Semin Thromb Hemost 2012; 38(07): 673-682
DOI: 10.1055/s-0032-1326782
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

D-Dimer Assays in Diagnosis and Management of Thrombotic and Bleeding Disorders

Shannon M. Bates
1   Department of Medicine, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
06 October 2012 (online)

Abstract

D-dimer is a global indicator of coagulation activation and fibrinolysis and, therefore, an indirect marker of thrombotic activity. The utility of D-dimer measurement has been evaluated in several clinical situations including the exclusion of venous thromboembolism (VTE), prediction of future risk of VTE, and the diagnosis and monitoring of disseminated intravascular coagulation (DIC). Assay standardization remains problematic and clinicians need to be aware of variability in D-dimer assay performance and the characteristics of their institution's test when making clinical decisions. This article will review the available evidence for the utilization of D-dimer antigen measurement in the management of thrombotic and bleeding disorders.

 
  • References

  • 1 Adam SS, Key NS, Greenberg CS ; SS. D-dimer antigen: current concepts and future prospects. Blood 2009; 113 (13) 2878-2887
  • 2 Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011; 57 (9) 1256-1262
  • 3 Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008; 6 (7) 1059-1071
  • 4 Hager K, Platt D. Fibrin degeneration product concentrations (D-dimers) in the course of ageing. Gerontology 1995; 41 (3) 159-165
  • 5 Dempfle CE. Validation, calibration, and specificity of quantitative D-dimer assays. Semin Vasc Med 2005; 5 (4) 315-320
  • 6 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 (3) 567-572
  • 7 Di Nisio M, Squizzato A, Rutjes AWS, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007; 5 (2) 296-304
  • 8 Rowbotham BJ, Carroll P, Whitaker AN , et al. Measurement of crosslinked fibrin derivatives—use in the diagnosis of venous thrombosis. Thromb Haemost 1987; 57 (1) 59-61
  • 9 Bounameaux H, Schneider PA, Reber G, de Moerloose P, Krahenbuhl B. Measurement of plasma D-dimer for diagnosis of deep venous thrombosis. Am J Clin Pathol 1989; 91 (1) 82-85
  • 10 Bounameaux H, Cirafici P, de Moerloose P , et al. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991; 337 (8735) 196-200
  • 11 Brotman DJ, Segal JB, Jani JT, Petty BG, Kickler TS. Limitations of D-dimer testing in unselected inpatients with suspected venous thromboembolism. Am J Med 2003; 114 (4) 276-282
  • 12 Arnason T, Wells PS, Forster AJ. Appropriateness of diagnostic strategies for evaluating suspected venous thromboembolism. Thromb Haemost 2007; 97 (2) 195-201
  • 13 Bates SM, Jaeschke R, Stevens SM , et al; American College of Chest Physicians. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl) e351S-e418S
  • 14 Couturaud F, Kearon C, Bates SM, Ginsberg JS. Decrease in sensitivity of D-dimer for acute venous thromboembolism after starting anticoagulant therapy. Blood Coagul Fibrinolysis 2002; 13 (3) 241-246
  • 15 Hull R, Hirsh J, Sackett DL , et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64 (3) 622-625
  • 16 Novelline RA, Baltarowich OH, Athanasoulis CA, Waltman AC, Greenfield AJ, McKusick KA. The clinical course of patients with suspected pulmonary embolism and a negative pulmonary arteriogram. Radiology 1978; 126 (3) 561-567
  • 17 Hull RD, Raskob GE, Coates G, Panju AA. Clinical validity of a normal perfusion lung scan in patients with suspected pulmonary embolism. Chest 1990; 97 (1) 23-26
  • 18 Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ 2004; 329 (7470) 821-829
  • 19 Wells PS, Anderson DR, Rodger M , et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349 (13) 1227-1235
  • 20 Kearon C, Ginsberg JS, 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 (7) 490-496
  • 21 Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis?. JAMA 2006; 295 (2) 199-207
  • 22 Bates SM, Kearon C, Crowther M , et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med 2003; 138 (10) 787-794
  • 23 Perrier A, Desmarais S, Miron MJ , et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999; 353 (9148) 190-195
  • 24 Anderson DR, Kovacs MJ, 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 (4) 645-651
  • 25 Schutgens REG, Ackermark P, Haas FJLM , 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 (4) 593-597
  • 26 Tick LW, Ton E, van Voorthuizen T , 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 (8) 630-635
  • 27 Janes S, Ashford N. Use of a simplified clinical scoring system and D-dimer testing can reduce the requirement for radiology in the exclusion of deep vein thrombosis by over 20%. Br J Haematol 2001; 112 (4) 1079-1082
  • 28 Aguilar C, Martinez A, Martinez A, Del Rio C, Vazquez M, Rodriguez FJ. Diagnostic value of d-dimer in patients with a moderate pretest probability of deep venous thrombosis. Br J Haematol 2002; 118 (1) 275-277
  • 29 Ruiz-Giménez N, Friera A, Artieda P , et al. Rapid D-dimer test combined a clinical model for deep vein thrombosis. Validation with ultrasonography and clinical follow-up in 383 patients. Thromb Haemost 2004; 91 (6) 1237-1246
  • 30 Elf JL, Strandberg K, Nilsson C, Svensson PJ. Clinical probability assessment and D-dimer determination in patients with suspected deep vein thrombosis, a prospective multicenter management study. Thromb Res 2009; 123 (4) 612-616
  • 31 Bernardi E, Camporese G, Büller HR , et al; Erasmus Study Group. Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial. JAMA 2008; 300 (14) 1653-1659
  • 32 Bernardi E, Prandoni P, Lensing AW , et al; The Multicentre Italian D-dimer Ultrasound Study Investigators Group. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 317 (7165) 1037-1040
  • 33 Kearon C, Ginsberg JS, Douketis J , et al; Canadian Pulmonary Embolism Diagnosis Study (CANPEDS) Group. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med 2006; 144 (11) 812-821
  • 34 Wells PS, Anderson DR, 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 (2) 98-107
  • 35 Anderson DR, Kovacs MJ, Dennie C , et al. Use of spiral computed tomography contrast angiography and ultrasonography to exclude the diagnosis of pulmonary embolism in the emergency department. J Emerg Med 2005; 29 (4) 399-404
  • 36 Goekoop RJ, Steeghs N, Niessen RW , et al. Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells' simplified decision rule. Thromb Haemost 2007; 97 (1) 146-150
  • 37 Leclercq MG, Lutisan JG, van Marwijk Kooy M , et al. Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and D-dimer levels: a management study. Thromb Haemost 2003; 89 (1) 97-103
  • 38 Ghanima W, Abelnoor M, Mowinckel MC, Sandset PM. The performance of STA-Liatest D-dimer assay in outpatients with suspected pulmonary embolism. Br J Haematol 2006; 132: 210-214
  • 39 Pasha SM, Klok FA, Snoep JD , et al. Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis. Thromb Res 2010; 125 (4) e123-e127
  • 40 van Belle A, Büller HR, Huisman MV , et al; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295 (2) 172-179
  • 41 Perrier A, Roy PM, Sanchez O , et al. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005; 352 (17) 1760-1768
  • 42 Carrier M, Righini M, Djurabi RK , et al. VIDAS D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies. Thromb Haemost 2009; 101 (5) 886-892
  • 43 Merminod T, Pellicciotta S, Bounameaux H. Limited usefulness of D-dimer in suspected deep vein thrombosis of the upper extremities. Blood Coagul Fibrinolysis 2006; 17 (3) 225-226
  • 44 Kucher N. Clinical practice. Deep-vein thrombosis of the upper extremities. N Engl J Med 2011; 364 (9) 861-869
  • 45 Elias A, Bonfils S, Daoud-Elias M , et al. Influence of long term oral anticoagulants upon prothrombin fragment 1.  + 2, thrombin-antithrombin III complex and D-Dimer levels in patients affected by proximal deep vein thrombosis. Thromb Haemost 1993; 69 (4) 302-305
  • 46 Sié P, Cadroy Y, Elias A, Boccalon H, Boneu B. D-dimer levels in patients with long-term antecedents of deep venous thrombosis. Thromb Haemost 1994; 72 (1) 161-162
  • 47 Bates SM, Kearon C, Kahn SR , et al. A negative D-dimer excludes recurrent deep vein thrombosis: results of a multicentre management trial. Blood 2007; 110: 214a
  • 48 Aguilar C, del Villar V. Combined D-dimer and clinical probability are useful for exclusion of recurrent deep venous thrombosis. Am J Hematol 2007; 82 (1) 41-44
  • 49 Prandoni P, Tormene D, Dalla Valle F, Concolato A, Pesavento R. D-dimer as an adjunct to compression ultrasonography in patients with suspected recurrent deep vein thrombosis. J Thromb Haemost 2007; 5 (5) 1076-1077
  • 50 Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial. Ann Intern Med 2004; 141 (11) 839-845
  • 51 Nolan TE, Smith RP, Devoe LD. Maternal plasma D-dimer levels in normal and complicated pregnancies. Obstet Gynecol 1993; 81 (2) 235-238
  • 52 Francalanci I, Comeglio P, Liotta AA , et al. D-dimer concentrations during normal pregnancy, as measured by ELISA. Thromb Res 1995; 78 (5) 399-405
  • 53 Ballegeer V, Mombaerts P, Declerck PJ, Spitz B, Van Assche FA, Collen D. Fibrinolytic response to venous occlusion and fibrin fragment D-dimer levels in normal and complicated pregnancy. Thromb Haemost 1987; 58 (4) 1030-1032
  • 54 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 (7) 1202-1204
  • 55 Chan WSCS, Bates S, Naguit I, Sood R, Johnston M. The prevalence of positive soluble fibrin and D-dimer results in health asymptomatic pregnant women. Blood 1999; 94: 20a
  • 56 Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005; 51 (5) 825-829
  • 57 Kovac M, Mikovic Z, Rakicevic L , et al. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2010; 148 (1) 27-30
  • 58 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 (3) 165-170
  • 59 Chan WS, Lee A, Spencer FA , et al. D-dimer testing in pregnant patients: towards determining the next 'level' in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010; 8 (5) 1004-1011
  • 60 Harper PL, 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 (9) 607-613
  • 61 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 (5) 357-361
  • 62 Carrier M, Le Gal G, Bates SM, Anderson DR, Wells PS. D-dimer testing is useful to exclude deep vein thrombosis in elderly outpatients. J Thromb Haemost 2008; 6 (7) 1072-1076
  • 63 Douma RA, le Gal G, Söhne M , et al. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010; 340: c1475
  • 64 Douma RA, Gibson NS, Schutgens REG , et al. Age-adjusted D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. Hematologica 2012; 97 . (e-pub ahead of print)
  • 65 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
  • 66 ten Wolde M, Kraaijenhagen RA, Prins MH, Büller HR. The clinical usefulness of D-dimer testing in cancer patients with suspected deep venous thrombosis. Arch Intern Med 2002; 162 (16) 1880-1884
  • 67 King V, Vaze AA, Moskowitz CS, Smith LJ, Ginsberg MS. D-dimer assay to exclude pulmonary embolism in high-risk oncologic population: correlation with CT pulmonary angiography in an urgent care setting. Radiology 2008; 247 (3) 854-861
  • 68 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 (4) 715-719
  • 69 Carrier M, Lee AYY, Bates SM, Anderson DR, Wells PS. Accuracy and usefulness of a clinical prediction rule and D-dimer testing in excluding deep vein thrombosis in cancer patients. Thromb Res 2008; 123 (1) 177-183
  • 70 Kearon C, Akl EA, Comerota AJ , et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl) e419S-e494S
  • 71 Verhovsek M, Douketis JD, Yi Q , et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149 (7) 481-490 , W94
  • 72 Bruinstroop E, Klok FA, Van De Ree MA, Oosterwijk FL, Huisman MV. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost 2009; 7 (4) 611-618
  • 73 Palareti G, Cosmi B, Legnani C , et al; PROLONG Investigators. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006; 355 (17) 1780-1789
  • 74 Cosmi B, Legnani C, Tosetto A , et al. Use of D-dimer testing to determine duration of anticoagulation, risk of cardiovascular events and occult cancer after a first episode of idiopathic venous thromboembolism: the extended follow-up of the PROLONG study. J Thromb Thrombolysis 2009; 28 (4) 381-388
  • 75 Baglin T, Luddington R, Brown K, Baglin C. High risk of recurrent venous thromboemoblism in men. J Thromb Haemost 2004; 2: 2152-2155
  • 76 Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurent venous thromboemoblism in men and women. N Engl J Med 2004; 350: 2558-2563
  • 77 McRae S, Tran H, Schulman S, Ginsberg JS, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis. Lancet 2006; 368 (9533) 371-378
  • 78 Cushman M, Glynn RJ, Goldhaber SZ , et al. Hormonal factors and risk of recurrent venous thrombosis: the prevention of recurrent venous thromboembolism trial. J Thromb Haemost 2006; 4 (10) 2199-2203
  • 79 Cosmi B, Legnani C, Tosetto A , et al; Prolong Investigators. Sex, age and normal post-anticoagulation D-dimer as risk factors for recurrence after idiopathic venous thromboembolism in the Prolong study extension. J Thromb Haemost 2010; 8 (9) 1933-1942
  • 80 Rodger MA, Kahn SR, Wells PS , et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179 (5) 417-426
  • 81 Tosetto A, Iorio A, Marcucci M , et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10 (6) 1019-1025
  • 82 Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119 (1) 60-68
  • 83 Heit JA, O'Fallon WM, Petterson TM , et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162 (11) 1245-1248
  • 84 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (6) 715-722
  • 85 Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009; 27 (29) 4839-4847
  • 86 Ay C, Vormittag R, Dunkler D , et al. D-dimer and prothrombin fragment 1.  + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009; 27 (25) 4124-4129
  • 87 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
  • 88 Ay C, Dunkler D, Marosi C , et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116 (24) 5377-5382
  • 89 Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost 2010; 36 (4) 458-467
  • 90 Taylor Jr FB, Toh CH, Hoots WK, Wada H. Levi M for the Scientific Subcommitee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327-1330
  • 91 Lee JH, Song JW, Song KS. Diagnosis of overt disseminated intravascular coagulation: a comparative study using criteria from the International Society versus the Korean Society on Thrombosis and Hemostasis. Yonsei Med J 2007; 48 (4) 595-600
  • 92 Wada H, Gabazza EC, Asakura H , et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol 2003; 74 (1) 17-22
  • 93 Gando S, Iba T, Eguchi Y , et al; Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med 2006; 34 (3) 625-631