A Red Blood Cell Agglutination d-Dimer Test to Exclude Deep Venous Thrombosis in Pregnancy

We have read with interest the recent article of Chan et al., who highlighted that the SimpliRED assay may be useful in pregnancy because a normal result would help rule out deep venous thrombosis (DVT), and occur frequently enough to be clinically helpful (1). This is a very provocative conclusion, in that d-dimer is an indispensable test in the diagnostic approach to DVT (2), but its use has been traditionally discouraged in pregnancy, due to the questionable diagnostic efficiency (3). Therefore, we would like to express some considerations on results of this clinical investigation. First, as correctly highlighted, the overall number of patients enrolled (n=149) and, especially, of those with episodes of DVT (n=12), is probably too low to provide a definitive diagnostic information. Then, the promising data shown in the article (the reported specificity was 60%) are referred to the entire study population, but they were not analyzed according to the trimester of pregnancy and the maternal age (2). Extrapolating data from the above mentioned article (1), we calculated that the positive predictive value (PPV) in the entire study population was 18% (this information was missing), whereas the specificity and the PPV in women after 28 weeks of gestation were reduced to 49% and 9%, respectively. Owing to the increasing and competing demands on primary care resources and the wedging pressure from cost containment policies, inefficient or inappropriate diagnostic testing places considerable organizational and economical problems. Moreover, it is also to mention that the high prevalence of false positive tests in women without DVT (39% on overall and 51% after 28 weeks of gestation) would entail unpredictable and even adverse psychological effects on the patient, being also potentially associated with further discomfort and increased costs for unnecessary and invasive testing. Therefore, we believe that until more convincing observations from larger studies will be available, the low values of both specificity and PPV of SimpliRED testing for diagnosing DVT, especially after 28 weeks of gestation, might lead to a questionable diagnostic information, wasted diagnostic efforts and expenses for the healthcare system.

References

1. Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165-70.

2. Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood 2002;100:3470-8.

Conflict of Interest:

None declared

Diagnosis of venous thromboembolic disease(DVT or PE) is not totally dependent on test results of D-dimer assay. It should be used in combination with pretest probability of the condition. A negative D-dimer in combination with low pretest probability can exclude almost all DVT or PE.(1) Thus some experts reserve the use of D-dimer for patients who have a low pretest probability for PE.(2)

If the clinical pretest probability is moderate or high, such as in some patients with cancer, a negative D-dimer is not useful because it doesn't have a sufficient negative predictive value for excluding the presence of DVT or PE.(3) Pregnancy is also one of the several hypercoagulable states like some forms of cancer. And this state further increases with the duration of pregnancy which the authors have also shown by the results of D-dimer assay in pregnant patients in whom DVT was not diagnosed. (4) Can pretest probability of DVT in pregnancy be considered low sufficient enough to exclude it based on the negative results of D- dimer only?

Further, it has been found that the introduction of a rapid D-dimer assay increased the number of VQ scans( and other modalities of investigation) performed because the number of patients screened for PE increased.(5) With high false positive results of the D-dimer assay in pregnancy , this would obviously increase the chances of further unnecessary and invasive tests which would directly or indirectly have adverse impact on maternal and child health.

References:

1.Ginsberg JS, Wells PS, Kearon C, et al. Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism. Ann Intern Med. 1998;129(12):1006-1011.

2.Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med. 2001;161(4):567-571

3. Lee AY, Julian JA, Levine MN, et al. Clinical utility of a rapid whole- blood D-dimer assay in patients with cancer who present with suspected acute deep venous thrombosis. Ann Intern Med. 1999;131(6):417 -423.

4.Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165-70.

5.Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med. 2001;161(4):567-571

Conflict of Interest:

None declared

Dr Lippi raises two important issues about our study of pregnant women with suspected deep vein thrombosis (DVT): a) the low specificity and positive predictive value (PPV) of the D-dimer test (SimpliREDTM) and b) the relatively small number of patients with DVT (n=13) in our cohort result in wide confidence intervals associated with the sensitivity and negative predictive value (NPV) of the test.

We agree that the PPV is far too low for to conclude that an abnormal test result is diagnostic of DVT. We emphasize that the purpose of our study was to show that this D-dimer assay is sensitive and therefore, has high NPV and that the specificity is sufficiently high to make the test useful. Based on the results, we concluded that a normal D-dimer test can be used to exclude the diagnosis of DVT in pregnant women.

With respect to the small sample size, our calculation of sensitivity of the D-dimer assay is based on only 13 patients with VTE and therefore, the corresponding 95% confidence interval is wide. However, the sensitivity and NPV of the D-dimer assay derived from our study, is consistent with the results of other studies evaluating this assay in non- pregnant patients [1-3]. Nevertheless, we agree that further large management studies are required, whereby further investigation and treatment for DVT are withheld when results of D-dimer testing are negative, either alone or in conjunction with a low pre-test probability and/or normal venous ultrasonography at presentation.

The importance of evaluating D-dimer testing in pregnant women, prior to dismissing it as a "useless" test cannot be over-emphasized. Despite the fact that venous thromboembolism is a major preventable cause of maternal mortality in developed countries [4], there are few prospective studies investigating the accurate diagnosis of DVT in pregnant women. The potential contribution of D-dimer testing (which is a non-invasive test and carries no radiation risk to the fetus) to accurately exclude DVT and more importantly pulmonary embolism, in pregnant women should be further studied. Indeed, if D-dimer testing is abandoned for pregnant women without further evaluation, the "cost" to mothers and their newborns could be even greater.

References

1. Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial. Ann Intern Med. 2004 Dec 7;141(11):839-45.

2. Kraaijenhagen RA, Piovella F, Bernardi E, Verlato F, Beckers EA, Koopman MM, Barone M, Camporese G, Potter Van Loon BJ, Prins MH, Prandoni P, Buller HR. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Intern Med. 2002 Apr 22;162(8):907-11.

3. Kearon C, Ginsberg JS, Douketis J, Crowther MA, Turpie AG, Bates SM, Lee A, Brill-Edwards P, Finch T, Gent M. A randomized trial of diagnostic strategies after normal proximal vein ultrasonography for suspected deep venous thrombosis: D-dimer testing compared with repeated ultrasonography. Ann Intern Med. 2005 Apr 5;142(7):490-6.

4. Rochat RW, Koorin LM, Atrash HK, et al. Maternal mortality in the United States: Report from the Maternal Mortality Collaborative. Obs Gyn 1988;(72)91-97.

Conflict of Interest:

None declared