D-dimer diagnostic role in thromboembolism: Difference between revisions

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==Overview==
==Overview==
D-dimer is used in the diagnosis of [[deep vein thrombosis]] and [[pulmonary embolism]] among patients with low or unlikely probability of [[venous thromboembolism]].<ref name="pmid16403932">{{cite journal| author=Wells PS, Owen C, Doucette S, Fergusson D, Tran H| title=Does this patient have deep vein thrombosis? | journal=JAMA | year= 2006 | volume= 295 | issue= 2 | pages= 199-207 | pmid=16403932 | doi=10.1001/jama.295.2.199 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16403932  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213132 Review in: Evid Based Med. 2006 Aug;11(4):119]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16813372 Review in: ACP J Club. 2006 Jul-Aug;145(1):24] </ref><ref name="pmid11453709">{{cite journal| author=Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D et al.| title=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. | journal=Ann Intern Med | year= 2001 | volume= 135 | issue= 2 | pages= 98-107 | pmid=11453709 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11453709  }} </ref>  While 500 ng/mL has long been the most commonly used cut off value for abnormal D-dimer concentration, recent studies suggest the use of an age adjusted cut-off concentration of D-dimer.  The age adjusted cut-off value of D-dimer is 500 ng/mL for subjects whose age is less than 50 years, and the age multiplied by 10 for subjects older than 50 years.<ref name="pmid22511491">{{cite journal| author=Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C et al.| title=Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. | journal=Haematologica | year= 2012 | volume= 97 | issue= 10 | pages= 1507-13 | pmid=22511491 | doi=10.3324/haematol.2011.060657 | pmc=PMC3487551 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22511491  }} </ref><ref name="pmid23645857">{{cite journal| author=Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA et al.| title=Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. | journal=BMJ | year= 2013 | volume= 346 | issue=  | pages= f2492 | pmid=23645857 | doi=10.1136/bmj.f2492 | pmc=PMC3643284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23645857  }} </ref><ref name="JAMA 2014"> Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135. </ref>
== D-dimer and Thromboembolism==
== D-dimer and Thromboembolism==
===Indications for D-dimer Testing===
* D-dimer testing is of clinical use when there is a suspicion of [[deep venous thrombosis]] (DVT) or [[pulmonary embolism]] (PE). In patients suspected of [[disseminated intravascular coagulation]] (DIC), D-dimers may aid in the diagnosis.  For DVT and PE, there are various scoring systems that are used to determine the ''a priori'' clinical probability of these diseases; the best-known were introduced by Wells ''et al'' (2003).
* For a very high score, or pretest probability, a D-dimer will make little difference and [[anticoagulant]] therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.
* For a moderate or low score, or pretest probability:<ref name="pmid14507948">{{cite journal |author=Wells PS, Anderson DR, Rodger M, ''et al'' |title=Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis |journal=N. Engl. J. Med. |volume=349 |issue=13 |pages=1227–35 |year=2003 |pmid=14507948 |doi=10.1056/NEJMoa023153|url=http://content.nejm.org/cgi/content/full/349/13/1227}}</ref>
* A negative D-dimer test will virtually rule out thromboembolism:<ref name="pmid22494827">{{cite journal| author=Goldhaber SZ, Bounameaux H| title=Pulmonary embolism and deep vein thrombosis. | journal=Lancet | year= 2012 | volume= 379 | issue= 9828 | pages= 1835-46 | pmid=22494827 | doi=10.1016/S0140-6736(11)61904-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22494827  }} </ref> the degree to which the d-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in your clinical setting: most available d-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
* If the D-dimer reads high, then further testing ([[medical ultrasonography|ultrasound]] of the leg veins or lung [[scintigraphy]] or [[CTPA|CT scanning]]) is required to confirm the presence of [[thrombus]].  [[Anticoagulant]] therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation. 
* In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high-probability.<ref>{{cite journal |last=Rathbun |first=SW |coauthors=TL Whitsett, SK Vesely, GE Raskob |year=2004 |title=Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings |journal=Chest |issue=125 |pages=851 |accessdate= 2007-11-17}}</ref>
=== Abnormal Levels ===
=== Abnormal Levels ===
* [[D-dimer|Plasma D-dimer]] levels > 500 ng/mL are abnormal.<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>
* The D-dimer cut-off values varies among tests; however, [[D-dimer|plasma D-dimer]] > 500 ng/mL is the most commonly used cut-off concentration.<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>


* However, the use of the cut off value 500 ng/mL for abnormal D-dimer limits the diagnostic role of D-dimer in the elderly, among whom D-dimer increases with age in the absence of any ongoing [[venous thromboemoblism]] process.  In a metanalysis of 5 cohort studies of 2818 subjects with low clinical probability of [[DVT]], the use of an age adjusted cut-off value of D-dimer increases the number of subjects in whom [[DVT]] can be excluded.<ref name="pmid22511491">{{cite journal| author=Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C et al.| title=Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. | journal=Haematologica | year= 2012 | volume= 97 | issue= 10 | pages= 1507-13 | pmid=22511491 | doi=10.3324/haematol.2011.060657 | pmc=PMC3487551 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22511491  }} </ref>  A metaanalysis of 13 cohorts of 12,497 patients with a low probability of [[venous thromboembolism]] revealed that the use of an age adjusted cut point for the D-dimer concentration increases the specificity of this test without altering its sensitivity.<ref name="pmid23645857">{{cite journal| author=Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA et al.| title=Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. | journal=BMJ | year= 2013 | volume= 346 | issue=  | pages= f2492 | pmid=23645857 | doi=10.1136/bmj.f2492 | pmc=PMC3643284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23645857  }} </ref>
* However, the use of the cut off value 500 ng/mL for abnormal D-dimer limits the diagnostic role of D-dimer in the elderly, among whom D-dimer increases with age in the absence of any ongoing [[venous thromboembolism]] process.  In a metanalysis of 5 cohort studies of 2818 subjects with low clinical probability of [[DVT]], the use of an age adjusted cut-off value of D-dimer increases the number of subjects in whom [[DVT]] can be excluded.<ref name="pmid22511491">{{cite journal| author=Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C et al.| title=Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. | journal=Haematologica | year= 2012 | volume= 97 | issue= 10 | pages= 1507-13 | pmid=22511491 | doi=10.3324/haematol.2011.060657 | pmc=PMC3487551 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22511491  }} </ref>  A metaanalysis of 13 cohorts of 12,497 patients with a low probability of [[venous thromboembolism]] revealed that the use of an age adjusted cut point for the D-dimer concentration increases the specificity of this test without altering its sensitivity.<ref name="pmid23645857">{{cite journal| author=Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA et al.| title=Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. | journal=BMJ | year= 2013 | volume= 346 | issue=  | pages= f2492 | pmid=23645857 | doi=10.1136/bmj.f2492 | pmc=PMC3643284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23645857  }} </ref>


* According to a multicenter, multinational prospective study of 3346 subjects presenting to the emergency department for suspicion of [[pulmonary embolism]], the use of a fixed D-dimer cut-off value is compared to an age adjusted D-dimer cut-off value. The use of the age adjusted cut-off value in patients with low clinical probability of [[pulmonary embolism]] is associated with an increased number of patients in whom [[pulmonary embolism]] is excluded with a decreased likelihood of the occurrence of subsequent [[venous thromboembolism]] episodes.
* According to a multicenter, multinational prospective study of 3346 subjects presenting to the emergency department for suspicion of [[pulmonary embolism]], the use of a fixed D-dimer cut-off value is compared to an age adjusted D-dimer cut-off value. The use of the age adjusted cut-off value in patients with low clinical probability of [[pulmonary embolism]] is associated with an increased number of patients in whom [[pulmonary embolism]] is excluded with a decreased likelihood of the occurrence of subsequent [[venous thromboembolism]] episodes.<ref name="JAMA 2014"> Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135. </ref>


* The age adjusted cut off value of D-dimer is the following:
* The age adjusted cut off value of D-dimer is the following:
** If age <50 years, the cut off value for D-dimer is 500 ng/mL.
** If age <50 years, the cut off value for D-dimer is 500 ng/mL.
** If age >50 years, the cut off value for D-dimer is age multiplied by 10.
** If age >50 years, the cut off value for D-dimer is age multiplied by 10.<ref name="pmid22511491">{{cite journal| author=Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C et al.| title=Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. | journal=Haematologica | year= 2012 | volume= 97 | issue= 10 | pages= 1507-13 | pmid=22511491 | doi=10.3324/haematol.2011.060657 | pmc=PMC3487551 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22511491  }} </ref><ref name="pmid23645857">{{cite journal| author=Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA et al.| title=Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. | journal=BMJ | year= 2013 | volume= 346 | issue=  | pages= f2492 | pmid=23645857 | doi=10.1136/bmj.f2492 | pmc=PMC3643284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23645857  }} </ref><ref name="JAMA 2014"> Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135. </ref>


=== Sensitivity and Specificity ===
=== Sensitivity and Specificity ===


====Sensitivity<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>====
====Sensitivity====
[[ELISA]] ''(p=0.020)'', [[ELISA|quantitative rapid ELISA]] ''(p=0.016)'' and [[ELISA|semi-quantitative ELISA]] ''(p=0.047)'' are shown to be statistically superior to [[agglutination|whole-blood agglutination]].
[[ELISA]] ''(p=0.020)'', [[ELISA|quantitative rapid ELISA]] ''(p=0.016)'' and [[ELISA|semi-quantitative ELISA]] ''(p=0.047)'' are shown to be statistically more sensitive for detecting [[VTE]] than[[agglutination|whole-blood agglutination]].<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>


====Specificity<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>====
====Specificity====
[[ELISA|Qualitative rapid ELISA]] has shown to be statistically superior to [[ELISA]] ''(p=0.004)'', [[ELISA|quantitative rapid ELISA]] ''(p=0.002)'', [[ELISA|semi-quantitative rapid ELISA]] ''(p=0.001)'', [[latex agglutination test|quantitative]] ''(p=0.005)'' and [[latex agglutination test|semi-quantitative]] latex agglutination assays ''(p=0.019)''.
[[ELISA|Qualitative rapid ELISA]] has shown to be statistically more specific for detecting [[VTE]] than to [[ELISA]] ''(p=0.004)'', [[ELISA|quantitative rapid ELISA]] ''(p=0.002)'', [[ELISA|semi-quantitative rapid ELISA]] ''(p=0.001)'', [[latex agglutination test|quantitative]] ''(p=0.005)'' and [[latex agglutination test|semi-quantitative]] latex agglutination assays ''(p=0.019)''.<ref name="pmid15096330">{{cite journal |author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK |title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review |journal=[[Annals of Internal Medicine]] |volume=140 |issue=8 |pages=589–602 |year=2004 |month=April |pmid=15096330 |doi= |url= |accessdate=2012-05-07}}</ref>




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=== False Results ===
====False Positives====
[[False positive]] readings can be due to various causes: [[liver]] disease, high [[rheumatoid factor]], [[inflammation]], [[cancer|malignancy]], [[Physical trauma|trauma]], [[pregnancy]], recent [[surgery]] as well as advanced age
====False Negatives====
[[False negative]] readings can occur if the sample is taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension.
=== Hemodynamically Stable Patients ===
=== Hemodynamically Stable Patients ===
====Incidence of Thromboembolic Events in Hemodynamically Stable Patients====
====Incidence of Thromboembolic Events in Hemodynamically Stable Patients====
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A new D-Dimer (DDMR) analyzer has shown to be more accurate in excluding patients with a low clinical pre-test probability.<ref name="pmid22245223">{{cite journal| author=Gosselin RC, Wu JR, Kottke-Marchant K, Peetz D, Christie DJ, Muth H et al.| title=Evaluation of the Stratus® CS Acute Care™ D-dimer assay (DDMR) using the Stratus® CS STAT Fluorometric Analyzer: A prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis. | journal=Thromb Res | year= 2012 | volume=  | issue=  | pages=  | pmid=22245223 | doi=10.1016/j.thromres.2011.12.015 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22245223  }} </ref>
A new D-Dimer (DDMR) analyzer has shown to be more accurate in excluding patients with a low clinical pre-test probability.<ref name="pmid22245223">{{cite journal| author=Gosselin RC, Wu JR, Kottke-Marchant K, Peetz D, Christie DJ, Muth H et al.| title=Evaluation of the Stratus® CS Acute Care™ D-dimer assay (DDMR) using the Stratus® CS STAT Fluorometric Analyzer: A prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis. | journal=Thromb Res | year= 2012 | volume=  | issue=  | pages=  | pmid=22245223 | doi=10.1016/j.thromres.2011.12.015 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22245223  }} </ref>


==ESC 2008 Guideline Recommendations <ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September |pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870 |accessdate=2011-12-07}}</ref>==  
==The 2008 Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)<ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September |pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870 |accessdate=2011-12-07}}</ref>==  


===Suspected Non High-risk PE Patients (DO NOT EDIT)<ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September |pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870 |accessdate=2011-12-07}}</ref>===
===Suspected Non High-risk PE Patients (DO NOT EDIT)<ref name="pmid18757870">{{cite journal |author=Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP |title=Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) |journal=Eur. Heart J. |volume=29|issue=18 |pages=2276–315 |year=2008 |month=September |pmid=18757870 |doi=10.1093/eurheartj/ehn310|url=http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18757870 |accessdate=2011-12-07}}</ref>===

Latest revision as of 15:45, 18 June 2014

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

D-dimer is used in the diagnosis of deep vein thrombosis and pulmonary embolism among patients with low or unlikely probability of venous thromboembolism.[1][2] While 500 ng/mL has long been the most commonly used cut off value for abnormal D-dimer concentration, recent studies suggest the use of an age adjusted cut-off concentration of D-dimer. The age adjusted cut-off value of D-dimer is 500 ng/mL for subjects whose age is less than 50 years, and the age multiplied by 10 for subjects older than 50 years.[3][4][5]

D-dimer and Thromboembolism

Indications for D-dimer Testing

  • D-dimer testing is of clinical use when there is a suspicion of deep venous thrombosis (DVT) or pulmonary embolism (PE). In patients suspected of disseminated intravascular coagulation (DIC), D-dimers may aid in the diagnosis. For DVT and PE, there are various scoring systems that are used to determine the a priori clinical probability of these diseases; the best-known were introduced by Wells et al (2003).
  • For a very high score, or pretest probability, a D-dimer will make little difference and anticoagulant therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.
  • For a moderate or low score, or pretest probability:[6]
  • A negative D-dimer test will virtually rule out thromboembolism:[7] the degree to which the d-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in your clinical setting: most available d-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
  • If the D-dimer reads high, then further testing (ultrasound of the leg veins or lung scintigraphy or CT scanning) is required to confirm the presence of thrombus. Anticoagulant therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation.
  • In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high-probability.[8]

Abnormal Levels

  • The D-dimer cut-off values varies among tests; however, plasma D-dimer > 500 ng/mL is the most commonly used cut-off concentration.[9]
  • However, the use of the cut off value 500 ng/mL for abnormal D-dimer limits the diagnostic role of D-dimer in the elderly, among whom D-dimer increases with age in the absence of any ongoing venous thromboembolism process. In a metanalysis of 5 cohort studies of 2818 subjects with low clinical probability of DVT, the use of an age adjusted cut-off value of D-dimer increases the number of subjects in whom DVT can be excluded.[3] A metaanalysis of 13 cohorts of 12,497 patients with a low probability of venous thromboembolism revealed that the use of an age adjusted cut point for the D-dimer concentration increases the specificity of this test without altering its sensitivity.[4]
  • According to a multicenter, multinational prospective study of 3346 subjects presenting to the emergency department for suspicion of pulmonary embolism, the use of a fixed D-dimer cut-off value is compared to an age adjusted D-dimer cut-off value. The use of the age adjusted cut-off value in patients with low clinical probability of pulmonary embolism is associated with an increased number of patients in whom pulmonary embolism is excluded with a decreased likelihood of the occurrence of subsequent venous thromboembolism episodes.[5]
  • The age adjusted cut off value of D-dimer is the following:
    • If age <50 years, the cut off value for D-dimer is 500 ng/mL.
    • If age >50 years, the cut off value for D-dimer is age multiplied by 10.[3][4][5]

Sensitivity and Specificity

Sensitivity

ELISA (p=0.020), quantitative rapid ELISA (p=0.016) and semi-quantitative ELISA (p=0.047) are shown to be statistically more sensitive for detecting VTE thanwhole-blood agglutination.[9]

Specificity

Qualitative rapid ELISA has shown to be statistically more specific for detecting VTE than to ELISA (p=0.004), quantitative rapid ELISA (p=0.002), semi-quantitative rapid ELISA (p=0.001), quantitative (p=0.005) and semi-quantitative latex agglutination assays (p=0.019).[9]


Method Sensitivity (95% CI) Specificity (95% CI) Positive Likelihood Ratio (95% CI) Negative Likelihood Ratio (95% CI) Time to obtain Results
Enzyme-linked immunosorbent assay (ELISA) 0.95 (0.85 to 1.00) NS NS 0.13 (0.03 to 0.58) ≥ 8 hours
Quantitative rapid ELISA 0.95 (0.83 to 1.00) NS NS 0.13 (0.02 to 0.84) 30 mins
Semi-Quantitative rapid ELISA 0.93 (0.79 to 1.00) NS NS 0.20 (0.04 to 0.96) 10 mins
Qualitative rapid ELISA NS 0.68 (0.50 to 0.87) NS 0.11 (0.01 to 0.93) 10 mins
Quantitative Latex Agglutination NS NS NS NS 10-15 mins
Semi-quantitative Latex Agglutination NS NS NS 0.17 (0.04 to 0.78) 5 mins
Whole-Blood Agglutination NS 0.74 (0.60 to 0.88) NS NS 2 mins

False Results

False Positives

False positive readings can be due to various causes: liver disease, high rheumatoid factor, inflammation, malignancy, trauma, pregnancy, recent surgery as well as advanced age

False Negatives

False negative readings can occur if the sample is taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension.

Hemodynamically Stable Patients

Incidence of Thromboembolic Events in Hemodynamically Stable Patients

Condition Incidence of thromboembolic event (%)
Patients not receiving anticoagulation with negative CT findings. 1.5%[10][11]
Patients with a high d-dimer level 1.5%
Patients with a normal d-dimer level 0.5%[10]
  • Multidetector CT is indicated in hemodynamically stable patients with a high clinical probability of PE and/or patients with elevated plasma d-dimer levels secondary to the lack of specificity.[11][12]
  • In patients with low-to-moderate suspicion of PE, a normal D-dimer level is considered sufficient to exclude the possibility of pulmonary embolism.[13][9][14]

Flowchart Summarizing the Role of D-dimer in the Diagnosis of PE

 
 
 
 
 
Patients with suspicion of
pulmonary embolism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically low or moderate
 
 
 
 
Clinically high
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer positive
 
D-dimer negative
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No treatment
 
Further tests
 
 
Further tests

A new D-Dimer (DDMR) analyzer has shown to be more accurate in excluding patients with a low clinical pre-test probability.[15]

The 2008 Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)[16]

Suspected Non High-risk PE Patients (DO NOT EDIT)[16]

Class I
"1. Plasma D-dimer measurement is recommended in emergency department patients to reduce the need for unnecessary imaging and irradiation, preferably with the use of a highly sensitive assay. (Level of Evidence: A) "

Low Clinical Probability (DO NOT EDIT)[16]

Class I
"1. Normal D-dimer level using either a highly or moderately sensitive assay excludes pulmonary embolism. (Level of Evidence: A) "

Intermediate Clinical Probability (DO NOT EDIT)[16]

Class I
"1. Normal D-dimer level using a highly sensitive assay excludes pulmonary embolism. (Level of Evidence: A) "
Class IIa
"1. Further testing should be considered if D-dimer level is normal when using a less sensitive assay. (Level of Evidence: B) "

High Clinical Probability (DO NOT EDIT)[16]

Class III
"1. D-dimer measurement is not recommended in high clinical probability patients as a normal result does not safely exclude pulmonary embolism even when using a highly sensitive assay. (Level of Evidence: C) "

References

  1. ↑ Wells PS, Owen C, Doucette S, Fergusson D, Tran H (2006). "Does this patient have deep vein thrombosis?". JAMA. 295 (2): 199–207. doi:10.1001/jama.295.2.199. PMID 16403932. Review in: Evid Based Med. 2006 Aug;11(4):119 Review in: ACP J Club. 2006 Jul-Aug;145(1):24
  2. ↑ Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D; et al. (2001). "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. 135 (2): 98–107. PMID 11453709.
  3. ↑ 3.0 3.1 3.2 Douma RA, Tan M, Schutgens RE, Bates SM, Perrier A, Legnani C; et al. (2012). "Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded". Haematologica. 97 (10): 1507–13. doi:10.3324/haematol.2011.060657. PMC 3487551. PMID 22511491.
  4. ↑ 4.0 4.1 4.2 Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA; et al. (2013). "Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis". BMJ. 346: f2492. doi:10.1136/bmj.f2492. PMC 3643284. PMID 23645857.
  5. ↑ 5.0 5.1 5.2 Righini M, Van Es J, Den Exter PL, et al. Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism: The ADJUST-PE Study. JAMA. 2014;311(11):1117-1124. doi:10.1001/jama.2014.2135.
  6. ↑ Wells PS, Anderson DR, Rodger M; et al. (2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". N. Engl. J. Med. 349 (13): 1227–35. doi:10.1056/NEJMoa023153. PMID 14507948.
  7. ↑ Goldhaber SZ, Bounameaux H (2012). "Pulmonary embolism and deep vein thrombosis". Lancet. 379 (9828): 1835–46. doi:10.1016/S0140-6736(11)61904-1. PMID 22494827.
  8. ↑ Rathbun, SW (2004). "Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings". Chest (125): 851. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  9. ↑ 9.0 9.1 9.2 9.3 Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK (2004). "D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review". Annals of Internal Medicine. 140 (8): 589–602. PMID 15096330. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  10. ↑ 10.0 10.1 Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL; et al. (2005). "Multidetector-row computed tomography in suspected pulmonary embolism". N Engl J Med. 352 (17): 1760–8. doi:10.1056/NEJMoa042905. PMID 15858185. in: J Fam Pract. 2005 Aug;54(8):653, 657
  11. ↑ 11.0 11.1 van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW; et al. (2006). "Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography". JAMA. 295 (2): 172–9. doi:10.1001/jama.295.2.172. PMID 16403929.
  12. ↑ Gupta RT, Kakarla RK, Kirshenbaum KJ, Tapson VF (2009). "D-dimers and efficacy of clinical risk estimation algorithms: sensitivity in evaluation of acute pulmonary embolism". AJR Am J Roentgenol. 193 (2): 425–30. doi:10.2214/AJR.08.2186. PMID 19620439.
  13. ↑ Bounameaux H, de Moerloose P, Perrier A, Reber G (1994). "Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview". Thromb. Haemost. 71 (1): 1–6. PMID 8165626.
  14. ↑ Bounameaux H, Perrier A, Righini M (2010). "Diagnosis of venous thromboembolism: an update". Vasc Med. 15 (5): 399–406. doi:10.1177/1358863X10378788. PMID 20926499.
  15. ↑ Gosselin RC, Wu JR, Kottke-Marchant K, Peetz D, Christie DJ, Muth H; et al. (2012). "Evaluation of the Stratus® CS Acute Care™ D-dimer assay (DDMR) using the Stratus® CS STAT Fluorometric Analyzer: A prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis". Thromb Res. doi:10.1016/j.thromres.2011.12.015. PMID 22245223.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur. Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870. Retrieved 2011-12-07. Unknown parameter |month= ignored (help)

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