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Semin Thromb Hemost 2006; 32(7): 678-693
DOI: 10.1055/s-2006-951296
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Different Accuracies of Rapid Enzyme-Linked Immunosorbent, Turbidimetric, and Agglutination D-Dimer Assays for Thrombosis Exclusion: Impact on Diagnostic Work-Ups of Outpatients with Suspected Deep Vein Thrombosis and Pulmonary Embolism

Jan J. Michiels1 , 7 , Alain Gadisseur1 , Marc van der Planken2 , Wilfried Schroyens1 , Marianne De Maeseneer3 , Jan T. Hermsen4 , Paul H. Trienekens4 , Henk Hoogsteden5 , Peter M.P Pattynama6
  • 1Hemostasis and Thrombosis Research, Department of Hematology, University Hospital Antwerp, Belgium
  • 2Hemostasis Laboratory Department of Clinical Biology, University Hospital Antwerp, Belgium
  • 3Vascular Laboratory, Department of Vascular Surgery, University Hospital Antwerp, Belgium
  • 4Medical Diagnostic Center Rijnmond, Rotterdam, The Netherlands
  • 5Department of Pulmonology, Erasmus Medical Center, Rotterdam, The Netherlands
  • 6Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands
  • 7Goodheart Institute, Hematology, Hemostasis & Thrombosis Science Center, Rotterdam, The Netherlands
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Publication History

Publication Date:
06 October 2006 (online)

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ABSTRACT

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1%, with a negative predictive value of more than 99 to 100% during 3-month follow-up. Compression ultrasonography (CUS) and spiral computed tomography (CT) currently are the methods of choice to confirm or rule out deep venous thrombosis (DVT) and pulmonary embolism (PE), respectively. CUS has a negative predictive value (NPV) of 97 to 98%, indicating the need to improve the diagnostic work-up of patients with suspected DVT by clinical score assessment and D-dimer testing. Spiral CT as a stand-alone method detects all clinically relevant PEs and a large number of alternative diagnoses. It rules out PE with a NPV of 98 to 99%. Spiral CT is expensive, emphasizing the need to improve the diagnostic work-up of patients with suspected PE by the use of clinical score assessment and D-dimer testing. Clinical score assessment for DVT and PE has not safely ruled out VTE in multicenter studies and in routine daily practices. Modification of the Wells clinical score assessment for DVT by elimination of the “minus 2 points” for alternative diagnosis will improve the reproducibility of the clinical score assessment. The combination of a first negative CUS and a negative SimpliRed or an enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer of < 1,000 ng/mL safely exclude DVT (NPV > 99%) irrespective of clinical score assessment and without the need to repeat CUS in ~60 to 70% of patients. The rapid quantitative and qualitative agglutination D-dimer assays for the exclusion of VTE are not sensitive enough as stand-alone tests and should be used in combination with clinical score assessment. A normal rapid ELISA VIDAS D-dimer test as a stand-alone test safely excludes DVT and PE, with a NPV of 99 to 100%, irrespective of clinical score, without the need of CUS or spiral CT. The combined strategy of a rapid ELISA VIDAS D-dimer followed by objective testing with CUS for DVT and by spiral CT for PE will reduce the need for noninvasive imaging techniques by 40 to 50%.

KEYWORDS

Deep vein thrombosis - pulmonary embolism - D-dimer assay - compression ultrasonography - clinical score - ventilation perfusion scan - spiral computed tomography

REFERENCES

  • 1 Michiels J J, Oortwijn W J, Naaborg R. Exclusion and diagnosis of deep vein thrombosis by a rapid ELISA D-dimer test, compression ultrasonography, and a simple clinical model.  Clin Appl Thromb Hemost. 1999;  5 171-180
    PubMedGoogle Scholar
  • 2 Michiels J J, Freyburger G, van der Graaf F, Janssen M CH, Oortwijn W, van Beek E JR. Strategies for the safe and effective exclusion and diagnosis of deep vein thrombosis by the sequential use of clinical score, D-dimer testing and compression ultrasonography.  Semin Thromb Hemost. 2000;  26 657-667
    PubMedGoogle Scholar
  • 3 Hull R, Hirsh J, Sackett D L et al.. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.  Circulation. 1981;  64 622-625
    CrossrefPubMedGoogle Scholar
  • 4 Pederson L M, Lerche A, Jørgensen M, Urhammer S, Steenberg P, Jensen R. Follow-up study of patients with clinically suspected deep vein thrombosis and a normal venogram.  J Intern Med. 1993;  234 457-460
    PubMedGoogle Scholar
  • 5 Cogo A, Lensing A WA, Prandoni P, Hirsch J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis.  Arch Intern Med. 1993;  153 2777-2780
    Google Scholar
  • 6 Cogo A, Lensing A W, Koopman M M et al.. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.  BMJ. 1998;  316 17-20
    Google Scholar
  • 7 Birdwell B G, Raskob G E, Whitsett T L et al.. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis.  Ann Intern Med. 1998;  128 1-7
    CrossrefPubMedGoogle Scholar
  • 8 Kearon C, Julian J A, Math M, Newman T E, Ginsberg J S. Non-invasive diagnosis of deep vein thrombosis.  Ann Intern Med. 1998;  128 663-677
    Google Scholar
  • 9 The PIOPED Investigators . Value of the ventilation/perfusion scan in acute pulmonary embolism.  JAMA. 1990;  263 2753-2759
    Google Scholar
  • 10 Oudkerk M, van Beek E JR, van Putten W LJ, Büller H S. Cost-effectiveness analysis of various strategies in the diagnostic management of pulmonary embolism.  Arch Intern Med. 1993;  153 947-954
    CrossrefPubMedGoogle Scholar
  • 11 Henry J W, Relyea B, Stein P D. Continuing risk of thromboembolism among patients with normal pulmonary angiograms.  Chest. 1995;  107 1735-1738
    PubMedGoogle Scholar
  • 12 Hull R D, Hirsh J, Carter C J et al.. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan.  Ann Intern Med. 1983;  98 891-899
    CrossrefPubMedGoogle Scholar
  • 13 Diffin D C, Leyendecker J R, Johnson S P, Zucker R J, Grebe P J. Effect of anatomic distribution of pulmonary emboli on inter-observer agreement in the interpretation of pulmonary angiography.  AJR Am J Roentgenology. 1998;  171 1085-1089
    CrossrefPubMedGoogle Scholar
  • 14 Michiels J J, Perrier A, Bounameaux H. Should a normal D-dimer rule out angiographic pulmonary embolism or unfavourable outcome in patients left untreated?.  Thromb Haemost. 2001;  85 753
    PubMedGoogle Scholar
  • 15 Michiels J J, Gadisseur A, Van Der Planken M et al.. A critical appraisal of non-invasive diagnosis and exclusion of deep vein thrombosis or pulmonary embolism: how many tests do we need?.  Int J Angiol. 2006;  24 27-39
    PubMedGoogle Scholar
  • 16 Ferreti G R, Bosson J-L, Buffaz P-D et al.. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex of the legs.  Radiology. 1997;  205 453-458
    PubMedGoogle Scholar
  • 17 Ost D, Rozenshstein A, Saffran L, Snider A. The negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with non-diagnostic ventilation-perfusion scans.  Am J Med. 2001;  110 16-21
    CrossrefPubMedGoogle Scholar
  • 18 Lomis N NT, Yoon H C, Miller F J. Clinical outcomes of patients after a negative spiral CT pulmonary angiogram in the evaluation of acute pulmonary embolism.  J Vasc Interv Radiol. 1999;  10 707-712
    PubMedGoogle Scholar
  • 19 Garg K, Sieler H, Welsh C H, Johnston R, Russ P. Clinical validity of helical CT being interpreted as negative for pulmonary embolism. Implications for patient treatment.  AJR Am J Roentgenology. 1999;  172 1627-1631
    PubMedGoogle Scholar
  • 20 Goodman L R, Lipchik R J, Kuzo R S, McAuliffe T L, O'Brien D J. Subsequent pulmonary embolism: risk after a negative helical CT pulmonary angiogram. Prospective comparison with scintigraphy.  Radiology. 2000;  215 535-542
    PubMedGoogle Scholar
  • 21 Göttsäter A, Berg A, Centegard J, Frennby B, Nirhov N, Nyman U. Clinically suspected pulmonary embolism: is it safe to withhold anticoagulation after a negative spiral CT?.  Eur J Radiol. 2001;  11 65-72
    PubMedGoogle Scholar
  • 22 Tillie-Leblond I, Mastora I, Radenne F et al.. Risk of pulmonary embolism after a negative spiral CT angiogram in patients with pulmonary disease: 1 year clinical follow-up study.  Radiology. 2002;  223 461-467
    PubMedGoogle Scholar
  • 23 Van Strijen M JL, de Monyé W, Schiereck J et al.. Helical CT as the primary diagnostic test in suspected pulmonary embolism: prospective ANTELOPEW multicenter trial in 512 patients.  Ann Intern Med. 2003;  138 307-314
    PubMedGoogle Scholar
  • 24 Musset D, Parent F, Meyer G et al.. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicenter outcome study.  Lancet. 2002;  360 1914-1920
    CrossrefPubMedGoogle Scholar
  • 25 Quiroz R, Kucher N, Zou K H et al.. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systemic review.  JAMA. 2005;  293 2012-2017
    Google Scholar
  • 26 Wells P, Hirsh J, Anderson D R et al.. Accuracy of clinical assessment of deep-vein thrombosis.  Lancet. 1995;  345 1326-1330
    CrossrefPubMedGoogle Scholar
  • 27 Wells P, Anderson D R, Bormanis J et al.. Value of assessment of pre-test probability of deep-vein thrombosis in clinical management.  Lancet. 1997;  350 1795-1798
    Google Scholar
  • 28 Michiels J J, Schroyens W, De Maeseneer M, Kasbergen A AH, Oudega R. The rehabilitation of clinical assessment in the diagnosis of deep vein thrombosis.  Semin Vasc Med. 2002;  1 1-5
    PubMedGoogle Scholar
  • 29 Michiels J J, Gadissear A, Van Der Planken M et al.. Screening for deep vein thrombosis and pulmonary embolism in outpatients with suspected DVT or PE by sequential use of clinical score, a sensitive quantitative D-dimer test and non-invasive diagnostic tolls.  Semin Vasc Med. 2005;  5 351-370
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Miron M J, Perrier A, Boumameaux H. Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment.  J Intern Med. 2000;  247 249-254
    CrossrefPubMedGoogle Scholar
  • 31 Anderson D R, Kovacs M J, Kovacs G et al.. Combined use of clinical assessment and D-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study).  J Thromb Haemost. 2003;  1 645-651
    Google Scholar
  • 32 Yamaki T, Nozaki M, Sakurai H, Takeuchi M, Soejima K, Kono T. Prospective evaluation of a screening protocol to exclude deep vein thrombosis on the basis of a combination of quantitative D-dimer testing and pretest clinical probability score.  J Am Coll Surg. 2005;  201 701-709
    CrossrefPubMedGoogle Scholar
  • 33 Kraaijenhagen R A, Piovelli F, Bernardi E et al.. Simplification of the diagnostic management of suspected deep vein thrombosis.  Arch Intern Med. 2002;  162 907-911
    CrossrefPubMedGoogle Scholar
  • 34 Tick L W, Ton E, van Voorthuizen Th et al.. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography and D-dimer test.  Am J Med. 2002;  113 630-635
    Google Scholar
  • 35 Cornuz J, Ghali W A, Hayoz D, Stoianov R, Depairon M, Yersin B. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative D-dimer testing.  Am J Med. 2002;  112 198-203
    CrossrefPubMedGoogle Scholar
  • 36 Constans J, Nelzy M L, Salmi L R et al.. Clinical prediction of lower limb deep vein thrombosis in symptomatic hospitalized patients.  Thromb Haemost. 2001;  86 985-990
    PubMedGoogle Scholar
  • 37 Schutgens R EG, Ackermark P, Haas F JLM et al.. Combination of a normal D-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep venous thrombosis.  Circulation. 2003;  107 593-597
    CrossrefPubMedGoogle Scholar
  • 38 Oudega R, Hoes A W, Moons K GM. The Wells rule does not adequately rule out deep venous thrombosis in primary care patients.  Ann Intern Med. 2005;  143 100-107
    CrossrefPubMedGoogle Scholar
  • 39 Douketis J D. Use of a clinical prediction score in patients with suspected deep vein thrombosis: two steps forward, one step back?.  Ann Intern Med. 2005;  143 140-142
    PubMedGoogle Scholar
  • 40 Elias A, Mallard L, Elias M et al.. A single complete ultrasound investigation of the venous network for diagnostic management of patients with a clinically suspected first episode of deep vein thrombosis of the lower limbs.  Thromb Haemost. 2003;  89 221-227
    Google Scholar
  • 41 Schellong S M, Schwarz T, Halbritter K et al.. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis.  Thromb Haemost. 2003;  89 228-234
    Google Scholar
  • 42 Stevens S M, Elliott G, Chan K J, Egger M J, Ahmed K M. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep vein thrombosis.  Ann Intern Med. 2004;  140 985-1001
    CrossrefPubMedGoogle Scholar
  • 43 Wells P, Brill-Edwards P, Stevens P et al.. A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis.  Circulation. 1995;  91 2184-2187
    PubMedGoogle Scholar
  • 44 Wells P S, Anderson D R, Rodger M et al.. Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis.  N Engl J Med. 2003;  349 1227-1235
    Google Scholar
  • 45 Kearon C, Ginsberg J S, Douketis J et al.. Management of suspected deep vein thrombosis in outpatients by using clinical assessment and D-dimer testing.  Ann Intern Med. 2001;  135 108-111
    PubMedGoogle Scholar
  • 46 Blätter W, Martinez I, Blätter I K. Diagnosis of deep vein thrombosis and alternative diseases in symptomatic outpatients.  Eur J Intern Med. 2004;  15 305-311
    PubMedGoogle Scholar
  • 47 Kearon C, Ginsberg J S, Douketis J et al.. 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;  142 490-496
    CrossrefPubMedGoogle Scholar
  • 48 Freyburger G, Trillaud H, Labrouche S et al.. D-Dimer strategy in thrombosis exclusion. A gold standard study in 100 patients suspected of deep vein thrombosis or pulmonary embolism: 8 DD methods compared.  Thromb Haemost. 1998;  79 31-37
    PubMedGoogle Scholar
  • 49 Van Der Graaf F, van den Borne H, van der Kolk M et al.. Exclusion of deep vein thrombosis with D-dimer testing.  Thromb Haemost. 2000;  83 191-198
    PubMedGoogle Scholar
  • 50 Perrier A, Desmarais S, Miron M J et al.. Non-invasive diagnosis of venous thrombo-embolism in outpatients.  Lancet. 1999;  353 190-195
    Google Scholar
  • 51 Michiels J J, Kasbergen H AA, Trienekens P H. Evidence for safe exclusion of deep vein thrombosis (DVT) by the rapid ELISA VIDAS D-dimer test at cut-off levels of 500 and 1000 ng/ml in 1046 consecutive outpatients with suspected DVT.  Blood. 2004;  XX 301 , (abst 1059)
    PubMedGoogle Scholar
  • 52 Oudega R, Moons K GM, Hoes A W. Ruling out deep venous thrombosis in primary care.  Thromb Haemost. 2005;  94 200-205
    PubMedGoogle Scholar
  • 53 Hyers T M. Venous thromboembolism.  Am J Respir Crit Care Med. 1999;  159 1-14
    PubMedGoogle Scholar
  • 54 Righini M, Le Gal G, Perrier A, Bounameaux H. The challenge of diagnosing pulmonary embolism in elderly patients: influence of age on commonly used diagnostic tests and strategies.  J Am Geriatr Soc. 2005;  53 1039-1045
    CrossrefPubMedGoogle Scholar
  • 55 Michiels J J, Schroyens W, De Backer W, Van Der Planken M, Hoogsteden H, Pattynama P MT. Non-invasive exclusion and diagnosis of pulmonary embolism by sequential use of the rapid ELISA D-dimer assay, clinical score and spiral CT.  Int J Angiol. 2003;  22 1-14
    PubMedGoogle Scholar
  • 56 Wells P S, Ginsberg J S, Anderson D R et al.. Use of a clinical model for safe management of patients with suspected pulmonary embolism.  Ann Intern Med. 1998;  129 997-1005
    Google Scholar
  • 57 Wells P S, Anderson D R, Rodger M et al.. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRed D-dimer.  Thromb Haemost. 2000;  83 416-420
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Wells P S, Anderson D R, Rodger M et al.. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer.  Ann Intern Med. 2001;  135 98-107
    Google Scholar
  • 59 Wicki J, Perneger T V, Junod A F, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score.  Arch Intern Med. 2001;  161 92-97
    CrossrefPubMedGoogle Scholar
  • 60 Chagnon I, Bounameaux H, Aujeskt D et al.. Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism.  Am J Med. 2002;  113 269-275
    CrossrefPubMedGoogle Scholar
  • 61 Christopher Study Investigators . Effectiveness of managing suspected pulmonary embolism Rapid quantitative ELISA based turbidimetric agglutination D-dimer assays including Tinaquant for the exclusion of VTE are not sensitive enough as a stand alone test and should be used in combination with clinical score assessment for DVT and PE using an algorithm combining clinical probability, D-dimer testing, and computed tomography.  JAMA. 2006;  295 172-179
    CrossrefPubMedGoogle Scholar
  • 62 Kearon C, Ginsberg J S, Douketis J et al.. An evaluation of D-dimer in the diagnosis of pulmonary embolism.  Ann Intern Med. 2006;  144 812-821
    CrossrefPubMedGoogle Scholar
  • 63 de Moerloose Ph, Desmarais S, Bounameaux H et al.. Contribution of a new rapid, individual and quantitative automated Vidas D-Dimer ELISA to exclude pulmonary embolism.  Thromb Haemost. 1996;  75 11-13
    PubMedGoogle Scholar
  • 64 Kruip M JHA, Slob M J, Schijen F HEM, van der Heul C, Büller H R. Use of a clinical decision rule in combination with D-dimer concentration in diagnostic workup of patients with suspected pulmonary embolism.  Arch Intern Med. 2002;  162 1631-1635
    CrossrefPubMedGoogle Scholar
  • 65 Perrier A, Roy P-M, Aujesky D et al.. Diagnosing pulmonary embolism in outpatients with clinical assessment, D-Dimer measurement, venous ultrasound, and helical computed tomography: a multicenter study.  Am J Med. 2004;  116 291-299
    Google Scholar
  • 66 Verschuren F R, Hainaut P, Thys F R et al.. ELISA D-dimer measurement for the clinical suspicion of pulmonary embolism in the emergency department: one-year observational study of the safety profile and physician's prescription.  Acta Clin Belg. 2003;  58 233-240
    PubMedGoogle Scholar
  • 67 Perrier A, Roy P M, Sanchez O et al.. Multidetector-row computed tomography in suspected pulmonary embolism.  N Engl J Med. 2005;  352 1760-1768
    CrossrefPubMedGoogle Scholar
  • 68 Kucher N, Kohler H P, Dornhoefer T, Wallmann D, Laemle B. Accuracy of D-dimer/fibrinogen ratio to predict pulmonary embolism: a prospective diagnostic study.  J Thromb Haemost. 2003;  1 708-713
    CrossrefPubMedGoogle Scholar

Jan J MichielsM.D. Ph.D. 

Goodheart Institute & Foundation, Hematology Hemostasis Thrombosis Science Center, Erasmus Tower

Veenmos 13, 3069 AT Rotterdam, The Netherlands

Email: postbus@goodheartcenter.demon.nl

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