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

19, 2017

CROWN COPYRIGHT ª 2017 PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN ISSN 0735-1097/$36.00

COLLEGE OF CARDIOLOGY FOUNDATION. ALL RIGHTS RESERVED. https://doi.org/10.1016/j.jacc.2017.09.024

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 fibrin degradation product that results from ordered breakdown of thrombi by the fibrinolytic system.
Numerous studies have shown that D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis.
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-
fication of medical patients at high risk for VTE. Thus, quantification 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;70:2411–20) Crown Copyright © 2017
Published by Elsevier on behalf of the American College of Cardiology Foundation. All rights reserved.

D -dimer is a biomarker of fibrin 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.

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

Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief From the a
Department of Medicine, McMaster University, Hamilton, Ontario, Canada; b
Department of Biochemistry and
Dr. Valentin Fuster. 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, Pfizer, and Portola. Dr. Eikelboom
has received honoraria or research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen,
Sanofi, 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.
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ABBREVIATIONS in the E domains. The knobs insert into cross-linked D-dimer that is absent in the D domain of
AND ACRONYMS pre-existing “holes” in the D domains, such fibrinogen and non–cross-linked fibrin monomers.
that the fibrin monomers spontaneously Although there are numerous commercial D-dimer
DIC = disseminated
intravascular coagulation
polymerize end to end in a half-staggered, assays, they are of 3 general types: whole-blood
overlapping manner to form double- agglutination assays, enzyme-linked immunosorbent
DVT = deep-vein thrombosis
stranded fibrin protofibrils. Individual pro- or immunofluorescent assays (ELISA and ELFA,
ELFA = enzyme-linked
immunofluorescence assay tofibrils associate with each other to form respectively), and latex agglutination assays (7).
ELISA = enzyme-linked
fibrils composed of hundreds of strands. Whole-blood agglutination assays use a bispecific
immunosorbent assay Because the monomers and protofibrils are antibody conjugate with binding sites for both
HIV = human immunodeficiency associated noncovalently, the fibrin network D-dimer and a red blood cell membrane antigen such
virus is unstable. Fibrin strength is enhanced by that red blood cell agglutination occurs when D-dimer
PE = pulmonary embolism factor XIIIa, a transglutaminase activated levels are elevated (Central Illustration, A). Whole-
VTE = venous by thrombin, which cross-links the D do- blood agglutination assays are semiquantitative and
thromboembolism mains of adjacent fibrin monomers, as well yield positive or negative results. By contrast, plasma
as the a -chains of opposing monomers to form D-dimer levels can be quantified using ELISA, ELFA, or
D-dimer and a -polymers, respectively (3). Therefore, latex agglutination assays. ELISA and ELFA rely on the
formation of cross-linked fibrin, the substrate for use of 2 monoclonal antibodies—one that captures the
D-dimer formation, requires activation of coagulation D-dimer in the sample, and a second labeled antibody
with the resultant generation of thrombin, conversion that is used to tag and quantify the captured D-dimer
of fibrinogen to fibrin monomers, polymerization of (Central Illustration, B). Contemporary latex aggluti-
the fibrin monomers to form fibrin polymers, and nation assays use immunoturbidometric techniques
cross-linking of the fibrin polymers by factor XIIIa. to detect D-dimer conjugated to antibody-coated latex
D-dimer is generated when the cross-linked fibrin beads. Latex agglutination assays are popular because
network undergoes plasmin-mediated degradation. they can be performed using automated coagulation
The degradation process starts when fibrin-bound analyzers (Central Illustration, C). Therefore, modern
plasminogen is converted to plasmin by tissue plas- assays provide rapid quantification of plasma D-dimer
minogen activator. Whereas plasminogen circulates levels.
in plasma, tissue plasminogen activator is released D-dimer results are not comparable among the
locally from endothelial cells in response to injury. various assays, even among those using similar
Plasminogen and tissue plasminogen activator bind formats (8). Reasons for this divergence include
to the fibrin surface to form a ternary complex that employment of monoclonal antibodies with varying
promotes plasminogen activation (4). Thus, plasmin specificities for D-dimer, differences in assay
formation is localized to fibrin, ensuring that methodology or instrumentation, and variations in
degradation of circulating fibrinogen is minimal. the values used to discriminate between positive
Fibrin-bound plasmin degrades the fibrin network and negative test results. Because of the multiple
into soluble fragments, the building block of which reasons for divergent results, standardization of the
is (DD)E: a complex consisting of D-dimer generated tests is difficult. As an additional confounder, levels
from cross-linked adjacent D domains (DD) non- are reported either as D-dimer concentration in
covalently bound to fragment E (5). Further plasmin- assays that use purified D-dimer as the calibrator,
mediated proteolysis of fragment E releases it from or as fibrinogen equivalent units in those that use
the (DD)E complex, and D-dimer then circulates in D-dimer–containing fragments that are generated
plasma with a half-life of approximately 8 h until it by clotting fibrinogen in the presence of factor XIIIa
is cleared by the kidneys and the reticuloendothelial and then exposing it to limited plasmin digestion.
system (6). Therefore, because it can only be gener- Fibrinogen equivalent units can be converted to
ated when there is formation and degradation of D-dimer concentration by dividing the level in half.
cross-linked fibrin, D-dimer provides a global marker Therefore, clinicians need to be aware of the per-
of activation of the coagulation and fibrinolytic sys- formance characteristics of the specific D-dimer
tems, and serves as an indirect marker of thrombotic assay used at their institution.
activity.
D-DIMER FOR DIAGNOSIS OF VTE
D-DIMER ASSAYS
D-dimer testing is an integral part of validated
D-dimer in whole blood or plasma is detected with algorithms for the diagnosis of deep-vein thrombosis
monoclonal antibodies that recognize an epitope on (DVT) and pulmonary embolism (PE) (9). A common
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F I G U R E 1 D-Dimer Formation

Fibrinogen is clotted by thrombin, and the fibrin monomers that are produced polymerize spontaneously in a half-staggered format into protofibrils.
The tensile strength of the fibrin network is enhanced by factor XIIIa, which crosslinks adjacent monomers. Plasminogen activation is enhanced with fibrin
formation, and the resultant plasmin digests the individual fibers. 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.
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C E NT R AL IL L U STR AT IO N Diagnostic Assays for D-Dimer Quantification

Weitz, J.I. et al. J Am Coll Cardiol. 2017;70(19):2411–20.

(A) Whole blood agglutination assays utilize a bi-specific 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 immunofluorescent assays (ELFA) involve
capture of D-dimer with an immobilized antibody specific for D-dimer. A second antibody tagged with horseradish peroxidase or a fluorescent marker binds D-dimer
and is used to generate a chromophore or fluorophore that is detected with a spectrophotometer or fluorimeter. (C) The latex agglutination assay uses latex beads
coated with D-dimer specific 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 categorized as likely or unlikely, or as high, inter-
persons each year (10). For every person diagnosed mediate, or low.
with VTE, the diagnosis is excluded in about 9 The clinical pre-test probability is used to guide
others. About two-thirds of these patients present further testing. If VTE is unlikely, D-dimer testing is
with suspected DVT, whereas the remainder present the next step (Figure 2). For this purpose, clinically
with suspected PE, with or without associated DVT. useful D-dimer assays can be divided into 2 main
Therefore, efficient diagnostic pathways are needed categories (Table 1)—those with high sensitivity
to avoid performing expensive radiological tests in (95% or greater), but lower specificity (about 40%),
all of these patients. and those with moderate sensitivity (80% to 94%),
Diagnosis of VTE in outpatients usually starts with but with higher specificity (up to 70%). In a
assessment of clinical pre-test probability using vali- meta-analysis of over 300 studies, ELISA, ELFA,
dated scoring systems such as the Wells score for DVT and quantitative latex agglutination assays were
and the Wells or Geneva score for PE (Figure 2) (11–13). more sensitive than whole-blood agglutination
The pre-test probability is higher if there are risk assays (14). Therefore, unless other assays are
factors for VTE, such as active cancer or recent unavailable, the whole-blood D-dimer assay should
surgery or immobilization, and if the symptoms not be used.
and signs are typical, particularly if they are severe. D-dimer levels are elevated in most patients with
Using such scores, clinical pre-test probability is acute thrombosis, but the levels also are increased
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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
inflammatory 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
specificity. 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 specificity 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 define a negative D-dimer test,
D-dimer quantification 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 ¼ computed tomography; DVT ¼ deep-vein
Because D-dimer levels increase with age, one thrombosis; PE ¼ 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 specificity 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 (15–17). Thus, for a
75-year-old patient, the D-dimer cutoff would be
750 m g/l. This approach increases the specificity 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, %, Specificity, %, Negative Predictive Value, %
Assay (95% CI) (95% CI) (95% CI)
suspected PE (18–20). For adjustment by pre-test
Whole blood
clinical probability, the cutoff of <500 m g/l is
SimplyRed 75 (63–87) 83 (77–89) 89 (82–97)
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 (83–98) 45 (29–65) 97 (95–100)
with a low pre-test probability (21–23). This approach Instant IA 87 (59–96) 65 (43–81) 91 (84–93)
has been prospectively validated in patients with ELFA
suspected DVT (24). Therefore, cutoff adjustments Vidas 96 (88–99) 57 (54–61) 99 (98–100)
by age or by clinical pre-test probability have the Latex

potential to increase the diagnostic efficacy of Tina-quant 95 (78–100) 61 (55–67) 99 (97–100)
STA-Liatest 95 (78–100) 48 (42–55) 99 (96–100)
D-dimer testing.
There are other limitations of D-dimer testing for Adapted from Di Nisio et al. (14) and manufacturers’ data. Sensitivity, specificity, and negative
diagnosis of VTE. The specificity of the test decreases predictive value can vary depending on the prevalence of VTE in the study’s population.
CI ¼ confidence interval; ELFA ¼ enzyme-linked immunofluorescence assay; ELISA ¼ enzyme-
with pregnancy, cancer, recent surgery, or trauma, linked immunosorbent assay; VTE ¼ venous thromboembolism.
and with being an inpatient (25). D-dimer levels
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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 benefit from
Cancer thromboprophylaxis.
Pregnancy or puerperium
Infection
D-DIMER FOR DETERMINING THE OPTIMAL
Chronic inflammation
DURATION OF ANTICOAGULATION THERAPY
Liver disease
IN VTE PATIENTS
Renal disease
Thrombolytic therapy
The optimal duration of anticoagulant therapy in
patients with a first 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 first 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 specificity 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 (30–32). Thus, D-dimer
this patient population. Although studies have yielded
levels have been incorporated into risk prediction
conflicting 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) (33–36).
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 sufficiently high to justify
Age, yrs Not assessed #50 $65 continued anticoagulant therapy, particularly with
Sex Male Male Males continue the favorable benefit–risk profiles 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 first 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 ¼ body mass index; DASH ¼ D-dimer, age, sex, and hormonal therapy; DVT ¼ deep-vein thrombosis; 10% at 1 year, whereas the risk is only about 5% at 1
HERDOO2 ¼ 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 ¼ pulmonary embolism; VTE ¼ venous thromboembolism.
year if the test is negative (37,38). Therefore, it may
be reasonable to stop anticoagulant therapy in
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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 fluid embolism, placental
sound was reported to double the risk of recurrence abruption, placenta previa, retained
products of conception
in one study (41). However, this finding was not
Vascular disorders Cavernous hemangioma, aortic
confirmed 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 ¼ 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 benefit
(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 benefit–risk of primary
thromboprophylaxis in cancer patients identified DIC is characterized by a consumptive coagulopathy
using these risk assessment models. as a result of increased thrombin generation and
enhanced fibrinolysis (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 insufficient 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 benefit of short-term thromboprophylaxis
platelet count, fibrinogen level, and the prothrombin
in hospitalized patients (54–56). 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 benefit–risk profile for longer periods of
thromboprophylaxis (57–59). 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 benefit from extended prophylaxis (60–62) including atrial fibrillation, 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 briefly discussed.
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ATRIAL FIBRILLATION. Patients with atrial fibrillation appear to be of no value for identifying those with
have higher levels of D-dimer than those without, and acute coronary syndrome or for determining prog-
the levels of D-dimer in atrial fibrillation patients nosis (79). Therefore, there is no role for routine
decrease with anticoagulant treatment or after success- measurement of D-dimer levels in patients with cor-
ful cardioversion (68–70). D-dimer levels are higher in onary artery disease.
atrial fibrillation patients with additional risk factors for HUMAN IMMUNODEFICIENCY VIRUS. With effective
stroke, such as hypertension, diabetes, or heart failure, antiretroviral therapy, HIV-infected individuals live
than in those without risk factors. Consequently, longer and succumb to non–HIV-related disorders,
D-dimer has been proposed as a biomarker for predict- particularly cardiovascular disease. The rate of car-
ing the risk of stroke in patients with atrial fibrillation. diovascular disease is higher with HIV infection than
However, its utility for this indication is limited because without (80). In addition to usual risk factors such as
other biomarkers such as troponin, N-terminal pro-B- dyslipidemia, diabetes, smoking, and hypertension,
type natriuretic peptide, and growth differentiation immune dysfunction characterized by elevated levels
factor-15 are better predictors of stroke than D-dimer of D-dimer, C-reactive protein, and interleukin-6 also
levels, and incorporating D-dimer into risk prediction may contribute (81). These biomarkers are better
models does not appear to increase their predictive predictors of cardiovascular disease in HIV-infected
value. Therefore, measurement of D-dimer levels is of individuals than in those without HIV infection, and
limited value for predicting the risk of stroke in atrial the levels decrease with antiretroviral therapy and
fibrillation patients. increase when treatment is stopped (81,82). The
ACUTE AORTIC DISSECTION. Rapid diagnosis of acute mechanism responsible for the immune dysfunction
aortic dissection is essential to limit mortality and is uncertain and studies evaluating the effect of in-
morbidity. D-dimer levels are elevated with acute terventions such as intensified HIV therapy and
aortic dissection and low in its absence (71,72). intravenous immunoglobulin have yielded mixed re-
Consequently, a normal D-dimer level may help to sults (83,84). Therefore, until more data are available,
exclude the diagnosis of aortic dissection. In patients measurement of D-dimer and other inflammatory
at low risk for acute aortic dissection, a pooled analysis markers in HIV-infected individuals remains a
of data from 4 studies that included 1,557 patients research tool.
concluded that a D-dimer level below 500 mg/l had a
CONCLUSIONS
sensitivity of 98% and a negative predictive value of
95% for ruling out the diagnosis. For those not at low
As a marker of activation of coagulation and fibrino-
risk, however, the test lacks sufficient sensitivity to be
lysis, D-dimer levels provide a rapid assessment of
of value (73). The American Heart Association risk
thrombotic activity. The test has an established role
score used to assess pre-test probability of acute aortic
in the diagnosis of VTE where it reduces the need for
dissection designates patients as low risk if there are
expensive imaging studies in the majority of patients
no high-risk findings, such as sudden onset of severe
with suspected DVT or PE. D-dimer also is used
chest, back, or abdominal pain, Marfan syndrome, or a
routinely for the diagnosis of DIC, and it may help to
new aortic insufficiency murmur (74). The prevalence
identify cancer and medically ill patients at high risk
of acute aortic dissection in low-risk patients is <6%,
for VTE who would benefit from extended thrombo-
and without any of these features, the diagnosis is
prophylaxis. D-dimer is of limited value in deter-
unlikely to be considered. Therefore, at present,
mining the optimal duration of anticoagulation in
D-dimer is of limited utility in patients with suspected
VTE patients and in ruling out acute aortic dissection.
acute aortic dissection.
Standardization of D-dimer assays and further
CORONARY ARTERY DISEASE. Longitudinal studies investigation of cutoff adjustment by age or pre-test
evaluating the utility of D-dimer levels to predict clinical probability would increase the effectiveness
myocardial infarction and cardiovascular death have of the test for the diagnosis of VTE. Although D-dimer
yielded conflicting results. Some prospective studies may be useful for risk assessment in other disorders,
suggest an association between elevated D-dimer additional studies are needed to establish its role.
levels at baseline and the subsequent risk of cardio-
vascular events, whereas others do not (75–77). Like- ADDRESS FOR CORRESPONDENCE: Dr. Jeffrey I.
wise, in patients with established coronary artery Weitz, Thrombosis and Atherosclerosis Research
disease, D-dimer levels are of uncertain value in Institute, McMaster University, 237 Barton Street East,
predicting future cardiovascular events (78). Finally, Hamilton, Ontario L8L 2X2, Canada. E-mail: weitzj@
in patients presenting with chest pain, D-dimer taari.ca.
JACC VOL. 70, NO. 19, 2017 Weitz et al. 2419
NOVEMBER 7, 2017:2411–20 A Test in Context: D-Dimer

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