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Thrombosis
Table 1: Conditions Associated with Increased overall rate of thromboembolic events of 0.45% (95% confidence
D-dimer Plasma Levels
interval [CI] 0.22–0.83%) among patients in whom anticoagulant
treatment was withheld on the basis of a low clinical score and a
Non-pathological Pathological
negative DD result, thus demonstrating the safety of this diagnostic
Age Trauma
work-up for the exclusion of both DVT and PE. No significant
Race (black population) Pre-eclampsia
difference in safety was observed with qualitative and quantitative
Cigarette smoking Malignancy
DD tests and with different decision rules. This diagnostic strategy,
Pregnancy and puerperium Infection
Post-operatively Chronic inflammatory diseases
requiring further specific tests in patients only with positive DD
Disseminated intravascular coagulation
and/or intermediate or high PCP, has also been reported to be the
Sickle cell disease
most advantageous in a cost-effectiveness analysis.
16
Arterial or venous thromboembolism
Acute coronary syndromes The use of DD testing for VTE diagnosis requires the identification of
Stroke
a cut-off level allowing clinicians to exclude the disease. This cut-off
Peripheral artery disease
value is the point within the measuring range that confers the best
Atrial fibrillation
sensitivity and specificity to a particular assay, and may not coincide
Congestive heart failure
with the upper limit of the reference interval, which is calculated in a
Haemorrhages
healthy population. When choosing a DD assay to be used in the
diagnostic work-up of DVT or PE, its sensitivity and cut-off level
Table 2: Features of Available D-dimer Assays
should be carefully evaluated in order to avoid false-negative
results.
17
Specificity is also important because it influences the yield
Type of D-dimer Assay Characteristics
of the test, determining the proportion of false-positive results. The
ELISA Assays
choice of the appropriate method for DD measurement also depends
Classic microplate ELISA High sensitivity, low specificity, observer-
on the place of the test in the diagnostic sequence of VTE. If used as
independent, not suitable for realtime
the first step with no additional tests in the event of a negative result,
single testing
the method of choice should have a sensitivity as close as possible
Rapid ELISA assays High sensitivity, low specificity, observer-
to 100% in order to minimise the proportion of false-negative results.
independent, suitable for realtime
single testing
In contrast, if a DD test is used in association with PCP assessment
or imaging techniques, a less sensitive test may be accepted.
Agglutination Assays
Semi-quantitative assays Intermediate sensitivity and specificity, rapid,
observer-dependent
The performance of several DD tests for either DVT or PE diagnosis
Quantitative assays High sensitivity, intermediate specificity, rapid,
was evaluated in a recent meta-analysis by Di Nisio et al.
18
The
(immunoturbidimetric assays) observer-independent sensitivities of the enzyme-linked immunofluorescence assay (ELFA)
Whole-blood assays
(DVT 96%, PE 97%), microplate ELISA (DVT 94%, PE 95%) and latex
High to intermediate sensitivity, intermediate quantitative assays (DVT 93%, PE 95%) were superior to those of the
specificity, rapid bedside execution,
whole-blood DD assays (DVT 83%, PE 87%), latex semi-quantitative
observer-dependent
assays (DVT 85%, PE 88%) and latex qualitative assays (DVT 69%, PE
ELISA = enzyme-linked immunosorbent assay.
75%). On the other hand, the latex qualitative and whole-blood DD
assays showed the highest specifities (99 and 71% for DVT and 99%
Various integrated strategies for VTE diagnosis have been proposed, and 69% for PE, respectively, compared with approximately 50% for
in which DD testing has different places in the diagnostic sequence: the highly sensitive assays). In a previous meta-analysis by Stein et
al.,
19
the sensitivity and negative predictive value of the ELISAs (in
• Initial DD testing for the exclusion of VTE with additional imaging particular the quantitative rapid ELISA) were superior to those of
tests in patients only with a positive DD result. This strategy was other DD tests, including latex quantitative assays.
adopted in a large, prospective management study of over 900
consecutive outpatients with suspected DVT or PE referred to The usefulness of DD testing in the diagnostic work-up of DVT or PE is
the emergency department of the Geneva Hospital.
7
affected not only by the choice of the appropriate assay, but also by
• DD testing after a first negative imaging test to identify patients patient characteristics and clinical context. Extent of VTE, duration of
who require a new specific evaluation. In this diagnostic strategy symptoms, anticoagulant treatments, age and co-morbid conditions
for suspected DVT, a positive DD result allows the selection of represent relevant sources of variation in DD tests affecting their
patients who require a new ultrasonographic evaluation one week sensitivity and specificity. DD levels are related to thrombus extension,
after a first negative one to detect extending calf DVT, which may being higher in the presence of larger thrombi. This may explain why DD
have altered a DD test without being detectable on first sensitivity has been reported to be lower in distal DVT
20
or subsegmental
ultrasound.
8
A similar use of DD testing has proved to be useful in PE.
21
There is an inverse relationship between DD plasma levels and
patients with suspected PE after a first negative lung scan.
9
duration of symptoms. DD concentration tends to decrease when a
• DD testing integrated with pre-test clinical probability (PCP) and patient has presented symptoms for several days before testing,
subsequent specific tests. Several studies have demonstrated that reaching 25% of the initial value after one to two weeks.
22
Anticoagulant
a negative DD result combined with a low PCP of disease can safely therapy (with both heparin and vitamin K antagonists) also determines a
exclude DVT or PE without additional diagnostic testing.
10–14
decrease in DD concentration, which has been estimated at around 25%
Recently, a systematic review of 11 management studies using a 24 hours after starting anticoagulation, with a consequent decrease in
combination of PCP and DD test results to rule out VTE
15
showed an sensitivity from 95.5% (95% CI 90–99%) to 89.4% (95% CI 84–95%).
23
38 EUROPEAN HAEMATOLOGY
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