The Role of D-dimer Testing in Patients with Suspected Venous Thromboembolism

ABSTRACT

D-dimer, the final degradation product of cross-linked fibrin, is typically elevated in patients with acute venous thromboembolism. With its high sensitivity and negative predictive value, D-dimer testing may have a role for ruling-out the diagnosis in patients with suspected deep vein thrombosis or pulmonary embolism. For this purpose, D-dimer testing has been integrated in sequential diagnostic strategies including those using pretest clinical probability assessment and imaging techniques. A large variety of assays are now available for D-dimer measurement, with different sensitivities and specificities for the diagnosis of venous thromboembolism. Attempts to standardize the various D-dimer assays have been made but without any definitive answers as yet. The diagnostic yield of D-dimer testing is affected not only by the choice of the appropriate assay but also by patient characteristics. As a consequence, the clinical usefulness of D-dimer testing for the exclusion of suspected venous thromboembolism should be carefully evaluated in special clinical settings.

KEYWORDS

D-dimer - venous thromboembolism - diagnosis

REFERENCES

• 1 Le Gal G, Bounameaux H. Diagnosing pulmonary embolism: running after the decreasing prevalence of cases among suspected patients.  J Thromb Haemost. 2004;  2 1244-1246
• 2 Wells P S. Integrated strategies for the diagnosis of venous thromboembolism.  J Thromb Haemost. 2007;  5(Suppl 1) 41-50
• 3 Righini M, Perrier A, de Moerloose P, Bounameaux H. D-dimer for venous thromboembolism diagnosis: 20 years later.  J Thromb Haemost. 2008;  6 1059-1071
• 4 Siragusa S. D-dimer testing: advantages and limitations in emergency medicine for managing acute venous thromboembolism.  Intern Emerg Med. 2006;  1 59-66
• 5 Squizzato A, Ageno W. What is the next step in D-dimer research? Education of physicians.  Intern Emerg Med. 2006;  2 165
• 6 Prisco D, Conti A, Giurlani L, Falciani M. Clinical application of fibrinolysis laboratory tests: a review.  Ann Ital Med Int. 1998;  13 81-87
• 7 Legnani C, Palareti G, Prisco D. Linee guida sull'impiego clinico del D-dimero.  Riv Med Lab-JLM. 2004;  5 225-239
• 8 Reber G, de Moerloose P. D-dimer assays for the exclusion of venous thromboembolism.  Semin Thromb Hemost. 2000;  26 619-624
• 9 Elms M J, Bunce I H, Bundesen P G et al.. Measurement of crosslinked fibrin degradation products – an immunoassay using monoclonal antibodies.  Thromb Haemost. 1983;  50 591-594
• 10 Pittet J L, de Moerloose P, Reber G et al.. VIDAS D-dimer: fast quantitative ELISA for measuring D-dimer in plasma.  Clin Chem. 1996;  42 410-415
• 11 Reber G, Bounameaux H, Perrier A, de Moerloose P. A new rapid point-of-care D-dimer enzyme-linked immunosorbent assay (Stratus CS D-dimer) for the exclusion of venous thromboembolism.  Blood Coagul Fibrinolysis. 2004;  15 435-438
• 12 Dempfle C E, Suvajac N, Elmas E, Borggrefe M. Performance evaluation of a new rapid quantitative assay system for measurement of D-dimer in plasma and whole blood: PATHFAST D-dimer.  Thromb Res. 2007;  120 591-596
• 13 Lippi G, Salvagno G L, Rossi L, Montagnana M, Franchini M, Guidi G C. Analytical performances of the D-dimer assay for the Immulite 2000 automated immunoassay analyser.  Int J Lab Hematol. 2007;  29 415-420
• 14 Legnani C, Pancani C, Palareti G et al.. Comparison of new rapid methods for D-dimer measurement to exclude deep vein thrombosis in symptomatic outpatients.  Blood Coagul Fibrinolysis. 1997;  8 296-302
• 15 Brown M D, Lau J, Nelson R D, Kline J A. Turbidimetric D-dimer test in the diagnosis of pulmonary embolism: a metaanalysis.  Clin Chem. 2003;  49 1846-1853
• 16 Sukhu K, Beavis J, Baker P M, Keeling D M. Comparison of an immuno-turbidometric method (STalia^® D-DI) with an established enzyme linked fluorescent assay (VIDAS^®) D-dimer for the exclusion of venous thromboembolism.  Int J Lab Hematol. 2008;  30 200-204
• 17 Mauron T, Baumgartner I, Z'Brun A et al.. SimpliRED D-dimer assay: comparability of capillary and citrated venous whole blood, between-assay variability, and performance of the test for exclusion of deep vein thrombosis in symptomatic outpatients.  Thromb Haemost. 1998;  79 1217-1219
• 18 de Monye W, Huisman M V, Pattynama P M. Observer dependency of the SimpliRed D-dimer assay in 81 consecutive patients with suspected pulmonary embolism.  Thromb Res. 1999;  96 293-298
• 19 Cini M, Legnani C, Cavallaroni K, Bettini F, Palareti G. A new rapid bedside assay for D-dimer measurement (Simplify D-dimer) in the diagnostic work-up for deep vein thrombosis.  J Thromb Haemost. 2003;  1 2681-2683
• 20 Kline J A, Runyon M S, Webb W B, Jones A E, Mitchell A M. Prospective study of the diagnostic accuracy of the simplify D-dimer assay for pulmonary embolism in emergency department patients.  Chest. 2006;  129 1417-1423
• 21 Legnani C, Fariselli S, Cini M, Oca G, Abate C, Palareti G. A new rapid bedside assay for quantitative testing of D-dimer (Cardiac D-Dimer) in the diagnostic work-up for deep vein thrombosis.  Thromb Res. 2003;  111 149-153
• 22 Jennings I, Woods T A, Kitchen D P, Kitchen S, Walker I D. Laboratory D-dimer measurement: improved agreement between methods through calibration.  Thromb Haemost. 2007;  98 1127-1135
• 23 Favaloro E J. Standardization, regulation, quality assurance and emerging technologies in hemostasis: issues, controversies, benefits, and limitations.  Semin Thromb Hemost. 2007;  33 290-297
• 24 Nieuwenhuizen W. A reference material for harmonisation of D-dimer assays. Fibrinogen Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.  Thromb Haemost. 1997;  77 1031-1033
• 25 Dempfle C E, Zips S, Ergul H, Heene D L. The Fibrin Assay Comparison Trial (FACT): evaluation of 23 quantitative D-dimer assays as basis for the development of D-dimer calibrators. FACT study group.  Thromb Haemost. 2001;  85 671-678
• 26 Meijer P, Haverkate F, Kluft C, de Moerloose P, Verbruggen B, Spannagl M. A model for the harmonisation of test results of different quantitative D-dimer methods.  Thromb Haemost. 2006;  95 567-572
• 27 Perrier A, Desmarais S, Miron M J et al.. Non invasive diagnosis of venous thromboembolism in outpatients.  Lancet. 1999;  353 190-195
• 28 Bernardi E, Prandoni P, Lensing AWA et al.. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study.  BMJ. 1998;  317 1037-1040
• 29 de Groot M R, Kooy M V, Pouwels JGJ, Engelage A H, Kuipers B F, Buller H R. The use of a rapid D-dimer blood test in the diagnostic work-up for pulmonary embolism: a management study.  Thromb Haemost. 1999;  82 1588-1592
• 30 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
• 31 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
• 32 Siragusa S, Anastasio R, Porta C et al.. Deferment of objective assessment of deep vein thrombosis and pulmonary embolism without increased risk of thrombosis: a practical approach based on the pretest clinical model, D-dimer testing, and the use of low-molecular weight heparins.  Arch Intern Med. 2004;  164 2477-2482
• 33 Kearon C, Ginsberg J S, Douketis J et al.. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial.  Ann Intern Med. 2006;  144 812-821
• 34 van Belle A, Buller H R, Huisman M V et al.. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography.  JAMA. 2006;  295 172-179
• 35 ten Cate-Hoek A J, Prins M H. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review.  J Thromb Haemost. 2005;  3 2465-2470
• 36 Perone N, Bounameaux H, Perrier A. Comparison of four strategies for diagnosing deep vein thrombosis: a cost-effectiveness analysis.  Am J Med. 2001;  110 33-40
• 37 Linkins L A, Bates S M, Ginsberg J S, Kearon C. Use of different D-dimer levels to exclude venous thromboembolism depending on clinical pretest probability.  J Thromb Haemost. 2004;  2 1256-1260
• 38 Nomura H, Wada H, Mizuno T et al.. Negative predictive value of D-dimer for diagnosis of venous thromboembolism.  Int J Hematol. 2008;  87 250-255
• 39 Tick L W, Nijkeuter M, Kramer MHH et al.. High D-dimer levels increase the likelihood of pulmonary embolism.  J Intern Med. 2008;  264 195-200
• 40 Legnani C, Cini M, Cavallaroni K et al.. D-dimer levels at diagnosis in relation to the site and extension of leg deep vein thrombosis (DVT).  Haematologica. 2008;  93(S3) 10-11
• 41 Di Nisio M, Squizzato A, Rutjes A W, Buller H R, Zwinderman A H, Bossuyt P M. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review.  J Thromb Haemost. 2007;  5 296-304
• 42 Stein P D, Hull R D, Patel K C et al.. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.  Ann Intern Med. 2004;  140 589-602
• 43 Siragusa S, Terulla V, Pirrelli S et al.. A rapid D-dimer assay in patients presenting at an emergency room with suspected acute venous thrombosis: accuracy and relation to clinical variables.  Haematologica. 2001;  86 856-861
• 44 Jennersjo C M, Fagerberg I H, Karlander S G, Lindahl T L. Normal D-dimer concentration is a common finding in symptomatic outpatients with distal deep vein thrombosis.  Blood Coagul Fibrinolysis. 2005;  16 517-523
• 45 de Monye W, Sanson B J, Mac Gillavry M R et al.. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism.  Am J Respir Crit Care Med. 2002;  165 345-348
• 46 D'Angelo A, D'Alessandro G, Tomassini L, Pittet J L, Dupuy G, Crippa L. Evaluation of a new rapid quantitative D-dimer assay in patients with clinically suspected deep vein thrombosis.  Thromb Haemost. 1996;  75 412-416
• 47 Couturaud F, Kearon C, Bates S M, Ginsberg J S. Decrease in sensitivity of D-dimer for acute venous thromboembolism after starting anticoagulant therapy.  Blood Coagul Fibrinolysis. 2002;  13 241-246
• 48 Miron M J, Perrier A, Bounameaux H et al.. Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients.  Eur Respir J. 1999;  13 1365-1370
• 49 Klok F A, Karamidjurabi R, Velthuis S I, Nijkeuter M, Huisman M V. Utility of D-dimer testing in patients with clinically suspected pulmonary embolism and elevated C-reactive protein levels.  Thromb Haemost. 2008;  99 972-974
• 50 Francalanci I, Comeglio P, Liotta A A et al.. D-dimer concentrations during normal pregnancy, as measured by ELISA.  Thromb Res. 1995;  78 399-405
• 51 Epiney M, Boehlen F, Boulvain M et al.. D-dimer levels during delivery and the postpartum.  J Thromb Haemost. 2005;  3 268-271
• 52 Harper P L, Theakston E, Ahmed J, Ockelford P. D-Dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly.  Intern Med J. 2007;  37 607-613
• 53 Righini M, Le Gal G, De Lucia S et al.. Clinical usefulness of D-dimer testing in cancer patients with suspected pulmonary embolism.  Thromb Haemost. 2006;  95 715-719
• 54 Le Gal G, Righini M, Roy P M et al.. Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism.  Arch Intern Med. 2006;  166 176-180
• 55 Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism.  Am J Med. 2000;  109 357-361
• 56 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
• 57 Sohne M, Kamphuisen P W, van Mierlo JWB, Buller H R. Diagnostic strategy using a modified clinical decision rule and D-dimer test to rule out pulmonary embolism in elderly in- and outpatients.  Thromb Haemost. 2005;  94 206-210
• 58 Righini M, Nendaz M, Leg G, Bounameaux H, Perrier A. Influence of age on the cost-effectiveness of diagnostic strategies for suspected pulmonary embolism.  J Thromb Haemost. 2007;  5 1869-1877
• 59 Carrier M, Le Gal G, Bates S M, Anderson D R, Wells P S. D-dimer testing is useful to exclude deep vein thrombosis in elderly outpatients.  J Thromb Haemost. 2008;  6 1072-1076
• 60 Righini M, de Moerloose P, Reber G, Perrier A, Bounameaux H. Should the D-dimer cut-off value be increased in elderly patients suspected of pulmonary embolism?.  Thromb Haemost. 2001;  85 744
• 61 Aguilar C, Martinez A, Martinez A, Del Rio C, Vazquez M. Diagnosis of deep vein thrombosis in the elderly: a higher D-dimer cut-off value is better?.  Haematologica. 2001;  86 E28
• 62 Masotti L, Antonelli F, Landini G. Potential applicability of the D-dimer assay in elderly patients with suspected venous thromboembolism: importance of the sensitivity and specificity of the methods.  Intern Med J. 2008;  38 222-225
• 63 Lee A Y, Julian J A, Levine M N 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;  131 417-423
• 64 ten Wolde M, Kraaijenhagen R A, Prins M H, Buller H R. The clinical usefulness of D-dimer testing in cancer patients with suspected deep venous thrombosis.  Arch Intern Med. 2002;  162 1880-1884
• 65 Di Nisio M, Rutjes AWS, Buller H R. Combined use of clinical pretest probability and D-dimer test in cancer patients with clinically suspected deep vein thrombosis.  J Thromb Haemost. 2006;  4 52-57
• 66 Di Nisio M, Sohne M, Kamphuisen P W, Buller H R. D-dimer test in cancer patients with suspected acute pulmonary embolism.  J Thromb Haemost. 2005;  3 1239-1242
• 67 Kline J A, Williams G W, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed.  Clin Chem. 2005;  51 825-829
• 68 Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis.  J Thromb Haemost. 2004;  2 1202-1204
• 69 Chan W S, Chunilal S D, Bates S, Naguit I, Sood R, Johnston M. The prevalence of positive soluble fibrin and D-dimer results in healthy asymptomatic pregnant women.  Blood. 1999;  94 20a
• 70 Chan W S, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg J S. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy.  Ann Intern Med. 2007;  147 165-170
• 71 Rathbun S W, Whitsett T L, Raskob G E. Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial.  Ann Intern Med. 2004;  141 839-845