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==Overview==
==Overview==
The lifetime incidence of [[DVT]] ranges from 2-5% in the general population. It accounts for a large number of ER visits and puts the patient at-risk for a life-threatening [[pulmonary embolism]]. The use of D-dimer after assessment of pre-test probability has been widely validated now and has led to a significant reduction in unnecessary procedures in the ER and hospital settings. This chapter will review the role of D-dimer in diagnosis of [[DVT]]. For a detailed discussion on D-dimer, please visit '''[[D-dimer]]'''.
D-dimer is used in the diagnosis of [[deep vein thrombosis]] 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="pmid24643601">{{cite journal| author=Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A et al.| title=Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. | journal=JAMA | year= 2014 | volume= 311 | issue= 11 | pages= 1117-24 | pmid=24643601 | doi=10.1001/jama.2014.2135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24643601  }} </ref>


==Laboratory Findings==
==Laboratory Findings==
=== Workup for Hypercoagulation ===
===D-Dimer===
*Activated [[protein C]] resistance
''For a detailed discussion on D-dimer, please click '''[[D-dimer|here]]'''.''
*[[factor V]] Leiden mutation
 
*[[Protein C]]
* [[D-dimer]] is a cross-linked [[fibrin degradation product]] and a marker of endogenous [[fibrinolysis]]. In the setting of ongoing thrombosis, D-dimer's concentration is elevated in the blood and thus makes it a screening tool to rule out [[DVT]].
*[[protein S]], free and total.
 
*[[Antithrombin]]
* D-dimer is the "test of choice" in patients who are considered to be at low or intermediate risk of DVT according to [[Wells score for DVT|pre-test probability]].  D-dimer is more useful if its negative rather than positive. It has a great '''negative predictive value''' in low to moderate risk patients.  If D-dimer is elevated, then [[DVT]] should be confirmed with [[Deep vein thrombosis ultrasound|ultrasound]].<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}}</ref><ref name="pmid12755550">{{cite journal |author=Bates SM, Kearon C, Crowther M, ''et al'' |title=A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis |journal=Ann. Intern. Med. |volume=138 |issue=10 |pages=787-94 |year=2003 |pmid=12755550 |doi=}}</ref>
*[[Lupus anticoagulant]]  
*[[Anticardiolipin antibodies]]
*Plasma [[homocysteine]] values


===D-Dimer===
* The cut off value for abnormal D-dimer concentration is 500 ng/mL.  Interpretation of D-dimer may be improved by using age adjusted levels:<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="pmid24643601">{{cite journal| author=Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A et al.| title=Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. | journal=JAMA | year= 2014 | volume= 311 | issue= 11 | pages= 1117-24 | pmid=24643601 | doi=10.1001/jama.2014.2135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24643601  }} </ref>
[[D-dimer]] is a cross-linked [[fibrin degradation product]] and a marker of endogenous [[fibrinolysis]]. In the setting of ongoing thrombosis, its levels should be elevated in the blood that makes it an excellent screening tool to rule out [[DVT]]. Interpretation may be improved by using age adjusted levels:<ref name="pmid24643601">{{cite journal| author=Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A et al.| title=Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. | journal=JAMA | year= 2014 | volume= 311 | issue= 11 | pages= 1117-24 | pmid=24643601 | doi=10.1001/jama.2014.2135 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24643601  }} </ref>
** Patients less than 50 years old: normal D-dimer is less than 500 µg/L
* Patients less than 50 years old: normal D-dimer is less than 500 µg/L.
** In patients 50 years or older: normal D-dimer is adjusted to be age multiplied by 10
* In patients 50 years or older: normal D-dimer is adjusted to be age multiplied by 10.


====Specificity and Sensitivity====
====Specificity and Sensitivity====
A large number of D-dimer assays are available and may vary in-between hospitals. In a meta-analysis of 217 studies involving [[DVT]] patients, the sensitivities of the D-dimer enzyme-linked immunofluorescence assay (ELFA) (96%), micro plate [[enzyme-linked immunosorbent assay]] (94%), and latex quantitative assay (93%; PE 95%) were superior to the whole-blood [[D-dimer]] assay (83%), and latex qualitative assay (69%). Because of this, [[ELISA]] assays are termed as "highly sensitive" and whole blood D-dimer assays is "moderately sensitive".
A large number of D-dimer assays are available and may vary in-between hospitals. In a meta-analysis of 217 studies involving [[DVT]] patients, the sensitivities of the D-dimer enzyme-linked immunofluorescence assay (ELFA) (96%), micro plate [[enzyme-linked immunosorbent assay]] (94%), and latex quantitative assay (93%; PE 95%) were superior to the whole-blood [[D-dimer]] assay (83%), and latex qualitative assay (69%). Because of this, [[ELISA]] assays are termed as "highly sensitive" and whole blood D-dimer assays is "moderately sensitive".
Thus, D-dimer has a high sensitivity ('''sNOUT''') and low specificity ('''sPIN''') for [[DVT]]. This means that D-dimer is a better test for "ruling out" [[DVT]] rather than "ruling in".
Thus, D-dimer has a high sensitivity (sNOUT) and low specificity (sPIN) for [[DVT]]. This means that D-dimer is a better test for "ruling out" [[DVT]] rather than "ruling in".


====Elevated in Other Conditions====
====D-dimer Elevation in Other Conditions====
D-dimer can be elevated in following conditions, which should be kept in mind while assessing its validity in patients with suspected [[DVT]]:
D-dimer can be elevated in following conditions, which should be kept in mind while assessing this biomarker in patients with suspected [[DVT]]:
* Malignancy
* Malignancy
* [[Disseminated intravascular coagulation]]
* [[Disseminated intravascular coagulation]]
Line 44: Line 40:
* [[Stroke]]
* [[Stroke]]


====Use in DVT Diagnosis====
=== Workup for Hypercoagulation ===
D-dimer is the "test of choice" in patients who are considered to be "low risk" according to [[Wells score for DVT|pre-test probability]]. More information regarding the use of D-dimer in diagnosis of [[DVT]] can be found [[Deep vein thrombosis diagnosis algorithm|here]]. If D-dimer is elevated, then [[DVT]] should be confirmed with [[Deep vein thrombosis ultrasound|ultrasound]].<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}}</ref><ref name="pmid12755550">{{cite journal |author=Bates SM, Kearon C, Crowther M, ''et al'' |title=A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis |journal=Ann. Intern. Med. |volume=138 |issue=10 |pages=787-94 |year=2003 |pmid=12755550 |doi=}}</ref>
*Workup for [[hypercoagulation]] includes:
**Activated [[protein C]] resistance
**[[Factor V Leiden]] mutation
**[[Protein C]]
**[[Protein S]] (free and total)
**[[Antithrombin]]
**[[Lupus anticoagulant]]  
**[[Anticardiolipin antibodies]]
**Plasma [[homocysteine]] values
 
* The hypercoagulability tests are not part of the routine workup for all patients with DVT.  The hypercoagulability workup should be considered in the case of unprovoked venous thrombosis at an early age (< 40 years), strong family history of more than 2 relative who had VTE symptoms, and pregnant women who had a previous VTE episode in the absence of a significant trigger.<ref name="pmid20128794">{{cite journal| author=Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S et al.| title=Clinical guidelines for testing for heritable thrombophilia. | journal=Br J Haematol | year= 2010 | volume= 149 | issue= 2 | pages= 209-20 | pmid=20128794 | doi=10.1111/j.1365-2141.2009.08022.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20128794  }} </ref>


D-dimer is more useful if its negative rather than positive. It has a great '''negative predictive value''' in low to moderate risk patients of DVT.
* The hypercoagulability workup should not be performed in the cases of:<ref name="pmid20128794">{{cite journal| author=Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S et al.| title=Clinical guidelines for testing for heritable thrombophilia. | journal=Br J Haematol | year= 2010 | volume= 149 | issue= 2 | pages= 209-20 | pmid=20128794 | doi=10.1111/j.1365-2141.2009.08022.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20128794  }} </ref>
** Upper limb thrombosis
** [[Central venous catheter]] related thrombosis
** [[Retinal vein]] occlusion
** Recent major [[surgery]]
** Recent [[trauma]]
** Recent immobilization
** Active [[cancer]]


==References==
==References==

Latest revision as of 15:09, 17 July 2014
Resident
Survival
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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] ; Kashish Goel, M.D.; Assistant Editor(s)-In-Chief: Justine Cadet

Deep Vein Thrombosis Microchapters

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Differentiating Deep vein thrombosis from other Diseases

Epidemiology and Demographics

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Risk calculators and risk factors for Deep vein thrombosis laboratory tests

Overview

D-dimer is used in the diagnosis of deep vein thrombosis 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]

Laboratory Findings

D-Dimer

For a detailed discussion on D-dimer, please click here.

  • D-dimer is the "test of choice" in patients who are considered to be at low or intermediate risk of DVT according to pre-test probability. D-dimer is more useful if its negative rather than positive. It has a great negative predictive value in low to moderate risk patients. If D-dimer is elevated, then DVT should be confirmed with ultrasound.[6][7]
  • The cut off value for abnormal D-dimer concentration is 500 ng/mL. Interpretation of D-dimer may be improved by using age adjusted levels:[3][4][5]
    • Patients less than 50 years old: normal D-dimer is less than 500 µg/L
    • In patients 50 years or older: normal D-dimer is adjusted to be age multiplied by 10

Specificity and Sensitivity

A large number of D-dimer assays are available and may vary in-between hospitals. In a meta-analysis of 217 studies involving DVT patients, the sensitivities of the D-dimer enzyme-linked immunofluorescence assay (ELFA) (96%), micro plate enzyme-linked immunosorbent assay (94%), and latex quantitative assay (93%; PE 95%) were superior to the whole-blood D-dimer assay (83%), and latex qualitative assay (69%). Because of this, ELISA assays are termed as "highly sensitive" and whole blood D-dimer assays is "moderately sensitive". Thus, D-dimer has a high sensitivity (sNOUT) and low specificity (sPIN) for DVT. This means that D-dimer is a better test for "ruling out" DVT rather than "ruling in".

D-dimer Elevation in Other Conditions

D-dimer can be elevated in following conditions, which should be kept in mind while assessing this biomarker in patients with suspected DVT:

Workup for Hypercoagulation

  • The hypercoagulability tests are not part of the routine workup for all patients with DVT. The hypercoagulability workup should be considered in the case of unprovoked venous thrombosis at an early age (< 40 years), strong family history of more than 2 relative who had VTE symptoms, and pregnant women who had a previous VTE episode in the absence of a significant trigger.[8]

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 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 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 Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A; et al. (2014). "Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study". JAMA. 311 (11): 1117–24. doi:10.1001/jama.2014.2135. PMID 24643601.
  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. ↑ Bates SM, Kearon C, Crowther M; et al. (2003). "A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis". Ann. Intern. Med. 138 (10): 787–94. PMID 12755550.
  8. ↑ 8.0 8.1 Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S; et al. (2010). "Clinical guidelines for testing for heritable thrombophilia". Br J Haematol. 149 (2): 209–20. doi:10.1111/j.1365-2141.2009.08022.x. PMID 20128794.

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