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D-dimer Testing and Venous Thromboembolism
Therefore, a DD result below the diagnostic cut-off obtained after anticoagulation showed that in patients who have completed
starting anticoagulation should be interpreted with caution in order to treatment for at least three months for a first episode of unprovoked
avoid false-negative results. In several clinical conditions associated with VTE and after approximately two years of follow-up, the annual rates
increased DD levels, the specificity of DD testing for VTE diagnosis may of recurrent VTE were significantly different between patients with
be greatly diminished due to a higher number of false-positive results. positive and negative DD results (8.9 and 3.5%, respectively). Similarly,
This is the reason why a reduced diagnostic usefulness of DD testing for a more than two-fold odds of recurrence in patients with unprovoked
VTE exclusion has been reported in surgical and non-surgical VTE and elevated DD levels measured one month after anticoagulation
inpatients,
24
inflammatory states,
25
pregnancy and post-partum,
26,27
withdrawal was found in another recently published meta-analysis.
46
elderly patients,
28
cancer patients
29
and those with previous VTE.
30
Therefore, efforts should be made to avoid inappropriate DD testing, Despite the increasing evidence of the usefulness of DD testing after
limiting its use to clinical settings in which DD-based management of anticoagulation withdrawal for discriminating between patients at
suspected VTE has been proved to be efficacious and safe. higher and lower risk of recurrent VTE, some matters still need to be
addressed. First, the lack of a worldwide standard for DD testing
D-dimer Testing to Predict Venous makes it difficult to compare results obtained with the different
Thromboembolism Recurrence After available assays. Therefore, each method should be evaluated
Anticoagulation Withdrawal separately in rigorous management studies to validate their use in
The optimal duration of anticoagulation after a first episode
of unprovoked VTE is still debated.
31
At least six months of
anticoagulation have been recommended because of presumed D-dimer testing is a promising method
higher rates of recurrence with shorter durations of treatment.
32,33
to identify patients at higher risk of
However, recent randomised trials have indicated that the duration of
anticoagulation seems to have little effect on the rate of disease recurrent venous thromboembolism,
recurrence in patients with unprovoked VTE, and longer treatment
and could therefore help with the
only delays recurrence until after anticoagulation is stopped.
34,35
Therefore, the major clinical decision is whether to stop or to continue decision of whether to continue or
anticoagulation, because stopping anticoagulant therapy may place
stop anticoagulant treatment.
some patients at risk of morbidity and mortality due to recurrent VTE,
whereas continuing anticoagulation exposes patients to the
increased risk of bleeding. clinical practice for assessing the risk of VTE recurrence. Second, the
DD cut-off level that best predicts recurrent VTE is not known,
Following the observation that DD plasma levels tend to increase in especially in patient subgroups in whom baseline DD levels are
some patients with previous VTE after oral anticoagulation increased, such as elderly persons.
withdrawal,
36–38
prospective studies initially showed that DD levels have
a strong predictive value for the occurrence of recurrent VTE episodes In the PROLONG study,
42
the qualitative, whole-blood Clearview
in these patients.
39–41
These studies suggested that a simple and easy-to- Simplify DD assay (Inverness Medical Professional Diagnostics)
implement strategy such as DD measurement after anticoagulation was used. In a post hoc analysis of the study,
47
Legnani et al.
withdrawal could help with the decision of whether to continue or stop retrospectively evaluated the performance of four quantitative DD
anticoagulant treatment. Indeed, a normal DD level may identify patients methods to predict the risk of VTE recurrence using plasma samples
at low risk of recurrent VTE, in whom anticoagulation therapy may of a subgroup of patients enrolled in the PROLONG study. This
be discontinued, whereas an abnormal DD level may identify patients analysis showed that quantitative DD assays may provide useful
with a persistent pro-thrombotic tendency who warrant long-term information for evaluating the individual risk of recurrence, and
anticoagulation, because they are at relatively high risk of recurrent VTE. seem particularly advantageous as they allow selection of different
cut-off levels according to age or other characteristics of patients.
In a prospective, randomised, multicentre trial, the PROLONG study,
42
Further prospective studies are needed to validate these cut-offs.
DD testing was performed one month after stopping anticoagulation in
patients with a first unprovoked proximal DVT or PE who had received Another matter to be considered is the timing of DD measurement
a vitamin K antagonist for at least three months. Patients with a normal after oral anticoagulation withdrawal. In the PROLONG study,
42
the
DD level did not resume anticoagulation, whereas those with an DD assay was performed only once, but during follow-up some
abnormal DD level were randomly assigned to either resume or patients with normal DD levels could have had abnormal results on
discontinue treatment. The results of this study showed that patients repeated testing. Therefore, repeated DD assays in patients with an
with abnormal DD levels one month after stopping anticoagulation had initial normal test may be useful in detecting late hypercoagulability.
a higher rate of VTE recurrence at 18-month follow-up than those with This matter has been addressed in the PROLONG II prospective
normal DD levels, and benefited from resumption of anticoagulation. cohort study, the results of which are not yet available.
This finding was confirmed at an extended follow-up of 2.5 years.
43
Thus, DD testing is a promising method to identify patients at higher risk
Moreover, in a post hoc analysis of the PROLONG study,
44
abnormal DD of recurrent VTE, and could therefore help with the decision of whether
levels one month after anticoagulation withdrawal were found to be to continue or stop anticoagulant treatment. Other possible predictors
predictive of VTE recurrence also in the subgroup of patients with of recurrent disease have been evaluated in patients with unprovoked
unprovoked PE. Recently, a systematic review by Verhovsek et al.
45
of VTE. For patients with DVT, the presence of residual vein obstruction on
seven studies that measured DD three to six weeks after stopping ultrasonography may predict an increased risk of recurrence,
48
although
EUROPEAN HAEMATOLOGY 39
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