular events, or for ruling out
acute aortic dissection is uncertain. The goals of this
narrative review are to: 1) describe how D-dimer is
generated; 2) review the assays used for its detection;
GENERATION OF D-DIMER
D-dimer is a plasmin-derived soluble degradation
product of cross-linked brin (1). Generation of
D-dimer requires the sequential activity of 3 en-
zymes: thrombin, activated factor XIII (factor XIIIa),
and plasmin (Figure 1). The process starts when
thrombin generated by the coagulation system
identifying converts soluble brinogen to brin monomers.
Each brinogen molecule is a symmetrical dimer
composed of 3 pairs of 3 intertwined polypeptide
chains, termed a , , and g , that extend laterally from
a central core. The chains are held together by di-
sulde bonds such that brinogen molecules consist
of a central E domain linked by coiled-coil regions
to 2 peripheral D domains (2). To form brin
monomers, thrombin cleaves short peptides from the
NH2-termini of the a - and b-chains to expose knobs

Listen to this manuscripts

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the a
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; b
Department of Biochemistry and
Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; and the cThrombosis and Atherosclerosis Research
Institute, McMaster University, Hamilton, Ontario, Canada. Dr. Weitz has been a consultant for and received honoraria from Bayer,
Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, Ionis, Novartis, Merck, Pzer, and Portola. Dr. Eikelboom
has received honoraria or research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pzer, Daiichi-Sankyo, Janssen,
Sano, and GlaxoSmithKline. Dr. Fredenburgh has reported that he has no relationships relevant to the contents of this paper to disclose.

Manuscript received July 30, 2017; revised manuscript received September 15, 2017, accepted September 18, 2017.
2412 Weitz et al.
A Test in Context: D-Dimer
ABBREVIATIONS in the E domains. The knobs insert into
AND ACRONYMS pre-existing holes in the D domains, such
that the brin monomers spontaneously
DIC = disseminated
intravascular coagulation
polymerize end to end in a half-staggered,
overlapping manner to form double-
DVT = deep-vein thrombosis
stranded brin protobrils. Individual pro-
ELFA = enzyme-linked
immunouorescence assay tobrils associate with each other to form
ELISA = enzyme-linked
brils composed of hundreds of strands.
immunosorbent assay Because the monomers and protobrils are
HIV = human immunodeciency associated noncovalently, the brin network
virus is unstable. Fibrin strength is enhanced by
PE = pulmonary embolism factor XIIIa, a transglutaminase activated
VTE = venous by thrombin, which cross-links the D do-
thromboembolism mains of adjacent brin monomers, as well
as the a -chains of opposing monomers to form
D-dimer and a -polymers, respectively (3). Therefore,
formation of cross-linked brin, the substrate for
D-dimer formation, requires activation of coagulation
with the resultant generation of thrombin, conversion
of brinogen to brin monomers, polymerization of
the brin monomers to form brin polymers, and
cross-linking of the brin polymers by factor XIIIa.
D-dimer is generated when the cross-linked brin
network undergoes plasmin-mediated degradation.
The degradation process starts when brin-bound
plasminogen is converted to plasmin by tissue plas-
minogen activator. Whereas plasminogen circulates
in plasma, tissue plasminogen activator is released
locally from endothelial cells in response to injury.
Plasminogen and tissue plasminogen activator bind
to the brin surface to form a ternary complex that
promotes plasminogen activation (4). Thus, plasmin
formation is localized to brin, ensuring that
degradation of circulating brinogen is minimal.
Fibrin-bound plasmin degrades the brin network
into soluble fragments, the building block of which
is (DD)E: a complex consisting of D-dimer generated
from cross-linked adjacent D domains (DD) non-
covalently bound to fragment E (5). Further plasmin-
mediated proteolysis of fragment E releases it from
the (DD)E complex, and D-dimer then circulates in
plasma with a half-life of approximately 8 h until it
is cleared by the kidneys and the reticuloendothelial
system (6). Therefore, because it can only be gener-
ated when there is formation and degradation of
cross-linked brin, D-dimer provides a global marker
of activation of the coagulation and brinolytic sys-
tems, and serves as an indirect marker of thrombotic
activity.
D-DIMER ASSAYS
D-dimer in whole blood or plasma is detected with
monoclonal antibodies that recognize an epitope on
JACC VOL. 70, NO. 19, 2017
NOVEMBER 7, 2017:241120
cross-linked D-dimer that is absent in the D domain of
brinogen and noncross-linked brin monomers.
Although there are numerous commercial D-dimer
assays, they are of 3 general types: whole-blood
agglutination assays, enzyme-linked immunosorbent
or immunouorescent assays (ELISA and ELFA,
respectively), and latex agglutination assays (7).
Whole-blood agglutination assays use a bispecic
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 (Central Illustration, A). Whole-
blood agglutination assays are semiquantitative and
yield positive or negative results. By contrast, plasma
D-dimer levels can be quantied using ELISA, ELFA, or
latex agglutination assays. ELISA and ELFA rely on the
use of 2 monoclonal antibodiesone that captures the
D-dimer in the sample, and a second labeled antibody
that is used to tag and quantify the captured D-dimer
(Central Illustration, B). Contemporary latex aggluti-
nation assays use immunoturbidometric techniques
to detect D-dimer conjugated to antibody-coated latex
beads. Latex agglutination assays are popular because
they can be performed using automated coagulation
analyzers (Central Illustration, C). Therefore, modern
assays provide rapid quantication of plasma D-dimer
levels.
D-dimer results are not comparable among the
various assays, even among those using similar
formats (8). Reasons for this divergence include
employment of monoclonal antibodies with varying
specicities for D-dimer, differences in assay
methodology or instrumentation, and variations in
the values used to discriminate between positive
and negative test results. Because of the multiple
reasons for divergent results, standardization of the
tests is difcult. As an additional confounder, levels
are reported either as D-dimer concentration in
assays that use puried D-dimer as the calibrator,
or as brinogen equivalent units in those that use
D-dimercontaining fragments that are generated
by clotting brinogen in the presence of factor XIIIa
and then exposing it to limited plasmin digestion.
Fibrinogen equivalent units can be converted to
D-dimer concentration by dividing the level in half.
Therefore, clinicians need to be aware of the per-
formance characteristics of the specic D-dimer
assay used at their institution.
D-DIMER FOR DIAGNOSIS OF VTE
D-dimer testing is an integral part of validated
algorithms for the diagnosis of deep-vein thrombosis
(DVT) and pulmonary embolism (PE) (9). A common
JACC VOL. 70, NO. 19, 2017 Weitz et al. 2413
NOVEMBER 7, 2017:241120 A Test in Context: D-Dimer

F I G U R E 1 D-Dimer Formation

Fibrinogen is clotted by thrombin, and the brin monomers that are produced polymerize spontaneously in a half-staggered format into protobrils.
The tensile strength of the brin network is enhanced by factor XIIIa, which crosslinks adjacent monomers. Plasminogen activation is enhanced with brin
formation, and the resultant plasmin digests the individual bers. Plasmin cleavage between the D and E domains yields (DD)E, the noncovalent complex of
D-dimer (DD) and fragment E. Further proteolysis liberates fragment E from DD.
2414 Weitz et al. JACC VOL. 70, NO. 19, 2017

A Test in Context: D-Dimer NOVEMBER 7, 2017:241120

C E NT R AL IL L U STR AT IO N Diagnostic Assays for D-Dimer Quantication

Weitz, J.I. et al. J Am Coll Cardiol. 2017;70(19):241120.

(A) Whole blood agglutination assays utilize a bi-specic antibody directed against an epitope on D-dimer (DD) and an epitope on red blood cells (RBC). In the presence
of D-dimer, RBC agglutination is monitored by turbidity. (B) Enzyme-linked immunosorbent assays (ELISA) or enzyme-linked immunouorescent assays (ELFA) involve
capture of D-dimer with an immobilized antibody specic for D-dimer. A second antibody tagged with horseradish peroxidase or a uorescent marker binds D-dimer
and is used to generate a chromophore or uorophore that is detected with a spectrophotometer or uorimeter. (C) The latex agglutination assay uses latex beads
coated with D-dimer specic antibodies. In the presence of D-dimer, latex bead agglutination is detected by turbidity.

disorder, VTE is diagnosed in about 1.5 per 1,000
persons each year (10). For every person diagnosed
with VTE, the diagnosis is excluded in about 9
others. About two-thirds of these patients present
with suspected DVT, whereas the remainder present
with suspected PE, with or without associated DVT.
Therefore, efcient diagnostic pathways are needed
to avoid performing expensive radiological tests in
all of these patients.
Diagnosis of VTE in outpatients usually starts with
assessment of clinical pre-test probability using vali-
dated scoring systems such as the Wells score for DVT
and the Wells or Geneva score for PE (Figure 2) (1113).
The pre-test probability is higher if there are risk
factors for VTE, such as active cancer or recent
surgery or immobilization, and if the symptoms
and signs are typical, particularly if they are severe.
Using such scores, clinical pre-test probability is
categorized as likely or unlikely, or as high, inter-
mediate, or low.
The clinical pre-test probability is used to guide
further testing. If VTE is unlikely, D-dimer testing is
the next step (Figure 2). For this purpose, clinically
useful D-dimer assays can be divided into 2 main
categories (Table 1)those with high sensitivity
(95% or greater), but lower specicity (about 40%),
and those with moderate sensitivity (80% to 94%),
but with higher specicity (up to 70%). In a
meta-analysis of over 300 studies, ELISA, ELFA,
and quantitative latex agglutination assays were
more sensitive than whole-blood agglutination
assays (14). Therefore, unless other assays are
unavailable, the whole-blood D-dimer assay should
not be used.
D-dimer levels are elevated in most patients with
acute thrombosis, but the levels also are increased
JACC VOL. 70, NO. 19, 2017 Weitz et al. 2415
NOVEMBER 7, 2017:241120 A Test in Context: D-Dimer

with advanced age, after surgery, during pregnancy

F I G U R E 2 Algorithm for Diagnosis of DVT or PE Using D-Dimer
and the puerperium, with cancer and chronic
inammatory conditions, and with many other
disorders (Table 2). Therefore, D-dimer is a sensitive Suspected DVT or PE
marker for detection of thrombosis, but it lacks
specicity. Exploiting these test characteristics, a
Clinical pre-test probability
normal high-sensitivity D-dimer level in these
settings helps to exclude the diagnosis of VTE.
Because of the low specicity of high-sensitivity
Low or intermediate High
D-dimer tests, however, some patients with
suspected VTE may have negative results.
D-dimer testing is of limited value in patients D-dimer
with a high pre-test probability because even if the
D-dimer level is normal, the negative predictive value
of the test is reduced by the high prevalence of VTE Compression ultrasound or
Normal Elevated
CT pulmonary angiogram
in such patients. Therefore, if the pre-test probability
is high, patients should go directly to diagnostic
Diagnosis
testing with compression ultrasonography for DVT excluded
Negative Positive
and computed tomography pulmonary angiography
for PE (Figure 2).
Two maneuvers show promise for increasing the Diagnosis Diagnosis
excluded established
diagnostic yield of D-dimer testing in patients where
VTE is unlikely. Both options involve adjustment of
the cutoff used to dene a negative D-dimer test,
D-dimer quantication aids clinical decision making for patients with low or intermediate
which traditionally has been a level below 500 m g/l. pre-test probability of DVT or PE. CT computed tomography; DVT deep-vein
Because D-dimer levels increase with age, one thrombosis; PE pulmonary embolism.
maneuver uses an age-adjusted cutoff. The other
maneuver adjusts the cutoff on the basis of the
pre-test clinical probability because the prevalence
of VTE is lower in patients with a low pre-test prob-
increase with gestational age and with complicated
ability than in those with a moderate pre-test
pregnancies (26). Therefore, by the third trimester,
probability.
only a minority of patients will have D-dimer
In the age-adjusted approach, the cutoff of
levels <500 mg/l. Although the specicity of D-dimer
<500 m g/l is retained for patients #50 years of age,
testing may be improved by using a higher cutoff (27),
whereas a threshold of 10 times the patient age
is used for those >50 years of age (1517). Thus, for a
75-year-old patient, the D-dimer cutoff would be
750 m g/l. This approach increases the specicity of T A B L E 1 Performance Characteristics of Commercially Available D-Dimer
Assays for Detection of VTE
D-dimer testing without compromising its sensitivity,
and has been prospectively validated in patients with Sensitivity, %, Specicity, %, Negative Predictive Value, %
Assay (95% CI) (95% CI) (95% CI)
suspected PE (1820). For adjustment by pre-test
Whole blood
clinical probability, the cutoff of <500 m g/l is
SimplyRed 75 (6387) 83 (7789) 89 (8297)
retained for patients with a moderate pre-test prob-
ELISA
ability, whereas a cutoff <1,000 m g/l is used for those
Asserachrome 95 (8398) 45 (2965) 97 (95100)
with a low pre-test probability (2123). This approach Instant IA 87 (5996) 65 (4381) 91 (8493)
has been prospectively validated in patients with ELFA
suspected DVT (24). Therefore, cutoff adjustments Vidas 96 (8899) 57 (5461) 99 (98100)
by age or by clinical pre-test probability have the Latex

potential to increase the diagnostic efcacy of Tina-quant 95 (78100) 61 (5567) 99 (97100)

D-dimer testing.
There are other limitations of D-dimer testing for
diagnosis of VTE. The specicity of the test decreases
with pregnancy, cancer, recent surgery, or trauma,
and with being an inpatient (25). D-dimer levels
STA-Liatest 95 (78100) 48 (4255) 99 (96100)
Adapted from Di Nisio et al. (14) and manufacturers data. Sensitivity, specicity, and negative
predictive value can vary depending on the prevalence of VTE in the studys population.
CI condence interval; ELFA enzyme-linked immunouorescence assay; ELISA enzyme-
linked immunosorbent assay; VTE venous thromboembolism.
2416 Weitz et al. JACC VOL. 70, NO. 19, 2017

A Test in Context: D-Dimer NOVEMBER 7, 2017:241120

in the intensive care unit. Because of the high

T A B L E 2 Patient Characteristics and Disorders Associated
With Increased D-Dimer Levels
frequency of false-positive results in these settings,
using D-dimer to screen for VTE increases the need
Venous or arterial thrombosis
Disseminated intravascular coagulation
for additional testing. However, an elevated D-dimer
Advanced age in hospitalized medically ill patients may help
Recent surgery or trauma identify patients at risk for VTE who may benet from
Cancer thromboprophylaxis.
Pregnancy or puerperium
Infection
D-DIMER FOR DETERMINING THE OPTIMAL
Chronic inammation
DURATION OF ANTICOAGULATION THERAPY
Liver disease
IN VTE PATIENTS
Renal disease
Thrombolytic therapy
The optimal duration of anticoagulant therapy in
patients with a rst unprovoked DVT or PE is
uncertain. Such patients require at least 3 months of
such an approach has yet to be validated in prospec-
anticoagulant therapy, and current guidelines sug-
tive management studies. Consequently, with the
gest extending anticoagulation treatment, provided
current cutoff, D-dimer testing is likely to be of
that the risk of bleeding is not high (29). A D-dimer
greater value in the rst and second trimester
level measured on anticoagulant therapy or 1 month
of pregnancy than in the third.
after stopping therapy and the sex of the patient may
The specicity of the D-dimer test in patients with
help to stratify patients according to their risk of
cancer is reduced by the high prevalence of VTE and
recurrent VTE, thereby providing an individualized
the higher frequency of elevated D-dimer values in
approach to management (3032). Thus, D-dimer
this patient population. Although studies have yielded
levels have been incorporated into risk prediction
conicting results about the negative predictive value
models, including the Males Continue and HERDOO2
of D-dimer assays in cancer patients, a pooled analysis
(hyperpigmentation, edema, or redness in either leg;
suggests that a negative D-dimer together with a
D-dimer level $250 m g/l; obesity with body mass
low or unlikely pre-test probability excludes VTE in
index $30; or older age, $65 years) rule and the DASH
cancer patients like it does in those without cancer
(D-dimer, age, sex, and hormonal therapy) and
(28). However, only about 15% of cancer patients
Vienna scores (Table 3) (3336).
have this combination of results. Therefore, most
Patients with a positive D-dimer test have about
cancer patients with suspected VTE should undergo
twice the risk of recurrence as those with a negative
diagnostic imaging rather than D-dimer testing.
test, and the risk of recurrence in men is about 2-fold
D-dimer testing for diagnosis of VTE should
higher than that in women. Furthermore, the risk of
be avoided in situations where it is expected to be
recurrence with these 2 factors appears to be additive.
positive, such as after major surgery or trauma or in
Thus, for men, the risk of recurrence with a positive
hospitalized medical patients, particularly those
D-dimer test 1 month after stopping anticoagulant
therapy is in the range of 15% to 18% at 1 year,
T A B L E 3 Incorporation of D-Dimer Levels Into Various Scoring Systems for whereas the risk of recurrence is about 8% to 10% at
Predicting the Risk of Recurrent VTE
1 year if the test is negative (37,38). In either case,
Vienna (34) DASH (35) HERDOO 2 (36) the risk of recurrence is sufciently high to justify
Age, yrs Not assessed #50 $65 continued anticoagulant therapy, particularly with
Sex Male Male Males continue the favorable benetrisk proles of reduced doses
Elevated D-dimer level After stopping After stopping On anticoagulation of apixaban or rivaroxaban for extended VTE treat-
anticoagulation anticoagulation (>250 mg/l)
(>500 mg/l) (>500 mg/l) ment (39,40). Therefore, D-dimer testing in men is of
Post-thrombotic Not assessed Not assessed Hyperpigmentation limited value for making decisions about the optimal
syndrome Erythrema
Redness
duration of anticoagulant therapy for a rst episode
Site of VTE PE versus DVT; Not assessed Not assessed of unprovoked VTE.
proximal versus D-dimer testing may be of value in women where
distal DVT
the risk of recurrence with a positive D-dimer test
Other factors Not assessed Hormone therapy BMI $30 kg/m2
1 month after stopping anticoagulant therapy is about
BMI body mass index; DASH D-dimer, age, sex, and hormonal therapy; DVT deep-vein thrombosis; 10% at 1 year, whereas the risk is only about 5% at 1
HERDOO2 hyperpigmentation, edema, or redness in either leg; D-dimer level $250 mg/l; obesity with body
mass index $30; or older age, $65 years; PE pulmonary embolism; VTE venous thromboembolism.
year if the test is negative (37,38). Therefore, it may
be reasonable to stop anticoagulant therapy in
JACC VOL. 70, NO. 19, 2017 Weitz et al. 2417
NOVEMBER 7, 2017:241120 A Test in Context: D-Dimer

women with a normal D-dimer level, and to continue

T A B L E 4 Disorders Associated With DIC
treatment if the level is elevated.
Sepsis
In patients with proximal DVT, an elevated D-dimer
Extensive trauma or burns
level 1 month after stopping anticoagulation together
Cancer
with residual vein occlusion on compression ultra- Obstetrical complications Amniotic uid embolism, placental
sound was reported to double the risk of recurrence abruption, placenta previa, retained
products of conception
in one study (41). However, this nding was not
Vascular disorders Cavernous hemangioma, aortic
conrmed in another study (42), and meta-analyses aneurysm
suggest that residual vein thrombosis in patients with Toxins Snake bites, drugs
DVT is a weak risk factor for recurrent VTE (43,44). Immunological disorders Transfusion reactions, organ rejection

D-DIMER IN CANCER PATIENTS DIC disseminated intravascular coagulation.

Patients with cancer are at increased risk of throm-

bosis, and VTE is the second leading cause of death in
Thromboembolism) score, enhances their capacity to
cancer patients (45,46). Furthermore, VTE in cancer
identify those at risk (63). Using elevated D-dimer
patients increases hospitalization and health care
levels to identify medically ill patients at risk for VTE,
costs by 3-fold (47) and may delay cancer treatments.
a recent study demonstrated that compared with a
Thromboprophylaxis has the potential to reduce the
10-day course of enoxaparin, a 35- to 42-day course of
burden of VTE in cancer patients, but needs to be
betrixaban, an oral factor Xa inhibitor, reduced the
targeted to those at highest risk. A validated risk
risk of VTE by 24% without increasing the rate of
assessment tool that includes the site of the cancer,
major bleeding (64). Betrixaban also reduced the rate
platelet count, white blood cell count, and hemoglo-
of new ischemic stroke from 0.9% to 0.5% (65).
bin level before chemotherapy, use of erythropoiesis
Betrixaban has been licensed for extended thrombo-
stimulating agent, and body mass index has been
prophylaxis in medically ill patients, and D-dimer
used to assess the risk of VTE in cancer patients
levels may help to identify those who will benet
(48,49). Adding measurement of D-dimer levels to
most from such treatment.
this scoring system may improve VTE risk prediction
(50). Therefore, prospective management studies are D-DIMER AND DIC
needed to determine the benetrisk of primary
thromboprophylaxis in cancer patients identied DIC is characterized by a consumptive coagulopathy
using these risk assessment models. as a result of increased thrombin generation and
enhanced brinolysis (66). DIC can complicate an
D-DIMER IN MEDICALLY ILL PATIENTS
array of disorders (Table 4), and patients with DIC
may present with thrombosis, bleeding, or both
Hospitalized medically ill patients are at risk of VTE
depending on the cause and the extent of the
while in hospital and for up to 3 months after
coagulopathy.
discharge (51,52). To reduce this risk, current guide-
D-dimer levels are helpful for the diagnosis of DIC.
lines recommend thromboprophylaxis for such
Because of its sensitivity, a normal D-dimer level
patients while in hospital, but recommend against
excludes the diagnosis of DIC (7). However, on its own,
extended prophylaxis after hospital discharge (53).
an elevated D-dimer level is insufcient to establish
The recommendation for in-hospital treatment
the diagnosis of DIC. Instead, scoring systems have
is based on randomized placebo-controlled trials
been developed that include determination of the
revealing a benet of short-term thromboprophylaxis
platelet count, brinogen level, and the prothrombin
in hospitalized patients (5456). By contrast, the
time in addition to the D-dimer level (67). Such scoring
recommendation against extended thromboprophy-
systems are helpful, not only for the diagnosis of DIC,
laxis is based on randomized trials that failed to show
but also for monitoring its progression.
a favorable benetrisk prole for longer periods of
thromboprophylaxis (5759). Elevated D-dimer levels D-DIMER AND OTHER DISORDERS
over twice the upper limit of normal identify
medically ill patients at increased risk of VTE who D-dimer levels are elevated in a variety of conditions
may benet from extended prophylaxis (6062) including atrial brillation, coronary artery disease,
and incorporating D-dimer determination into vali- acute aortic dissection, and HIV infection. The value
dated risk assessment models such as the IMPROVE of D-dimer measurement in each of these disorders
(International Medical Prevention Registry on Venous is briey discussed.
2418 Weitz et al.
A Test in Context: D-Dimer
ATRIAL FIBRILLATION. Patients with atrial brillation
have higher levels of D-dimer than those without, and
the levels of D-dimer in atrial brillation patients
decrease with anticoagulant treatment or after success-
ful cardioversion (6870). D-dimer levels are higher in
atrial brillation patients with additional risk factors for
stroke, such as hypertension, diabetes, or heart failure,
than in those without risk factors. Consequently,
D-dimer has been proposed as a biomarker for predict-
ing the risk of stroke in patients with atrial brillation.
However, its utility for this indication is limited because
other biomarkers such as troponin, N-terminal pro-B-
type natriuretic peptide, and growth differentiation
factor-15 are better predictors of stroke than D-dimer
levels, and incorporating D-dimer into risk prediction
models does not appear to increase their predictive
value. Therefore, measurement of D-dimer levels is of
limited value for predicting the risk of stroke in atrial
brillation patients.
ACUTE AORTIC DISSECTION. Rapid diagnosis of acute
aortic dissection is essential to limit mortality and
morbidity. D-dimer levels are elevated with acute
aortic dissection and low in its absence (71,72).
Consequently, a normal D-dimer level may help to
exclude the diagnosis of aortic dissection. In patients
at low risk for acute aortic dissection, a pooled analysis
of data from 4 studies that included 1,557 patients
concluded that a D-dimer level below 500 mg/l had a
sensitivity of 98% and a negative predictive value of
95% for ruling out the diagnosis. For those not at low
risk, however, the test lacks sufcient sensitivity to be
of value (73). The American Heart Association risk
score used to assess pre-test probability of acute aortic
dissection designates patients as low risk if there are
no high-risk ndings, such as sudden onset of severe
chest, back, or abdominal pain, Marfan syndrome, or a
new aortic insufciency murmur (74). The prevalence
of acute aortic dissection in low-risk patients is <6%,
and without any of these features, the diagnosis is
unlikely to be considered. Therefore, at present,
D-dimer is of limited utility in patients with suspected
acute aortic dissection.
CORONARY ARTERY DISEASE. Longitudinal studies
evaluating the utility of D-dimer levels to predict
myocardial infarction and cardiovascular death have
yielded conicting results. Some prospective studies
suggest an association between elevated D-dimer
levels at baseline and the subsequent risk of cardio-
vascular events, whereas others do not (7577). Like-
wise, in patients with established coronary artery
disease, D-dimer levels are of uncertain value in
predicting future cardiovascular events (78). Finally,
in patients presenting with chest pain, D-dimer
JACC VOL. 70, NO. 19, 2017
NOVEMBER 7, 2017:241120
appear to be of no value for identifying those with
acute coronary syndrome or for determining prog-
nosis (79). Therefore, there is no role for routine
measurement of D-dimer levels in patients with cor-
onary artery disease.
HUMAN IMMUNODEFICIENCY VIRUS. With effective
antiretroviral therapy, HIV-infected individuals live
longer and succumb to nonHIV-related disorders,
particularly cardiovascular disease. The rate of car-
diovascular disease is higher with HIV infection than
without (80). In addition to usual risk factors such as
dyslipidemia, diabetes, smoking, and hypertension,
immune dysfunction characterized by elevated levels
of D-dimer, C-reactive protein, and interleukin-6 also
may contribute (81). These biomarkers are better
predictors of cardiovascular disease in HIV-infected
individuals than in those without HIV infection, and
the levels decrease with antiretroviral therapy and
increase when treatment is stopped (81,82). The
mechanism responsible for the immune dysfunction
is uncertain and studies evaluating the effect of in-
terventions such as intensied HIV therapy and
intravenous immunoglobulin have yielded mixed re-
sults (83,84). Therefore, until more data are available,
measurement of D-dimer and other inammatory
markers in HIV-infected individuals remains a
research tool.
CONCLUSIONS
As a marker of activation of coagulation and brino-
lysis, D-dimer levels provide a rapid assessment of
thrombotic activity. The test has an established role
in the diagnosis of VTE where it reduces the need for
expensive imaging studies in the majority of patients
with suspected DVT or PE. D-dimer also is used
routinely for the diagnosis of DIC, and it may help to
identify cancer and medically ill patients at high risk
for VTE who would benet from extended thrombo-
prophylaxis. D-dimer is of limited value in deter-
mining the optimal duration of anticoagulation in
VTE patients and in ruling out acute aortic dissection.
Standardization of D-dimer assays and further
investigation of cutoff adjustment by age or pre-test
clinical probability would increase the effectiveness
of the test for the diagnosis of VTE. Although D-dimer
may be useful for risk assessment in other disorders,
additional studies are needed to establish its role.
ADDRESS FOR CORRESPONDENCE: Dr. Jeffrey I.
Weitz, Thrombosis and Atherosclerosis Research
Institute, McMaster University, 237 Barton Street East,
Hamilton, Ontario L8L 2X2, Canada. E-mail: weitzj@
taari.ca.
JACC VOL. 70, NO. 19, 2017
NOVEMBER 7, 2017:241120
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KEY WORDS D-dimer, deep-vein
thrombosis, disseminated intravascular
coagulation, pulmonary embolism, venous
thromboembolism