|

Received: 12 February 2018    Accepted: 16 April 2018

DOI: 10.1111/ijlh.12864

REVIEW

Use of D-­dimer in oral anticoagulation therapy

L. Zhang1  | Y. Long2 | H. Xiao2 | J. Yang1 | P. Toulon3 | Z. Zhang1

1
Department of Clinical Laboratory and
Pathology, Wuhan Asia Heart Hospital, Abstract
Wuhan, China Individualized anticoagulation management and improvement of the safety and ef-
2
Heart Center, Wuhan Asia Heart Hospital,
fectiveness of oral anticoagulant have always been the focus of clinicians’ attention.
Wuhan, China
3 D-­dimer, a sensitive marker of thrombosis and coagulation activation, is not only tra-
Service d’Hématologie Biologique, CHU
Pasteur, Université Nice Sofia-Antipolis, ditionally used in the diagnosis of venous thromboembolism, acute aortic dissection,
Nice, France
and disseminated intravascular coagulation but can also be used as a helpful marker
Correspondence in the management of oral anticoagulant, including evaluating the anticoagulation
Zhenlu Zhang, Department of Clinical
quality, predicting clinical outcomes, and determining the optimal duration and inten-
Laboratory and Pathology, Wuhan Asia
Heart Hospital, Wuhan University, Wuhan, sity of anticoagulation.
China.
Email: zhenluzhangwh@163.com
KEYWORDS

Funding information anticoagulation therapy, D-dimer, direct oral anticoagulants, vitamin K antagonists
Health and Family Planning Commission of
Wuhan Municipality, Grant/Award Number:
WX14D11; Innovation Fund of Wuhan Asia
Heart Hospital, Grant/Award Number:
2013CX2-A06

1 |  I NTRO D U C TI O N 2 | G E N E R ATI O N O F D - ­D I M E R

Oral anticoagulants, including vitamin K antagonists (VKAs) and
direct oral anticoagulants (DOACs), are widely used to prevent
thrombosis in patients with venous thromboembolism (VTE) and
atrial fibrillation (AF).1-3 How to improve the safety and efficacy
of anticoagulation therapy has always been a focus of clinicians’
concerns. Previous studies showed that even in a stable anticoag-
ulant therapy, some patients still suffered subsequent thrombosis
and hemorrhage and even died.4-6 These studies revealed that the
“one-­f it-­all” anticoagulation strategy in a single therapeutic range
or a single drug dose does not apply to all patients, and the oral
anticoagulation therapy should be assessed comprehensively and
individually.
D-­dimer, a product of cross-­linked fibrin degradation, is a sensitive
marker of thrombosis or hypercoagulability.7 D-­dimer assay plays an
important role in diagnosis of VTE, disseminated intravascular coagula-
tion (DIC), and other diseases.7-10 Subsequently, its specific applications
in oral anticoagulation therapy are attracting more and more attention.
This article aimed to summarize the use of D-­dimer in oral anticoagulation
therapy.
The D-­dimer molecule consists of 2 cross-­linked D fragments from
fibrinogen, which is the smallest fibrinolysis-­specific degradation
product found in circulation. During the activation of a coagulation
system (Figure 1), thrombin catalyzes fibrinogen to fibrin and then
FXIII stabilizes fibrin to crossed fibrin with a formed network. Then,
the plasmin degrades crossed fibrin into fragments of different sizes,
which are named fibrin degradation products (FDPs). D-­dimer is one
of the FDPs.7 It has a half-­life of approximately 8 hours and is elevated
in blood approximately 2 hours after crossed-­fibrin formation.11 The
D-­dimer level is very low but detectable in health population and
rises with advancing age.12,13 It is slightly higher in females than in
males, and it will increase significantly during pregnancy.14-16
3 | D - ­D I M E R M E A S U R E M E NT A N D IT S
TR A D ITI O N A L A PPLI C ATI O N
All methodologies of D-­
dimer measurement are based on the
antigen-­antibody reaction, such as enzyme-­linked immunosorbent

Int J Lab Hem. 2018;1–5. © 2018 John Wiley & Sons Ltd |  1
wileyonlinelibrary.com/journal/ijlh  
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2       ZHANG et al.
or immunofluorescent assays, latex-­enhanced immunoturbidimetry,
9
or whole-­blood agglutination assays. D-­dimer levels in plasma can
be detected quantitatively and simply by employing automated
coagulation analyzers; however, the standardization and harmoni-
9,17
zation of D-­dimer assay are still unsatisfactory, which might be
attributed to several reasons: the absence of international refer-
ence preparation for traceability, varying specificity of monoclonal
antibody for D-­dimer detection, and differences in detection per-
formance among methodologies or various assays. In addition, the
reporting unit of D-­dimer assay, D-­dimer unit vs the fibrinogen
equivalent unit, and the magnitude of the units (eg ng/mL, μg/mL,
μg/L) are expressed differently by different manufacturers.18 All
these factors may confuse both laboratories and clinicians. Thus, it
is important to know clearly the specific D-­dimer assay used in their
institutions.
D-­dimer assay is widely used despite its measurement problems.
D-­dimer plays an important role in VTE exclusion, acute aortic dis-
section, DIC diagnosis, and other clinical settings, which has been
well reviewed previously.7-10 Furthermore, because of the close
relationship between coagulation, inflammation, and endothelial
injury, elevation of D-­dimer level is also observed in patients with
infection, surgery or trauma, malignance, and other nonthrombotic
7,19-22
diseases.
4 |  U S E O F D - ­D I M E R I N O R A L
A NTI COAG U L ATI O N TH E R A PY
4.1 | Effect of VKA and DOAC on D-­dimer level
Elevated D-­dimer levels are frequently observed in patients with
AF and VTE who have not received anticoagulation therapy. 20
Generally, increased level of D-­
dimer is positively associated
23,24
with an increased risk of adverse events. VKAs and DOACs
are globally accepted as oral anticoagulants to prevent throm-
bosis.1,2,25 Both of these oral anticoagulants can reduce the DD
level. However, they do not act on D-­dimer directly; their antico-
agulant effect inhibits the activation of coagulation and fibrino-
lytic system, resulting in the decreased production of D-­dimer
(Figure 1). 25,26 Lip et al found that warfarin was able to reduce
F I G U R E   1   Oral anticoagulants and
generation of D-­dimer. FDPs, fibrin
degradation products; PLT, platelet; VKAs,
vitamin K antagonists [Colour figure can
be viewed at wileyonlinelibrary.com]
the DD level by approximately two-­thirds in patients with AF. 27
A recent subgroup analysis of the RE-­LY study by Siegbahn et al
showed that warfarin can reduce the DD level of patients with
AF by 44%, whereas dabigatran can decrease the DD level by
51%, which indicated that dabigatran exerted a better effect than
warfarin. This may partly explain the cause of DOAC having more
advantages than Warfarin. 23 D-­dimer may be used to indicate the
anticoagulation effect of selected anticoagulants.
4.2 | Use of D-­dimer to predict clinical outcomes
The most common complications during oral anticoagulation are
thrombosis and bleeding, such as stroke, VTE, peripheral arterial
embolism, intracerebral hemorrhage, and gastrointestinal bleed-
ing. 26 Most of these complications are common diseases or states
that cause elevation of the D-­dimer level.8-10 Previously, the lack
of specificity has been regarded as a disadvantage of D-­
dimer.
However, low specificity has presently been transformed into one of
its advantage in the evaluation of anticoagulation prognosis.
First, D-­dimer predicts VTE recurrence. Patients with a positive
D-­dimer test have approximately 2-­to 4-­fold higher risk of recur-
rence than those with a negative test. 28,29 Tosetto et al carried out a
meta-­analysis of 7 studies including 1818 subjects and showed that
D-­dimer elevation is an independent predictor of VTE recurrence.30
At present, D-­dimer has been incorporated into several risk pre-
diction models of VTE recurrence, such as HERDOO2, DASH, and
Vienna.30-32
Second, D-­dimer predicts the outcomes of AF patients. A pro-
spective study including 269 patients with atrial fibrillation within
a period of 2 years of follow-­up showed that approximately 23% of
subjects had abnormal D-­dimer levels; even their INR levels were
in the therapeutic range. The results showed that the incidence of
subsequent thrombotic events and combined cardiovascular events
were 15.8-­and 7.64-­fold higher among patients with abnormal D-­
dimer than those with negative D-­dimer levels, respectively.5 Two
large international multicenter, double-­blind randomized controlled
trials, ARISTOTLE trial and RE-­LY study, observed similar results. 23,24
Even if patients with AF accepted VKA or DOAC anticoagulation,
D-­dimer level was positively related to the risk of adverse events
ZHANG et al.
during anticoagulation therapy, and D-­dimer could also improve the
24
C-­indices of CHADS2 and CHA 2DS2-­VASc scores.
Third, D-­dimer predicts the clinical outcomes of patients with
mechanical heart valve replacement (MHVR). Two prospective stud-
ies with 2 years of follow-­up and involving 132 and 618 subjects
showed that the risk of clinical events in post-­MHVR patients with
abnormal D-­dimer levels is approximately fivefold higher than those
with normal D-­dimer levels.33,34 Multivariate regression analysis ex-
hibited that D-­dimer level is an independent predictor of thrombotic
events during anticoagulation therapy. Moreover, among patients
with heart failure, cancer, and other conditions requiring anticoagu-
lation therapy, the abnormal level of D-­dimer is significantly associ-
ated with subsequent deaths, cancer-­related VTE, and other adverse
outcomes.19,22,35,36 In conclusion, D-­dimer can be a useful predictor
of all-­cause events during oral anticoagulation therapy.
4.3 | Use of D-­dimer to determine the optimal
duration of anticoagulation in VTE
The optimal duration of anticoagulation after the first episode
of unprovoked VTE remains unsettled. In DOAC or VKA, the cur-
rent guidelines recommended that patients should receive at least
3 months of anticoagulation therapy, and the decision to stop or ex-
tend anticoagulation therapy should be based on weighing the risk of
bleeding and VTE recurrence.1,37 D-­dimer test combined with other
additive factors can provide valuable information for individualized
therapy.
First, D-­
dimer determines whether the anticoagulant can be
stopped. A prospective study enrolled 528 subjects with VTE.38
D-­dimer was detected after receiving 3 months of anticoagulant
therapy on the basis of guideline. The study showed that patients
with a positive D-­dimer result have approximately twice the risk of
recurrence compared with those with a negative D-­dimer. An ex-
tended anticoagulation therapy should be considered for those with
positive D-­dimer levels without high bleeding risks. This conclusion
was partly supported by another multicenter cohort study involving
39
410 subjects, which concluded that the risk of VTE recurrence in
patients with negative D-­dimer level is low enough to justify stop-
39
ping the therapy in women but may be not low enough in men.
This finding revealed that a negative D-­dimer level may not be safe
enough to justify stopping therapy in men, which is also confirmed
40
by another study. Recently, Kearon et al found that patients with
a first unprovoked VTE who had antiphospholipid antibodies still
suffer a high risk of subsequent recurrence even after anticoagulant
therapy was stopped in response to negative D-­dimer tests.41 All the
findings mentioned above indicate that VTE recurrence is associated
with multiple factors, and many potential factors are still unsettled,
which still need to be clarified in future studies. Thus, guidelines have
not made recommendations based on these uncertain factors.1,37
Second, D-­dimer determines whether VTE patients need to
resume anticoagulant after withdrawal. The PROLONG study, 28 a
large multicenter, prospective, and randomized controlled study,
included 619 patients with a first unprovoked proximal VTE who
|
      3
had received VKA for at least 3 months. D-­
dimer was tested
1 month after the discontinuation of anticoagulation. Moreover,
63.3% of patients with normal D-­dimer levels did not resume anti-
coagulation, whereas those with abnormal D-­dimer levels (36.7%)
were randomly assigned either to resume or to discontinue treat-
ment. Patients with abnormal D-­dimer levels 1 month after the
discontinuation of anticoagulation had a significant incidence of
recurrent VTE (hazard ratio [HR] 2.27, 95% confidence interval
[CI]: 1.15-­4.46), which is reduced by the resumption of anticoagu-
lation (HR 4.26, 95% CI: 1.23-­14.6). Hence, it is suggested that VTE
patients can resume anticoagulation according to their D-­dimer
results analyzed 1 month after withdrawal. Then, their team con-
ducted the subsequent PROLONG II study.42 Patients with normal
D-­dimer levels 1 month after stopping anticoagulation repeated
D-­dimer testing every 2 months for 1 year. D-­dimer was normal
in 68% (243/355) of patients 1 month after anticoagulation sus-
pension. Patients in whom D-­dimer levels became abnormal at the
third month of therapy and remained abnormal afterward had a
higher risk of recurrence than those with normal D-­dimer levels.
Repeated D-­dimer testing after anticoagulation withdrawal could
help tailor the duration of oral anticoagulation therapy. Notably,
patients’ sex and other additive factors should be considered, as
well as the descriptions above.
4.4 | Use of D-­dimer to guide the optimal
intensity of anticoagulation in MHVR
DOAC cannot be used in anticoagulant therapy for patients with
MHVR, and VKA is still the only choice. 2 The standard anticoagulant
intensity of MHVR recommended by domestic and overseas guide-
lines is as follows: aortic valve replacement (INR 2.0-­3.0) and mitral
valve replacement (INR 2.5-­3.5).43 However, whether these unified
anticoagulant intensities are applicable to all populations is still con-
troversial.44 The intensity of anticoagulation shall be localized and
individualized due to the differences in genes, thrombophilia factors,
and diets.45-47 For example, low-­intensity anticoagulation is sug-
gested to most Asian patients because they would suffer higher fre-
quency of bleeding than their Caucasian counterparts.44,48 However,
some Asian patients may need high-­intensity anticoagulation due to
several thrombophilia factors.4,49 These potential risks cannot be
identified by INR test alone; therefore, supplemental markers are
needed to improve individualized anticoagulation. D-­
dimers can
screen out patients with inadequate anticoagulation.
Based on previous studies, our team carried out a prospective,
randomized controlled trial involving 748 subjects.4 The partici-
pants were randomized into 3 groups in a 1:1:1 ratio: D-­dimer-­
guided group (D-­dimer negative: INR 1.8-­2 .6; D-­dimer positive:
INR 2.5-­
3 .5), low-­
intensity group (INR: 1.8-­
2 .6), and standard-­
intensity group (INR: 2.5-­3 .5). The results showed that D-­dimer-­
guided anticoagulation effectively balances the safety and efficacy
of anticoagulation therapy in the control group, and the adverse
events are significantly lower than the standard and low-­intensity
anticoagulation. Thus, D-­dimer could serve as a complementary
 |
4       ZHANG et al.
marker to INR to find the optimal anticoagulation intensity for
post-­MHVR patients. Of course, future studies are required to
confirm this conclusion and whether the D-­dimer-­t ailored antico-
agulation strategy can be applied to other ethnic counterparts or
other diseases.
4.5 | Use of D-­dimer to evaluate
anticoagulation quality
During VKA therapy, patients are generally required to maintain
INR as stable as possible. Generally, the time in therapeutic range
(TTR, %) is often employed to evaluate the anticoagulant quality.50
A TTR above 70%, as recommended by the European Society of
Cardiology AF guidelines for VKA, was considered an appropriate
anticoagulation control.51 The low anticoagulant quality was corre-
lated with the increase in risk of bleeding or thromboembolism.52-54
Low TTR (<67%) was associated with the increase in D-­dimer level.55
Moreover, INR variation during the anticoagulation period (INR co-
efficient of variation, INR-­C V%), which is another indicator of an-
ticoagulation quality, was also a cause of the increase in D-­dimer
level.55 Thus, abnormal D-­dimer levels may indicate low anticoagula-
tion quality, such as low TTR and high INR-­C V%, even if average INR
is in the therapeutic range.
As a sensitive marker of thrombosis and hypercoagulability, D-­
dimer is no longer limited to VTE exclusion diagnosis, DIC monitor-
ing, and other traditional applications. D-­dimer has an irreplaceable
role in individualized anticoagulant therapy whether in traditional
VKAs or DOACs. The usefulness of D-­dimer has opened a new area
in the management of oral anticoagulation.
AC K N OW L E D G E M E N T S
This work was supported by the Fund of Health and Family Planning
Commission of Wuhan Municipality (WX14D11) and the Innovation
Fund of Wuhan Asia Heart Hospital (2013CX2-­A06).
ORCID
L. Zhang  http://orcid.org/0000-0003-4918-611X
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How to cite this article: Zhang L, Long Y, Xiao H, Yang J,
Toulon P, Zhang Z. Use of D-­dimer in oral anticoagulation
therapy. Int J Lab Hem. 2018;00:1–5. https://doi.org/10.1111/
ijlh.12864