D-Diamer to Diagnose DVT in Pregnancy

ORIGINAL ARTICLE

D-dimer testing in pregnant patients: towards determiningthe next ‘level’ in the diagnosis of deep vein thrombosis

W.-S .CHAN,* A . LEE ,�� F . A . SPENCER ,� S . CHUNILAL ,§ M. CR OWTHER ,� W. WU,–

M . JO H NS T ON ,* * M. RO DG E R�� and J . S . G INSBERG�*Department of Medicine, Women’s College Hospital, Toronto, ON; �Department of Medicine, University of British Columbia, Vancouver, BC;

�Department of Medicine, McMaster University, Hamilton, ON, Canada; §Department of Haematology, North Shore Hospital, Takapuna, New

Zealand; –Women’s College Research Institute and Women’s College Hospital; **Hemostasis Reference Laboratory, Henderson Hospital,

Hamilton, ON; and ��Department of Medicine, University of Ottawa, Ottawa, ON, Canada

To cite this article: Chan W-S, Lee A, Spencer FA, Chunilal S, Crowther M, Wu W, Johnston M, Rodger M, Ginsberg JS. D-dimer testing in

pregnant patients: towards determining the next �level’ in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010; 8: 1004–11.

Summary. Background: The role ofD-dimer in excluding deep

vein thrombosis (DVT) in pregnancy is currently uncertain.We

hypothesized that the specificity of sensitive D-dimer assays

could be improved without compromising sensitivity by using

higher D-dimer cut-off values.Objective: To determine the test

characteristics of two rapid enzyme-linked immunosorbent

assays and three latex agglutination assays in pregnancy.

Method: We recruited consecutive pregnant women who

presented to participating centers with suspected DVT for the

study. Symptomatic women were investigated with compres-

sion ultrasonography, and received 3 months of clinical follow-

up to assess for the presence of venous thrombosis. Plasma

samples for D-dimer were collected and frozen at the time of

presentation. The median and mean D-dimer values for

respective trimesters of pregnancy in patients with and without

DVT were calculated. Receiver operating curves (ROCs) were

plotted for respective assays to establish the best cut-points. The

test characteristics corresponding to standard cut-points and

these �pregnancy’ cut-points are presented. Results: The prev-

alence of DVT in our cohort was 6.6% (95% confidence

interval 4.0–10.6%). The mean and median D-dimer values

were significantly increased throughout pregnancy. Overall,

women with confirmed DVT had higher D-dimer levels than

womenwithoutDVT (P < 0.0001). Improved specificities (62–

79%) were observed with the use of higher cut-points obtained

from ROCs for all five assays, and high sensitivities were

manintained (80–100%) forDVTdiagnosis.Conclusion: Using

higher cut-points than those used in non-pregnant patients, the

specificity of D-dimer assays for the diagnosis of DVT in

pregnancy can be improved without compromising sensitivity.

Validation in prospective management studies is needed.

Keywords: D-dimer, deep vein thrombosis, pregnancy.

Background

Venous thromboembolism (VTE) is a major cause of maternal

morbidity and mortality [1–4] in developed countries. As

physiologic changes occurring during pregnancy can mimic

symptoms of VTE, objective testing to determine the presence

or absence of deep vein thrombosis (DVT) is of particular

importance.

In addition to compression ultrasonography, the primary

imaging modality for diagnosing DVT, diagnostic algorithms

involving D-dimer testing, have been developed to assist

clinicians in the management of non-pregnant patients with

suspected DVT [5–7]. In combination with clinicians’ assess-

ments of pretest probability, D-dimer results have been shown

to be useful in stratifying patients into those who do and do not

require further diagnostic testing, thereby decreasing the

number of compression ultrasound scans that must be

performed and minimizing unnecessary treatment when ultra-

sonography is not immediately available. Unfortunately, the

utility of D-dimer testing in pregnancy remains unclear,

because most diagnostic studies have excluded pregnant

women [5–7] and because D-dimer levels are often elevated in

pregnancy in the absence of DVT [8–10]. Given the relative

frequency with which symptoms suggestive of DVT occur in

pregnant women, a better understanding of the utility of D-

dimer testing in pregnant women will improve our manage-

ment in this cohort of patients.

Currently available D-dimer assays vary in their accuracy

and utility in diagnosingDVT [11]. Quantitative enzyme-linked

immunosorbent assay (ELISA)-based assays are highly

sensitive and can reliably exclude DVT in patients with

suspected DVT. However, the false-positive rates of these

Correspondence: Wee-Shian Chan, Women’s College Hospital,

Department of Medicine, 76 Grenville Street, Toronto, ON M5G

1B2, Canada.

Tel.: +1 416 323 6272; fax: +1 416 323 7739.

E-mail: [email protected]

Received 18 December 2009, accepted 22 January 2010

Journal of Thrombosis and Haemostasis, 8: 1004–1011 DOI: 10.1111/j.1538-7836.2010.03783.x

� 2010 International Society on Thrombosis and Haemostasis

assays are also high, particularly in patients with alternative

reasons for an elevated D-dimer level, such as pregnancy. In

one study, most asymptomatic pregnant women were found to

have elevated D-dimer levels by a rapid ELISA after 16 weeks

of gestation [8]. In another study, only 22% of women in the

second trimester and none in the third trimester had normal D-

dimer values as measured by a latex agglutination assay using

standard �non-pregnant’ cut-points [9].In contrast, the use of assays with lower sensitivity but higher

specificity may reduce false-positive rates, but may not reliably

excludeDVT in symptomatic patients. However, a recent study

[12] evaluating the performance of a qualitative whole blood

agglutination (lower sensitivity and higher specificity) D-dimer

assay in pregnant women with suspected DVT showed that the

sensitivity was 100% [95% confidence interval (CI) 77–100%),

the specificity was 60% (95% CI 52–68%), and the negative

predictive value (NPV) was 100% (95% CI 95–100%).

Although this assay appeared to be promising for use in

pregnant patients, it is being rapidly replaced in clinical practice

by more �sensitive’ D-dimer assays.

The primary objective of this study was to determine the test

characteristics of five D-dimer assays for DVT diagnosis in

symptomatic pregnant patients. We hypothesized that the use

of higher cut-points to discriminate normal from abnormal

results could compensate for the higher baseline D-dimer

values in pregnancy and improve the specificity of sensitive

D-dimer assays, without lowering the sensitivity, in this

population. To test this hypothesis, we conducted a retrospec-

tive study using stored plasma samples from a cohort of

pregnant women who presented with suspected DVT, and who

were all investigated with compression ultrasonography for

DVT [12].

Materials and methods

Study population

Consecutive pregnant women presenting to one of five

Canadian centers between June 2000 and August 2008 with

suspected DVT were potentially eligible for the study. The

protocol was reviewed and approved by the Ethics Research

Boards of all participating centers. Written informed consent

was obtained from all study participants.

The five centers included: Women’s College Hospital,

Toronto; Hamilton Health Sciences, McMaster University

Medical Centre Site and Henderson Hospital Site, Hamilton;

St Joseph’s Healthcare Centre, Hamilton; andOttawaHospital

Civic and General Campuses, Ottawa. The Hamilton and

Ottawa centers are tertiary referral sites for thrombosis; the

Toronto, McMaster, St Joseph’s and Ottawa sites are tertiary

referral centers for obstetric management.

Patients with one or more of the following criteria were

excluded from the study: a previous history of VTE; treatment

with �full-dose’ anticoagulation for 24 h or longer; concomitant

symptoms consistent with pulmonary embolism (PE); unable

or unwilling to return for follow-up; geographic inaccessibility;

and failure of patient or attending physician to provide

consent.

DVT diagnosis

Details of the diagnostic algorithm used to confirm or refute a

diagnosis of DVT are described elsewhere [12]. Briefly, all

patients underwent compression ultrasonography of the symp-

tomatic leg(s) at presentation. Compression ultrasonography

was performed with gentle compression of the common

femoral, superficial femoral and popliteal veins, as well as the

calf trifurcation. If isolated iliac vein thrombosis was suspected,

visualization of the iliac vein by direct imaging and Doppler

flow was also obtained. If the initial compression ultrasonog-

raphy finding was negative, patients received repeated com-

pression ultrasonography testing on days 3 and/or 7, based on

the clinician’s empirical assessment of pretest probability. DVT

was diagnosed on the basis of a non-compressible venous

segment and, for the iliac veins, by the absence of flow within

the iliac vein and/or the presence of a visible thrombus

according to B-mode imaging. All patients with DVT were

treated with unfractionated or low molecular weight heparin.

Patients whose compression ultrasonography finding was

normal had anticoagulants withheld and underwent clinical

follow-up for at least 3 months. These patients were either seen

or contacted at the end of 3 months to ensure that no

intervening event had occurred after initial presentation. This

approach has been used successfully by several groups

(including our own) [7,13,14] to categorize patients as DVT-

positive or DVT-negative in the validation of diagnostic tests

for DVT in non-pregnant patients.

Laboratory testing

Blood was collected into 5-mL Vacutainer tubes containing

0.105 M (3.2%) buffered sodium citrate at the time of

enrollment, and processed by laboratory technicians blinded

to the clinical status and the results of other diagnostic testing

for DVT. Samples were gently mixed, and then centrifuged for

15 min at 1700 · g within 1 h of collection. Plasma was

removed and recentrifuged for 5 min to obtain platelet-free

plasma, which was then stored at ) 70 �C in 500-lL aliquots at

each participating center. At the end of the study, all aliquots

were then shipped on dry ice to the central laboratory

(Hemostasis Reference Laboratory at Hamilton Health Sci-

ences Henderson Hospital) for batch assays.

Five commercially available D-dimer assays (two ELISAs

and three quantitative immunoturbidometric microparticle

assays) were tested. The ELISAs were Vidas D-dimer (Bio-

Merieux, Durham, NC, USA) and Asserachrome D-dimer

(Stago, Asnieres, France). The three automated quantitative

immunoturbidometric microparticle latex assays used were the

ILTest (Instrumentation Laboratories, Lexington,MA,USA),

the Sta-Lia Test (Stago), and Innovance D-Dimer lg mL)1

dimer units (Siemens, Marburg, Germany). All findings are

reported in lg mL)1 fibrinogen equivalent units (FEU) except

D-dimer testing in pregnant patients 1005


for the IL Test, the findings of which are reported in lg mL)1

dimer units. Assays were performed according to the manu-

facturers’ specifications. Technologists performing assays were

masked to patient characteristics and DVT status.

Analysis

For the analysis, patients were categorized as �DVT-positive’ if

they had a diagnostic compression ultrasonography result at

presentation or an objectively confirmed, symptomatic DVT or

PE during follow-up. Patients with a negative compression

ultrasonography result at presentation and no VTE during

3 months of follow-up were categorized as �DVT-negative’.

The median and mean of D-dimer values, with the

corresponding interquartile range and standard deviation,

were calculated for each trimester of pregnancy in women with

and without DVT. The results for women with and without

DVT were compared using the Mann–Whitney U-test. A

receiver operating characteristic (ROC) curve was generated

for each of the four assays, by plotting the sensitivity against

1 – specificity using a Wilcoxon estimate. For each of the

optimal cut-points generated by the ROC curves, the test

characteristics (sensitivity, specificity, NPV, and negative

likelihood ratios) and their corresponding 95% CIs were

calculated. Test characteristics were also calculated for all five

assays using standard cut-points established for non-pregnant

patients. All analyses were performed using SAS statistical

software version 9.1 (SAS Institute Inc., Cary, NC, USA) and

STATSDIRECT statistical software version 2.7.3 (StatsDirect Ltd,

Altrincham, UK).

Choice of optimal cut-point for each assay

On the basis of a desired NPV of 98% (consistent with that

reported in non-pregnant subjects after normal venography,

the reference standard diagnostic test) and an estimated

incidence of DVT of � 10%, we estimated that a sensitivity

of 80% would suffice, provided that the specificity was at least

60%. Therefore, the �optimal cut-points’ were established on

the basis of two criteria: an observed NPV of ‡ 98%, and a

specificity of at least 60%. This would reduce the number of

false-positives and improve the utility of the test without

reducing safety.

Results

A total of 249 pregnant women who presented with suspected

DVT were enrolled in the study over an 8-year period. Plasma

was collected and available for testing in 228 (91.2%) of these

patients. Among these patients, 15 were diagnosed with DVT,

resulting in an incidence of 6.6% (95% CI 4.0–10.6). Of the 21

patients in whom D-dimer levels were not determined at

presentation, two had DVT.

Themajority of these patients presentedwith suspectedDVT

in the second (36.4%) or third (59.6%) trimesters of pregnancy.

The distribution of DVT was 26.6%, 26.7% and 46.7%,

respectively, in the first, second and third trimesters of

pregnancy. DVT was diagnosed on initial presentation in

80% (12/15) of patients; in the remaining three patients, DVT

was diagnosed on serial testing over 7 days. The first patient

initially had a great saphenous vein thrombosis, which

progressed into the femoral vein over 6 days, the second

patient had two negative compression ultrasonography results,

followed by a positive third compression ultrasonography

result on day 7 that demonstrated extensive DVT involving the

ileofemoropopliteal veins, and the third patient had a popliteal

veinDVTdiagnosed 4 days after the initial negative ultrasound

result. No patients developed PE during follow-up.

The mean and median D-dimer values for each assay are

presented by trimester and the presence or absence of DVT in

Table 1. As expected, both mean and median D-dimer levels

increased with progressive trimesters of pregnancy among

women who did not have acute thrombosis. D-dimer values

were also significantly higher in those women who were

diagnosed with DVT than in those who were not (Mann–

Whitney U-test, P < 0.0001), for each of the five assays.

Correlations for all five assays were good (data available on

request).

The ROC curves associated with respective D-dimer assay

were plotted and are shown in Figs 1–5. The optimal cut-points

were 1.89 lg mL)1 FEU for the Vidas assay, 1.51 lg mL)1

FEU for the Asserachrome assay, 0.57 lg mL)1 dimer units

for the IL assay, 1.38 lg mL)1 FEU for the Sta-Lia assay, and

1.50 lg mL)1 FEU for the Innovance assay. The area under

the curves ranged between 0.82 and 0.87 for all five assays,

suggesting that the ability of these assays to discriminate

between pregnant women with and without DVT is good.

The test characteristics corresponding to established and

pregnancy cut-points for all five assays are shown in Table 2. In

all five assays, the sensitivities are high with the use of standard

cut-points (100%) as derived from published studies [15–19];

however, the specificities in all cases are poor (range, 6–23%).

Conversely, using the optimal cut-points for pregnant patients

derived from the ROC curves, there is improved specificity

(range, 61–79%), with only a small reduction in sensitivity in

four of the five assays (range, 93–100%) and a modest

reduction in the fifth assay (80%). With the low incidence of

DVT in the cohort, the NPV is, as expected, high in all cases, at

more than 98%.

Discussion

Our findings suggest that the currently available sensitive

D-dimer assays that are used for the exclusion of DVT in

symptomatic non-pregnant patients have the potential to

exclude DVT in symptomatic pregnant patients with the

application of higher cut-points. We showed that even as

D-dimer levels increase several-fold during pregnancy, we can

still use higher D-dimer cut-points to exclude a DVT without

worrying about missing one in pregnancy.

The findings from our study are important because we are

unaware of similar studies investigating the potential use of

1006 W.-S. Chan et al


available D-dimer assays for the diagnosis of DVT in

pregnant patients. In non-pregnant patients with suspected

DVT, use of a clinical prediction tool and the D-dimer assay is

sufficient to safely exclude DVT in low-risk patients. Whether

this will prove true in pregnant patients requires further

careful and cautious study. At the very least, D-dimer testing

may allow for minimization and/or elimination of the need for

serial ultrasound testing in patients with an initial negative

study. In addition, increased understanding of the utility of

D-dimer assays for the exclusion of DVT in pregnant women

will serve as a basis for subsequent studies evaluating its use in

pregnant patients with suspected PE. This will be of great

importance, as D-dimer assays in this setting may allow for

omission or at least minimization of radiologic testing (e.g.

computed tomography, ventilation/perfusion scan) in this

high-risk population.

With the use of current established cut-points, many

pregnant women would test �positive’ (with abnormally

elevated D-dimer levels) in the absence of DVT. Raising the

cut-points can improve the specificity of these tests, but a high

degree of sensitivity must be preserved to avoid misdiagnosis.

The criteria that we used to decide upon the optimal cut-points

were those providing an NPV of at least 98% and a specificity

of at least 60%.We recognize the limitations of such an

approach, because some clinicians are adamant that missing

any VTE during pregnancy is unacceptable and that the

sensitivity and NPV of the assays should both be 100%. Such

an approach is impractical for some assays, as the specificity

falls too low for the assays to be useful. Furthermore, we

believe that it is an irrational �emotional’ response that is not

consistent with day-to-day practice. Finally, we consider these

cut-points to represent �a good start’ for prospective evaluation,in which the D-dimer assays could be combined with clinical

pretest probability or compression ultrasonography, and

should not be used as stand-alone tests. Our study demon-

strates that such a strategy is possible for at least four of the five

commercially available D-dimer assays evaluated. With use of

the cut-points identified with ROC curves, the false-positive

rate of D-dimer testing (proportion of pregnant women who

test positive on the basis of elevated D-dimer levels who do not

haveDVT) would decrease from about 75% to about 25–35%.

Raising the cut-points would improve the utility of these

available commercial assays. Whether setting different cut-

points for each trimester of pregnancy will fine-tune and

improve accuracy is an unanswered question, but we were

unable to address this, owing to the small number of patients

and events in each trimester.

Our study has several limitations. The sample size is small

and the incidence of DVT among symptomatic patients is low,

so the CIs associated with our point estimates of the accuracy

indexes (particularly the sensitivities) are wide. However, the

inclusion of unselected patients and the use of objective testing

to confirm DVT diagnosis reduce the likelihood of sampling

and diagnostic biases in our study. The incidence of DVT in

our study is also consistent with other studies in pregnant

women, suggesting that the NPVs are not likely to be inflatedTable1Themeanan

dmedianD-dim

ervalues

forfourD-dim

erassays

bytrim

esteran

ddeepvein

thrombosisstatus

D-dim

erassay

(units)

DVT

Trimester1(lessthan12weeks)

Trimester2(12to

less

than

28weeks)

Trimester3(28weeksorlater)

All

nMean(SD)

Median(IQR)

nMean(SD)

Median(IQR)

nMean(SD)

Median(IQR)

nMean(SD)

Median(IQR)

Vidas(lgmL

)1

FEU)

Positive

48.53(9.79)

4.60(2.50–14.56)

42.00(0.37)

1.98(1.76–2.23)

73.77(1.52)

3.74(2.10–5.19)

15

4.57(5.32)

3.03(1.96–5.19)

Negative

50.90(0.91)

0.60(0.15–1.35)

79

0.98(1.21)

0.71(0.55–0.95)

129

3.39(7.94)

1.48(0.97–2.05)

212

2.43(6.32)

1.04(0.71–1.75)

Asserachrome

(lgmL

)1FEU)

Positive

44.98(3.08)

5.41(2.38–7.58)

42.13(0.35)

2.26(1.91–2.34)

73.47(2.09)

2.75(1.86–4.89)

15

3.52(2.26)

2.52(1.87–4.89)

Negative

50.90(0.89)

0.65(0.19–1.17)

79

0.97(1.23)

0.66(0.51–0.89)

129

1.90(1.80)

1.25(0.84–2.19)

211

1.53(1.66)

0.96(0.63–1.67)

ILTest(lgmL

)1

dim

erunits)

Positive

42.12(2.05)

1.59(0.58–3.66)

40.69(0.19)

0.72(0.54–0.84

71.13(0.68)

1.04(0.57–1.55)

15

1.28(1.19)

0.79(0.57–1.55)

Negative

50.78(0.36)

0.82(0.47–1.04)

79

0.40(0.77)

0.27(0.21–0.34)

129

0.75(1.04)

0.42(0.29–0.70)

210

0.62(0.95)

0.35(0.25–0.58)

Sta-Lia

(lgmL

)1

FEU)

Positive

410.27(12.76)

5.40(1.99–18.55)

41.62(0.73)

1.60(1.09–2.15)

73.09(1.39)

2.76(1.72–3.92)

15

4.62(6.98)

2.61(1.52–3.92)

Negative

50.76(0.69)

0.48(0.22–1.06)

79

0.97(2.15)

0.52(0.33–0.82)

129

2.50(6.49)

0.99(0.67–1.77)

213

1.89(5.26)

0.82(0.46–1.33)

Innovance

(lgmL

)1FEU)

Positive

48.88(8.24)

7.23(2.35–15.41)

42.03(0.58)

2.02(1.53–2.54)

74.35(2.11)

4.67(2.05–5.70)

15

4.94(4.85)

3.04(1.80–5.70)

Negative

51.03(0.96)

0.80(0.21–1.51)

79

1.30(1.93)

0.93(0.74–1.17)

129

3.70(8.49)

1.56(1.10–2.67)

209

2.74(6.79)

1.26(0.87–1.96)

DVT,deepveinthrombosis;

FEU,fibrinogen

equivalentunits;

IQR,interquartilerange;

Negative,

absence

ofdeepveinthrombosis;

Positive,

presence

ofdeepveinthrombosis;

SD,standard

deviation.



by an unusually low incidence of DVT in our study sample.

Also, we have minimized diagnostic suspicion bias by batch-

testing our plasma samples and blinding our laboratory

technicians to the disease status of the study patients.

Another limitation of this study is that stored plasma

samples were used. Owing to budgetary constraints, we did not

perform these assays at the time of presentation. Blood samples

were collected at the time of presentation for the specific

purpose of D-dimer testing. Owing to the lengthy enrollment

period that was necessary to conduct the diagnostic study,

samples were frozen and batch-tested for up to 8 years after the

collection date. Although great care was taken to process and

store these samples at ) 70 �C during this time, it is possible

that some degradation of the samples may have occurred.

However, D-dimers are end-products of fibrinolysis, and levels

in frozen samples should remain stable because there is no

in vitro clearance or production. The mean levels in our

samples were also consistent with those in another published

study [8,9]. Performance of the assays at a central laboratory

also allowed for better control of testing conditions and

1.00

0.75

0.50

0.25

0.000.00 0.25 0.50 0.75 1.00

1-Specificity

Sensitivity

Optimum cut-off point selected = 1.89 µg mL–1 FEU

DVTDdPos 14 45

Pos

Neg 1 167

Neg

Fig. 1. Receiver operating characteristic (ROC) curve for Vidas D-dimer assay. Dd, D-dimer; DVT, deep vein thrombosis; FEU, fibrinogen equivalent

units; Pos, Positive; Neg, negative; Dd Pos, level at or above cut-point; Dd Neg, level below cut-point. Area under ROC curve by Wilcoxon

estimate = 0.87 (95% confidence interval 0.82–0.92).

0.000.00 0.25 0.50

DVTDdPos 15 55

Pos

Neg 0 156

Neg

0.75 1.001-Specificity

0.25

0.50

0.75


1.00Sensitivity

Fig. 2. Receiver operating characteristic (ROC) curve for Asserachrome D-dimer assay. Dd, D-dimer; DVT, deep vein thrombosis; FEU, fibrinogen

equivalent units; Pos, Positive; Neg, negative; Dd Pos, level at or above cut-point; Dd Neg, level below cut-point. Area under ROC curve by Wilcoxon

estimate = 0.87 (95% confidence interval 0.81–0.92).



eliminated variability in assay performance over time. Neve-

theless, prospective studies are needed to validate these results

before the results of this study can be applied to clinical

practice.

It is established that D-dimer testing, combined with pretest

probability using a prediction rule, is important in the diagnosis

of VTE in the general population, and there is also increasing

evidence supporting the use of D-dimer testing in excluding

recurrent DVT [6] as well as for the prediction of future DVT

recurrence [20]. We have shown that D-dimer testing could be

extended to pregnant women by using higher cut-points than in

the general population. The use of D-dimer testing (at higher

cut-points), combined with pretest probability assessment, in

pregnant patients for the diagnosis of DVT should now be

evaluated prospectively.

Conclusion

With the use of higher cut-points, currently available sensitive

D-dimer assays appear to be sufficiently sensitive and specific

for use in pregnant women with suspected DVT. Combined

with pretest probability assessment, D-dimer testing may

prove to be useful for the exclusion of DVT in pregnant

women.

0.000.00 0.25 0.50 0.75 1.00

1-Specificity

0.25

0.50

0.75


1.00Sensitivity

Fig. 4. Receiver operating characteristic curve (ROC) for Sta-Lia D-dimer assay. Dd, D-dimer; DVT, deep vein thrombosis; FEU, fibrinogen equivalent

units; Pos, Positive; Neg, negative; Dd Pos, level at or above cut-point; Dd Neg, level below cut-point. Area under ROC curve by Wilcoxon esti-

mate = 0.85 (95% confidence interval 0.78–0.92).

0.000.00 0.25 0.50

DVTDdPos

Pos

12 53Neg

Neg

3 157

0.75 1.001-Specificity

0.25

0.50

Optimum cut-off point selected = 0.57 µg mL–1 dimer units0.75

1.00Sensitivity

Fig. 3. Receiver operating characteristic curve (ROC) for IL D-dimer assay. Dd, D-dimer; DVT, deep vein thrombosis; Pos, Positive; Neg, negative; Dd

Pos, level at or above cut-point; DdNeg, level below cut-point. Area under ROC curve byWilcoxon estimate = 0.82 (95% confidence interval 0.74–0.90).



Addendum

W.-S. Chan, A. Lee, S. Chunilal and J.S. Ginsberg were

responsible for overall study design and methodology; A. Lee,

F.A. Spencer, J.S. Ginsberg andM. Johnston were responsible

for selection of D-dimer assays and testing;W.-S. Chan andW.

Wu were responsible for statistical analysis; W.-S. Chan, F.A.

Spencer, M. Crowther, M. Rodger and J.S. Ginsberg were

responsible for patient recruitment and data collection; W.-S.

Chan, A. Lee, F.A. Spencer, J.S. Ginsberg and M. Johnston

were responsible for manuscript preparation. All other authors

approved the final manuscript.

Acknowledgements

The authors wish to acknowledge N. McEwen, J. McGrath

and E. Ali for testing the samples. We would also like to thank

M. Quilacio, A.M. Clement and P. Stevens for their assistance

in patient recruitment.

J. S. Ginsberg and F. A. Spencer are recipients of a Career

Investigator Award of the Heart and Stroke Foundation of

Ontario. Partial funding was provided in the first 2 years by the

Heart and Stroke Foundation of Ontario (Grant no.

NA 5048). No external funding was obtained for D-dimer

assays or testing.

Disclosure of Conflict of Interests

The authors state that they have no conflict of interest.

References

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0.000.00 0.25 0.50 0.75 1.00

1-specificity

DVT


DdPos

Pos Neg

15 81Neg 0 128

0.25

0.50

0.75

1.00Sensitivity

Fig. 5. Receiver operator curve (ROC) for Innovance D-dimer assay. Dd, D-dimer; DVT, deep vein thrombosis; FEU, fibrinogen equivalent units; Pos,

Positive; Neg, negative; Dd Pos, level at or above cut-point; Dd Neg, level below cut-point. Area under ROC curve by Wilcoxon estimate = 0.83 (95%

confidence interval 0.76–0.90).

Table 2 Test characteristics of the D-dimer assays in symptomatic pregnant patients at non-pregnant and pregnant cut-points

Assay

D-dimer level cut-points

(lg mL)1 FEU)

Sensitivity, %

(95% CI)

Specificity, %

(95% CI)

NPV, %

(95% CI)

Negative likelihood

ratio (95% CI)

Vidas Non-pregnant, 0.50 100 (74.7–100) 10.3 (6.63–15.5) 100 (80.8–100) 0.09 (0.01–0.56)

Pregnant, 1.89 93.3 (68.1–99.8) 78.8 (72.7–84.1) 99.4 (96.2–100)

Asserachrome Non-pregnant, 0.50 100 (74.7–100) 12.3 (8.28–17.8) 100 (83.4–100) 0 (–)*

Pregnant, 1.51 100 (78.2–100) 73.9 (67.5–79.7) 100 (97.0–100)

IL Test� Non-pregnant, 0.23� 100 (74.7–100) 17.8 (13.0–24.0) 100 (88.0–100) 0.27 (0.10–0.74)

Pregnant, 0.57� 80.0 (51.9–95.7) 74.8 (68.3–80.5) 98.1 (94.2–99.5)

STA-Lia Non-pregnant, 0.50 100 (74.7–100) 22.9 (17.5–29.4) 100 (90.6–100) 0.09 (0.01–0.59)

Pregnant, 1.38 93.3 (68.1–99.8) 75.6 (69.3–81.2) 99.4 (96.1–100)

Innovance Non-pregnant, 0.50 100 (74.7–100) 6.22 (3.49–10.6) 100 (71.7–100) 0 (–)*

Pregnant, 1.50 100 (74.7–100) 61.2 (54.3–67.8) 100 (96.4–100)

CI, confidence interval; FEU, fibrinogen equivalent units; NPV, negative predictive value. *One or more cells contains a �zero’ value, so 95% CI

cannot be calculated. �Measured in dimer units.



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D-Diamer to Diagnose DVT in Pregnancy

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