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__NOTOC__
__NOTOC__
{{SI}}
{{D-dimer}}
'''Editor(s)-In-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:charlesmichaelgibson@gmail.com], {{ATI}}; {{AE}} {{CZ}}


==Overview==
{{CMG}}; {{AE}} {{Rim}}
[[D-dimer]] is a [[fibrin degradation product]]. D-dimer levels are elevated in the plasma after the acute formation of a blood clot. The majority of patients with pulmonary embolism have some degree of endogenous [[fibrinolysis]] with  an elevation in [[D-dimer]] levels, therefore there is a high [[negative predictive value]] in ruling out a pulmonary embolism when D-dimer levels are low. However a wide range of diseases are associated with mild degree of [[fibrinolysis]] which elevate [[D-dimer]] levels and contribute towards a reduced [[specificity]] and a poor [[positive predictive value]] of a high D-dimer level. This means that it is more likely that one can rule out a PE with a low D-dimer level, but cannot necessarily confirm the diagnosis of a PE based on a high D-dimer level. Other disease states  that can also have a high d-dimer level include [[pneumonia]], [[Congestive heart failure|congestive heart failure (CHF)]], [[Myocardial infarction|myocardial infarction (MI)]] and [[malignancy]]. [[False-negative]] values may occur in patients with prolonged symptoms of [[venous thromboembolism]] (≥14 days), patients on therapeutic [[heparin|heparin therapy]], and patients with suspected [[deep venous thrombosis]] on oral anticoagulation, as these patients have will have low D-dimer levels in the presence of a PE.<ref name="pmid19712840">{{cite journal| author=Bruinstroop E, van de Ree MA, Huisman MV| title=The use of D-dimer in specific clinical conditions: a narrative review. | journal=Eur J Intern Med | year= 2009 | volume= 20 | issue= 5 | pages= 441-6 | pmid=19712840 | doi=10.1016/j.ejim.2008.12.004 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19712840  }} </ref><ref name="pmid20592294">{{cite journal| author=Agnelli G, Becattini C| title=Acute pulmonary embolism. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 3 | pages= 266-74 | pmid=20592294 | doi=10.1056/NEJMra0907731 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20592294  }} </ref>


==Historical Perspective==
D-dimer testing was originally developed in the diagnosis of disseminated intravascular coagulation. In the [[1990s]], they turned out to be useful in diagnosing thromboembolic process.


==Physiology==
== [[D-dimer overview|Overview]] ==
[[Fibrin degradation product]]s (FDPs) are formed whenever [[fibrin]] is [[proteolysis|broken down]] by [[enzyme]]s. In fact, FDP are formed as a result of the sequential actions of the following three different enzymes: [[thrombin]], [[factor VIII]] and [[plasmin]].  Determining FDPs is not considered useful, as this does not indicate whether the fibrin is part of a blood clot (or being generated as part of [[inflammation]]).


D-dimers are unique in that they are the breakdown products of a fibrin mesh that has been stabilized by [[Factor XIII]]. This factor crosslinks the E-element to ''two'' D-elements. This is the final step in the generation of a thrombus.
== [[D-dimer historical perspective|Historical Perspective]] ==


[[Plasmin]] is a [[fibrinolysis|fibrinolytic]] enzyme that organizes clots and breaks down the fibrin mesh. It cannot, however, break down the bonds between one E and two D units. The protein fragment thus left over is a D-dimer.<ref name="pmid19008457‎">{{cite journal| author=Adam SS, Key NS, Greenberg CS| title=D-dimer antigen: current concepts and future prospects. | journal=Blood | year= 2009 | volume= 113 | issue= 13 | pages= 2878-87 | pmid=19008457‎ | doi=10.1182/blood-2008-06-165845 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19008457  }} </ref>
== [[D-dimer physiology|Physiology]] ==


Shown below is an immage summarizing the formation of D-dimers and other [[fibrin degradation product]]s as a result of the sequential action of the three enzymes: [[thrombin]], [[factor VIII]] and [[plasmin]].
== Clinical Correlation==
[[High D-dimer causes|Causes of High D-dimer]] | [[D-dimer diagnostic role in thromboembolism|Diagnostic Role in Thromboembolism]] | [[D-dimer prognostic role in mortality|Prognostic Role in Mortality]] | [[D-dimer prognostic role in thromboembolism occurrence|Prognostic Role in Thromboembolism Occurrence]] | [[D-dimer prognostic role in thromboembolism recurrence|Prognostic Role in Thromboembolism Recurrence]] | [[D-dimer prognostic role in non thromboembolism conditions|Prognostic Role in Non-Thromboembolism]]


==Cinical Trials==
[[D-dimer landmark trials|Landmark Trials]]


[[Image:D-dimer-formation.gif|500px|left|Formation of D-dimer]]
<br clear="left"/>
==D-Dimer Test==
D-dimer assays rely on [[monoclonal antibody|monoclonal antibodies]] to bind to this specific protein fragment. The first patented MoAb of the kind was ''D Dimer-3B6/22'', although others have been developed.
===Indications===
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: 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>
===Reference Range===
Most sampling kits have 0-300 [[1 E-12 kg|ng]]/[[millilitre|ml]] as normal range. Values exceeding 250, 300 or 500 ng/ml (different for various kits) are considered positive.
For patients over age 50 a value of ageX10 may be abnormal.<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="pmid22072293">{{cite journal| author=van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T et al.| title=The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. | journal=Thromb Haemost | year= 2012 | volume= 107 | issue= 1 | pages= 167-71 | pmid=22072293 | doi=10.1160/TH11-08-0587 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22072293  }} </ref><ref name="pmid20354012">{{cite journal| author=Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A et al.| title=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. | journal=BMJ | year= 2010 | volume= 340 | issue=  | pages= c1475 | pmid=20354012 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20354012 | doi=10.1136/bmj.c1475 }} </ref>
===Types of Assays===
* [[ELISA]] (e.g. Vidas)
* Latex turbidimetric assay (automated immunoassay, e.g. Roche Tina-quant, MDA D-dimer)
* Enhanced microlatex
* Latex-enhanced photometric
* Whole Blood Agglutination (e.g. SimpliRED)
* Rapid Lateral Flow (e.g. Clearview Simplify)
===Test Properties===
Various kits have a 93-95% sensitivity and about 50% specificity in the diagnosis of thrombotic disease.<ref>Schrecengost JE, LeGallo RD, Boyd JC, Moons KG, Gonias SL, Rose CE Jr, Bruns DE. Comparison of diagnostic accuracies in outpatients and hospitalized patients of D-dimer testing for the evaluation of suspected pulmonary embolism. Clin Chem 2003;49:1483-90. PMID 12928229.</ref>
* [[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 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.
* Likelihood ratios are derived from sensitivity and specificity to adjust pretest probability.
== D-dimer and Thromboembolism==
=== 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>
=== 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>====
[[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]].
====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>====
[[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)''.
{| border="1"
|+
! Method !! Sensitivity (95% CI) !! Specificity (95% CI) !! Positive Likelihood Ratio (95% CI) !! Negative Likelihood Ratio (95% CI) !! Time to obtain Results
|-
| [[ELISA|Enzyme-linked immunosorbent assay (ELISA)]]
| align= "center" | 0.95 (0.85 to 1.00)
| align= "center" | NS
| align= "center" | NS
| align= "center" | 0.13 (0.03 to 0.58)
| align= "center" | ≥ 8 hours
|-
| [[ELISA|Quantitative rapid ELISA]]
| align= "center" | 0.95 (0.83 to 1.00)
| align= "center" | NS
| align= "center" | NS
| align= "center" | 0.13 (0.02 to 0.84)
| align= "center" | 30 mins
|-
| [[ELISA|Semi-Quantitative rapid ELISA]]
| align= "center" | 0.93 (0.79 to 1.00)
| align= "center" | NS
| align= "center" | NS
| align= "center" | 0.20 (0.04 to 0.96)
| align= "center" | 10 mins
|-
| [[ELISA|Qualitative rapid ELISA]]
| align= "center" | NS
| align= "center" | 0.68 (0.50 to 0.87)
| align= "center" | NS
| align= "center" | 0.11 (0.01 to 0.93)
| align= "center" | 10 mins
|-
| [[Latex agglutination test|Quantitative Latex Agglutination]]
| align= "center" | NS
| align= "center" | NS
| align= "center" | NS
| align= "center" | NS
| align= "center" | 10-15 mins
|-
| [[Latex agglutination test|Semi-quantitative Latex Agglutination]]
| align= "center" | NS
| align= "center" | NS
| align= "center" | NS
| align= "center" | 0.17 (0.04 to 0.78)
| align= "center" | 5 mins
|-
| [[Latex agglutination test|Whole-Blood Agglutination]]
| align= "center" | NS
| align= "center" | 0.74 (0.60 to 0.88)
| align= "center" | NS
| align= "center" | NS
| align= "center" | 2 mins
|}
==Causes of Elevated D-Dimer==
* [[Age]]
* [[Aortic dissection]]
* [[Atherosclerosis]]
* [[Atrial fibrillation]]
* [[Heart failure]]
* [[Ischemic heart disease]]
* [[Liver disease]]
* [[Malignancy]]
* [[Pregnancy]]
* [[Primary pulmonary hypertension]]
* [[Renal disease]]
* [[Sickle cell disease]]
* [[Stroke]]
* [[Surgery]]
* [[Thromboembolism]]
* [[Trauma]]
=== Hemodynamically Stable Patients ===
====Incidence of Thromboembolic Events in Hemodynamically Stable Patients====
{| border="1"
|+
! Condition !! Incidence of thromboembolic event (%)
|-
| Patients not receiving anticoagulation with negative CT findings.
| 1.5%<ref name="pmid15858185">{{cite journal| author=Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL et al.|title=Multidetector-row computed tomography in suspected pulmonary embolism. | journal=N Engl J Med | year= 2005 | volume= 352|issue= 17 | pages= 1760-8 | pmid=15858185 | doi=10.1056/NEJMoa042905 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15858185}}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16118905Review in: J Fam Pract. 2005 Aug;54(8):653, 657] </ref><ref name="pmid16403929">{{cite journal| author=van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW et al.|title=Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. | journal=JAMA | year= 2006 | volume= 295 |issue= 2 | pages= 172-9 | pmid=16403929 | doi=10.1001/jama.295.2.172| pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16403929 }} </ref>
|-
| Patients with a high d-dimer level
| 1.5%
|-
| Patients with a normal d-dimer level
| 0.5%<ref name="pmid15858185">{{cite journal| author=Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL et al.|title=Multidetector-row computed tomography in suspected pulmonary embolism. | journal=N Engl J Med | year= 2005 | volume= 352|issue= 17 | pages= 1760-8 | pmid=15858185 | doi=10.1056/NEJMoa042905 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15858185}}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16118905Review in: J Fam Pract. 2005 Aug;54(8):653, 657] </ref>
|}
*[[Pulmonary embolism CT#Multi-Detector CT|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.<ref name="pmid16403929">{{cite journal| author=van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW et al.| title=Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. | journal=JAMA | year= 2006 | volume= 295 | issue= 2 | pages= 172-9 | pmid=16403929 | doi=10.1001/jama.295.2.172 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16403929  }} </ref><ref name="pmid19620439">{{cite journal| author=Gupta RT, Kakarla RK, Kirshenbaum KJ, Tapson VF| title=D-dimers and efficacy of clinical risk estimation algorithms: sensitivity in evaluation of acute pulmonary embolism. |journal=AJR Am J Roentgenol | year= 2009 | volume= 193 | issue= 2 | pages= 425-30 | pmid=19620439 |doi=10.2214/AJR.08.2186 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19620439 }} </ref>
*In patients with low-to-moderate suspicion of PE, a normal [[D-dimer]] level is considered sufficient to exclude the possibility of pulmonary embolism.<ref name="pmid8165626">{{cite journal |author=Bounameaux H, de Moerloose P, Perrier A, Reber G|title=Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview |journal=Thromb. Haemost.|volume=71 |issue=1 |pages=1-6 |year=1994 |pmid=8165626 |doi=}}</ref>
=== Flowchart Summarizing the Role of D-dimer in the Diagnosis of PE ===
{{familytree/start |summary=Use of D-Dimer.}}
{{familytree | | | | GMa | GMa=Patients with suspection of [[Pulmonary embolism]]}}
{{familytree | |,|-|-|^|-|-|-|.| | | }}
{{familytree |JOE| | | | |SIS| | | JOE=Clinically Low or Moderate|SIS=Clinically High}}
{{familytree |,|^|-|.| | | | |!| }}
{{familytree |!| | |!| | | | |!| }}
{{familytree |!| | |ME| | |!|ME=D-Dimer Positive}}
{{familytree |!| | | |!| | | |!| }}
{{familytree |MOM| |!| | | |!| |MOM=D-Dimer Negative|}}
{{familytree | |!| | |!| | | |!| }}
{{familytree |GPa| |ME| |SIS|GPa=No treatment|ME=Further Tests|SIS=Further Tests}}
{{familytree/end}}
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>
==Prognostic Role of D-dimer==
===Mortality and Thromboembolism===
* Several studies have investigated the role of D-dimer as a prognostic marker for patients diagnosed with [[pulmonary embolism]].  In fact, according to several studies D-dimer level is suggested to have a prognostic role as higher levels of D-dimer are associated with a higher mortality risk.<ref name="pmid22648488">{{cite journal| author=Sanchez O, Planquette B, Roux A, Gosset-Woimant M, Meyer G| title=Triaging in pulmonary embolism. | journal=Semin Respir Crit Care Med | year= 2012 | volume= 33 | issue= 2 | pages= 156-62 | pmid=22648488 | doi=10.1055/s-0032-1311794 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22648488  }} </ref> 
* Measurement of the level of D-dimer was done on 366 patients presenting to the emergency department.  Follow up on these patients revealed a higher mortality risk among patients having a D-dimer level higher than 5500 mg/L.  In fact, the overall mortality increased from 1.1% to 9% among patients with D-dimer levels less than 1500mg/L and greater than 5500 mg/L respectively. The [[sensitivity]] and [[specificity]] of D-dimer in predicting mortality were 95% and 26% respectively, while the [[PPV]] and [[NPV]] were 7 % and 99% respectively.<ref name="pmid17003925">{{cite journal| author=Aujesky D, Roy PM, Guy M, Cornuz J, Sanchez O, Perrier A| title=Prognostic value of D-dimer in patients with pulmonary embolism. | journal=Thromb Haemost | year= 2006 | volume= 96 | issue= 4 | pages= 478-82 | pmid=17003925 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17003925  }} </ref>
* Another study supported the same association of high D-dimer levels and increased mortality risk and suggested that the best cut-off level of D-dimer to predict mortality is more than 3000 ng/mL (OR= 7.29, CI=95%).  In addition to their association with higher mortality risk, elevated levels of D-dimer are associated with centrally located pulmonary embolism.<ref name="pmid18028485">{{cite journal| author=Klok FA, Djurabi RK, Nijkeuter M, Eikenboom HC, Leebeek FW, Kramer MH et al.| title=High D-dimer level is associated with increased 15-d and 3 months mortality through a more central localization of pulmonary emboli and serious comorbidity. | journal=Br J Haematol | year= 2008 | volume= 140 | issue= 2 | pages= 218-22 | pmid=18028485 | doi=10.1111/j.1365-2141.2007.06888.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18028485  }} </ref>
* Data results from RIETE registry also supports the association between high levels of D-dimer and fatality from pulmonary embolism (OR=1.8, CI=95%) as well as higher risk of major bleeding.<ref name="pmid19691481">{{cite journal| author=Lobo JL, Zorrilla V, Aizpuru F, Grau E, Jiménez D, Palareti G et al.| title=D-dimer levels and 15-day outcome in acute pulmonary embolism. Findings from the RIETE Registry. | journal=J Thromb Haemost | year= 2009 | volume= 7 | issue= 11 | pages= 1795-801 | pmid=19691481 | doi=10.1111/j.1538-7836.2009.03576.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19691481  }} </ref>
* The prognostic role of D-dimer in hemodynamically stable patients does not have a solid ground.  In fact, mixed results are present regarding the association between D-dimer and mortality.  According to a study conducted on 292 stable patients with [[PE]], high levels of D-dimer more than 5000 ng/mL were not associated with a higher mortality.<ref name="pmid21288930">{{cite journal| author=Stein PD, Janjua M, Matta F, Alrifai A, Jaweesh F, Chughtai HL| title=Prognostic value of D-dimer in stable patients with pulmonary embolism. | journal=Clin Appl Thromb Hemost | year= 2011 | volume= 17 | issue= 6 | pages= E183-5 | pmid=21288930 | doi=10.1177/1076029610395129 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21288930  }} </ref>
===Recurrence of Thromboembolism===
* D-dimer seems to have a good prognostic role in predicting recurrence of thromboembolism.  According to PROLONG study, normal levels of D-dimer 1 month following discontinuation of [[anticoagulation]] were associated with a decreased level of thromboembolism recurrences.<ref name="pmid17065639">{{cite journal| author=Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A et al.| title=D-dimer testing to determine the duration of anticoagulation therapy. | journal=N Engl J Med | year= 2006 | volume= 355 | issue= 17 | pages= 1780-9 | pmid=17065639 | doi=10.1056/NEJMoa054444 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17065639  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17335152 Review in: ACP J Club. 2007 Mar-Apr;146(2):29]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17400637 Review in: Evid Based Med. 2007 Apr;12(2):45] </ref>
* PROLONG II study investigated the association between the levels of D-dimers more than one month after [[anticoagulation]] suspension for unprovoked venous [[thromboembolism]].  The results of this study showed that patients who have high levels of D-dimer at 3 months after [[anticoagulation]] suspension have higher thromboembolism recurrences risks than patients who have normal levels of D-dimer.  Hence, these studies suggest that the measurement of D-dimer levels at several months intervals following anticoagulation suspension in patient suffering from a first episode of VTE might be beneficial in triaging patients and targeting their therapies.<ref name="pmid21288930">{{cite journal| author=Stein PD, Janjua M, Matta F, Alrifai A, Jaweesh F, Chughtai HL| title=Prognostic value of D-dimer in stable patients with pulmonary embolism. | journal=Clin Appl Thromb Hemost | year= 2011 | volume= 17 | issue= 6 | pages= E183-5 | pmid=21288930 | doi=10.1177/1076029610395129 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21288930  }} </ref>
===Sepsis and Mortality===
* Increase level of D-dimer is correlated with worsening severity and death.  For instance, according to one study  higher D-dimer levels were correlated with high risk of 28 day mortality such as the odds ratio are 2.07 (CI=95%) and 3.03 (CI=95%) in patients having a D-dimer level >1180 and >2409 respectively.<ref name="pmid22795996">{{cite journal| author=Rodelo JR, De la Rosa G, Valencia ML, Ospina S, Arango CM, Gómez CI et al.| title=D-dimer is a significant prognostic factor in patients with suspected infection and sepsis. | journal=Am J Emerg Med | year= 2012 | volume= 30 | issue= 9 | pages= 1991-9 | pmid=22795996 | doi=10.1016/j.ajem.2012.04.033 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22795996  }} </ref>
* On the other hand, its decrease was associated with resolution of sepsis.<ref name="pmid11236773">{{cite journal| author=Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al.| title=Efficacy and safety of recombinant human activated protein C for severe sepsis. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 10 | pages= 699-709 | pmid=11236773 | doi=10.1056/NEJM200103083441001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11236773  }} </ref><ref name="pmid15025782">{{cite journal| author=Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A et al.| title=Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. | journal=Crit Care | year= 2004 | volume= 8 | issue= 2 | pages= R82-90 | pmid=15025782 | doi=10.1186/cc2459 | pmc=PMC420030 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15025782  }} </ref><ref name="pmid16781920">{{cite journal| author=Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S et al.| title=Severe sepsis and septic shock: review of the literature and emergency department management guidelines. | journal=Ann Emerg Med | year= 2006 | volume= 48 | issue= 1 | pages= 28-54 | pmid=16781920 | doi=10.1016/j.annemergmed.2006.02.015 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16781920  }} </ref>
* Higher D-dimer levels were correlated with high risk of 28 day mortality such as the odds ratio are 2.07 (CI=95%) and 3.03 (CI=95%) in patients having a D-dimer level >1180 and >2409 respectively.<ref name="pmid22795996">{{cite journal| author=Rodelo JR, De la Rosa G, Valencia ML, Ospina S, Arango CM, Gómez CI et al.| title=D-dimer is a significant prognostic factor in patients with suspected infection and sepsis. | journal=Am J Emerg Med | year= 2012 | volume= 30 | issue= 9 | pages= 1991-9 | pmid=22795996 | doi=10.1016/j.ajem.2012.04.033 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22795996  }} </ref>
===Primary Pulmonary Hypertension===
Elevated D-dimer levels are shown to be associated with idiopathic primary [[pulmonary hypertension]] (PPH) and correlates with severity of disease, New York Heart Association (NYHA) functional class, and survival when evaluated in a small study that included 14 patients.<ref name="pmid12426270">{{cite journal| author=Shitrit D, Bendayan D, Bar-Gil-Shitrit A, Huerta M, Rudensky B, Fink G et al.| title=Significance of a plasma D-dimer test in patients with primary pulmonary hypertension. | journal=Chest | year= 2002 | volume= 122 | issue= 5 | pages= 1674-8 | pmid=12426270 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12426270  }} </ref><ref name="pmid19572023">{{cite journal| author=Arunthari V, Burger CD| title=Utility of d-dimer in the diagnosis of patients with chronic thromboembolic pulmonary hypertension. | journal=Open Respir Med J | year= 2009 | volume= 3 | issue=  | pages= 85-9 | pmid=19572023 | doi=10.2174/1874306400903010085 | pmc=PMC2703202 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19572023  }} </ref>
===Liver Disease===
D-dimer is suggested to have a prognostic role in liver disease because it was found to be a significant predictor of death.<ref name="pmid18329968">{{cite journal| author=Primignani M, Dell'Era A, Bucciarelli P, Bottasso B, Bajetta MT, de Franchis R et al.| title=High-D-dimer plasma levels predict poor outcome in esophageal variceal bleeding. | journal=Dig Liver Dis | year= 2008 | volume= 40 | issue= 11 | pages= 874-81 | pmid=18329968 | doi=10.1016/j.dld.2008.01.010 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18329968  }} </ref>
===Malignancy===
Not only is D-dimer associated with the presence of malignancy, but also it correlates with [[tumor]] bulk, [[metastasis]], and overall patient prognosis and mortality.<ref name="pmid11875705">{{cite journal| author=Dirix LY, Salgado R, Weytjens R, Colpaert C, Benoy I, Huget P et al.| title=Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer. | journal=Br J Cancer | year= 2002 | volume= 86 | issue= 3 | pages= 389-95 | pmid=11875705 | doi=10.1038/sj.bjc.6600069 | pmc=PMC2375200 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11875705  }} </ref>
==D-Dimer and Non Thromboembolism Conditions==
D-dimer lab test can be elevated in conditions other than venous thromboembolism.  Because D-dimer is a sensitive test that lacks [[specificity]], it is considered only useful in ruling out [[DVT]] and/or [[PE]].  Since D-dimer elevation is a physiologic process related to fibrinolytic activity that counteracts the extrinsic [[coagulation pathway]] activation, it is understandably not exclusive to venous thromboembolism (VTE) and can be present in other physiologic and pathological processes.<ref name="pmid17986466">{{cite journal| author=Sodeck G, Domanovits H, Schillinger M, Ehrlich MP, Endler G, Herkner H et al.| title=D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study. | journal=Eur Heart J | year= 2007 | volume= 28 | issue= 24 | pages= 3067-75 | pmid=17986466 | doi=10.1093/eurheartj/ehm484 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17986466  }} </ref>  D-dimer elevation is not diagnostic of PE and can sometimes be a misleading lab value that  is cost-inefficient, predisposes patients to high doses of unnecessary computed tomography (CT) radiation exposure, and delays appropriate diagnostic and therapeutic work-up.<ref name="pmid12392839">{{cite journal| author=Dunn KL, Wolf JP, Dorfman DM, Fitzpatrick P, Baker JL, Goldhaber SZ| title=Normal D-dimer levels in emergency department patients suspected of acute pulmonary embolism. | journal=J Am Coll Cardiol | year= 2002 | volume= 40 | issue= 8 | pages= 1475-8 | pmid=12392839 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12392839  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12585983 Review in: J Fam Pract. 2003 Feb;52(2):99, 103] </ref><ref name="pmid22319245">{{cite journal| author=Chopra N, Doddamreddy P, Grewal H, Kumar PC| title=An elevated D-dimer value: a burden on our patients and hospitals. | journal=Int J Gen Med | year= 2012 | volume= 5 | issue=  | pages= 87-92 | pmid=22319245 | doi=10.2147/IJGM.S25027 | pmc=PMC3273370 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22319245  }} </ref>
===Age===
D-dimer levels physiologically increase with age, making the usefulness of D-dimer among the elderly less significant.  The exact mechanism of D-dimer increase with age is poorly understood.  It is thought to be related to the expected increase in patient co-morbidities and thrombotic events that occur with age, and that also happen to elevate D-dimer levels.  The use of D-dimer in elderly nonetheless remains helpful in diagnosing VTE in low and intermediate risk patients.  Age-adjusted D-dimer levels are thought to be useful, especially for the elderly.  However, specific age-adjusted values have not been released yet.<ref name="pmid22046531">{{cite journal| author=Der Sahakian G, Claessens YE, Allo JC, Kansao J, Kierzek G, Pourriat JL| title=Accuracy of D-Dimers to Rule Out Venous Thromboembolism Events across Age Categories. | journal=Emerg Med Int | year= 2010 | volume= 2010 | issue=  | pages= 185453 | pmid=22046531 | doi=10.1155/2010/185453 | pmc=PMC3195346 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22046531  }} </ref>
===Aortic Dissection===
Elevated levels of D-dimer lab test has been used to rapidly rule out emergencies such as acute [[aortic dissection]] (AAD).  More than 15 studies that enrolled more than 400 patients have evaluated the use of D-dimer in AAD.  With the absence of specific biomarkers, the clinical diagnosis of AAD remains a challenge for clinicians based on clinical suspicion alone.  A meta analysis for D-dimer testing in AAD revealed that D-dimer has 97% sensitivity and 59% specificity in diagnosis of AAD.  The diagnostic cut-off D-dimer value for patients with AAD ranges between 0.1 and 0.9 µg/mL., with sensitivities ranging between 100% and 86% respectively. Using D-dimer cut-off value similar to that for [[PE]] at a level of 0.5 µg/mL is considered an appropriate level that has a negative predictive value that approximately reaches 100%.<ref name="pmid17986466">{{cite journal| author=Sodeck G, Domanovits H, Schillinger M, Ehrlich MP, Endler G, Herkner H et al.| title=D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study. | journal=Eur Heart J | year= 2007 | volume= 28 | issue= 24 | pages= 3067-75 | pmid=17986466 | doi=10.1093/eurheartj/ehm484 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17986466  }} </ref>
===Renal Disease===
D-dimer levels is correlated with [[nephrotic syndrome]] and other renal diseases.  While some postulate that D-dimer elevation is associated with renal clearance,<ref name="pmid15010654">{{cite journal| author=Shlipak MG, Fried LF, Stehman-Breen C, Siscovick D, Newman AB| title=Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study. | journal=Am J Geriatr Cardiol | year= 2004 | volume= 13 | issue= 2 | pages= 81-90 | pmid=15010654 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15010654  }} </ref> data is conflicting as to whether D-dimer elevation may be less likely correlated with renal clearance as much as it is associated with [[proteinuria]].<ref name="pmid23221061">{{cite journal| author=Sexton DJ, Clarkson MR, Mazur MJ, Plant WD, Eustace JA| title=Serum D-dimer concentrations in nephrotic syndrome track with albuminuria, not estimated glomerular filtration rate. | journal=Am J Nephrol | year= 2012 | volume= 36 | issue= 6 | pages= 554-60 | pmid=23221061 | doi=10.1159/000345475 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23221061  }} </ref>  Nevertheless, the increase of hemostatic markers, such as D-dimer in renal disease, are considered risk factors for [[VTE]] in patients with renal disease.<ref name="pmid21269477">{{cite journal| author=Dubin R, Cushman M, Folsom AR, Fried LF, Palmas W, Peralta CA et al.| title=Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis. | journal=BMC Nephrol | year= 2011 | volume= 12 | issue=  | pages= 3 | pmid=21269477 | doi=10.1186/1471-2369-12-3 | pmc=PMC3037849 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21269477  }} </ref>
[[Nephrotic syndrome]] is considered a hypercoagulable state that is notoriously associated with [[DVT]] and [[PE]].  Among 100 patients with proteinuria, 53% had elevated D-dimer levels.  When proteinuria was more than 1g/24 hours, elevation of D-dimer levels was seen in 69% of patients with proteinuria.  D-dimer is believed to be related to the heavy proteinuria in nephrotic syndrome and subsequent hepatic synthesis of [[fibrinogen]], where strong association between D-dimer elevation and hypoalbuminemia is found.  It is also suggested that elevated serum fibrinopeptide A, thrombin-antithrombin III complex, along with products of [[thrombin]] and [[prothrombin]], and the state of activated hemostasis in nephrotic syndrome causes the elevation of D-dimer with no evidence of clinical [[thrombosis]].<ref name="pmid8238000">{{cite journal| author=Chen TY, Huang CC, Tsao CJ| title=Hemostatic molecular markers in nephrotic syndrome. | journal=Am J Hematol | year= 1993 | volume= 44 | issue= 4 | pages= 276-9 | pmid=8238000 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8238000  }} </ref><ref name="pmid15990160">{{cite journal| author=Singhal R, Brimble KS| title=Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management. | journal=Thromb Res | year= 2006 | volume= 118 | issue= 3 | pages= 397-407 | pmid=15990160 | doi=10.1016/j.thromres.2005.03.030 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15990160  }} </ref><ref name="pmid23221061">{{cite journal| author=Sexton DJ, Clarkson MR, Mazur MJ, Plant WD, Eustace JA| title=Serum D-dimer concentrations in nephrotic syndrome track with albuminuria, not estimated glomerular filtration rate. | journal=Am J Nephrol | year= 2012 | volume= 36 | issue= 6 | pages= 554-60 | pmid=23221061 | doi=10.1159/000345475 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23221061  }} </ref>
===Sepsis and Septic Shock===
D-dimer levels are almost always increased in patients with [[sepsis]], [[septic shock]], and [[disseminated intravascular coagulation]] (DIC).  According to the Recombinant Human Activated Protein C Woldwide Evaluation in Severe Sepsis (PROWESS) trial that included 1,690 septic patients, D-dimer was elevated in approximately 100% of patients.<ref name="pmid11236773">{{cite journal| author=Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al.| title=Efficacy and safety of recombinant human activated protein C for severe sepsis. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 10 | pages= 699-709 | pmid=11236773 | doi=10.1056/NEJM200103083441001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11236773  }} </ref><ref name="pmid15025782">{{cite journal| author=Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A et al.| title=Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. | journal=Crit Care | year= 2004 | volume= 8 | issue= 2 | pages= R82-90 | pmid=15025782 | doi=10.1186/cc2459 | pmc=PMC420030 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15025782  }} </ref><ref name="pmid16781920">{{cite journal| author=Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S et al.| title=Severe sepsis and septic shock: review of the literature and emergency department management guidelines. | journal=Ann Emerg Med | year= 2006 | volume= 48 | issue= 1 | pages= 28-54 | pmid=16781920 | doi=10.1016/j.annemergmed.2006.02.015 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16781920  }} </ref>
===Surgery===
D-dimer levels may be elevated after [[surgery]] and [[trauma]] independent of [[VTE]] and [[PE]].  The diagnosis of post-operative VTE, a common complication following surgery, becomes even a more challenging diagnosis for this specific subset of patients given the unpredictable and heterogeneous variation of post-operative D-dimer levels.  The dynamics behind D-dimer elevation following surgery and trauma are poorly understood.<ref name="pmid11833854">{{cite journal| author=Lippi G, Veraldi GF, Fraccaroli M, Manzato F, Cordiano C, Guidi G| title=Variation of plasma D-dimer following surgery: implications for prediction of postoperative venous thromboembolism. | journal=Clin Exp Med | year= 2001 | volume= 1 | issue= 3 | pages= 161-4 | pmid=11833854 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11833854  }} </ref>
In a study of 154 patients categorized according to different types of abdominal surgeries, surgeries that did not include entering the abdominal cavity did not reveal elevation in D-dimer.  In contrast, approximately 44% of open and laparoscopic intra-abdominal and retroperitoneal (and liver) surgeries were associated with elevated D-dimer levels that normalized after 25 and 38 days post-operatively respectively.  D-dimer was found to generally peak around day 7 post-operation. The right time post-operatively to use D-dimer without the effect of the surgery itself is yet to be determined, but believed to be more than 5 weeks following intra-abdominal and retroperitoneal. It is thought that following peak, D-dimer levels decline at a rate of 6% every day.( PMID: 19474701 - Dindo et al. 200).  The length of the surgery was associated with the elevation of D-dimer.  However, no cut-off surgery length is determined.<ref name="pmid19474701">{{cite journal| author=Dindo D, Breitenstein S, Hahnloser D, Seifert B, Yakarisik S, Asmis LM et al.| title=Kinetics of D-dimer after general surgery. | journal=Blood Coagul Fibrinolysis | year= 2009 | volume= 20 | issue= 5 | pages= 347-52 | pmid=19474701 | doi=10.1097/MBC.0b013e32832a5fe6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19474701  }} </ref>
Orthopedic surgeries are also associated with an increase in D-dimer levels. In a study that recruited 78 patients with cemented or hybrid total hip replacement and uncemented total knee replacement. During the first 7 days post-op, D-dimers were significantly elevated particularly on day 1 and 7 post-operatively, showing a double-peak distribution.<ref name="pmid12181657">{{cite journal| author=Shiota N, Sato T, Nishida K, Matsuo M, Takahara Y, Mitani S et al.| title=Changes in LPIA D-dimer levels after total hip or knee arthroplasty relevant to deep-vein thrombosis diagnosed by bilateral ascending venography. | journal=J Orthop Sci | year= 2002 | volume= 7 | issue= 4 | pages= 444-50 | pmid=12181657 | doi=10.1007/s007760200077 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12181657  }} </ref><ref name="pmid18325211">{{cite journal| author=Rafee A, Herlikar D, Gilbert R, Stockwell RC, McLauchlan GJ| title=D-Dimer in the diagnosis of deep vein thrombosis following total hip and knee replacement: a prospective study. | journal=Ann R Coll Surg Engl | year= 2008 | volume= 90 | issue= 2 | pages= 123-6 | pmid=18325211 | doi=10.1308/003588408X261627 | pmc=PMC2443306 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18325211  }} </ref>
===Sickle Cell Disease===
The pathogenesis and clinical manifestations of [[sickle cell disease]] are mostly related to its hypercoagulable sickle-shaped red blood cells that contain phosphatydil [[serine]] moieties that contribute to their thrombogenic nature.  In addition, [[endothelial]] dysfunction, sluggish [[blood]] flow, and increased transit time, all of which are associated with generation of subclinical or clinically relevant [[thrombin]],  are all factors generally augmented in patients with sickle cell disease.  Elevated D-dimer levels is commonly found in up to 68% of homozygous sickle cell disease patients experiencing sickling crises and frequently associated with abnormal chest X-ray (CXR) findings.<ref name="pmid21063468">{{cite journal| author=Dar J, Mughal I, Hassan H, Al Mekki TE, Chapunduka Z, Hassan IS| title=Raised D-dimer levels in acute sickle cell crisis and their correlation with chest X-ray abnormalities. | journal=Ger Med Sci | year= 2010 | volume= 8 | issue=  | pages= Doc25 | pmid=21063468 | doi=10.3205/000114 | pmc=PMC2975260 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21063468  }} </ref><ref name="pmid11719358">{{cite journal| author=Setty BN, Rao AK, Stuart MJ| title=Thrombophilia in sickle cell disease: the red cell connection. | journal=Blood | year= 2001 | volume= 98 | issue= 12 | pages= 3228-33 | pmid=11719358 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11719358  }} </ref>
===Primary Pulmonary Hypertension===
The sensitivity of D-dimer in diagnosing chronic thromboembolic pulmonary hypertension (CTEPH) is low in comparison to its sensitivity in other utilities.  In a study that included 34 patients with CTEPH, the sensitivity of D-dimer in diagnosing CTEPH was only 37%, whereas the specificity was 46%.  Hence, it cannot be used to rule in or rule out CTEPH.<ref name="pmid12426270">{{cite journal| author=Shitrit D, Bendayan D, Bar-Gil-Shitrit A, Huerta M, Rudensky B, Fink G et al.| title=Significance of a plasma D-dimer test in patients with primary pulmonary hypertension. | journal=Chest | year= 2002 | volume= 122 | issue= 5 | pages= 1674-8 | pmid=12426270 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12426270  }} </ref><ref name="pmid19572023">{{cite journal| author=Arunthari V, Burger CD| title=Utility of d-dimer in the diagnosis of patients with chronic thromboembolic pulmonary hypertension. | journal=Open Respir Med J | year= 2009 | volume= 3 | issue=  | pages= 85-9 | pmid=19572023 | doi=10.2174/1874306400903010085 | pmc=PMC2703202 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19572023  }} </ref>
===Liver Disease===
[[Cirrhosis]] is considered a hypercoagulable state due to altered physiology of [[hemostasis]] secondary to the disease due to the physiological role the [[liver]] plays in the synthesis of thrombopoietin and [[coagulation factor]]s,<ref name="pmid20400681">{{cite journal| author=Lisman T, Porte RJ| title=Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. | journal=Blood | year= 2010 | volume= 116 | issue= 6 | pages= 878-85 | pmid=20400681 | doi=10.1182/blood-2010-02-261891 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20400681  }} </ref> decrease in fibrinolytic inhibitors, and reduced clearance of [[tissue plasminogen activator]].<ref name="pmid23396402">{{cite journal| author=Sacerdoti D, Serianni G, Gaiani S, Bolognesi M, Bombonato G, Gatta A| title=Thrombosis of the portal venous system. | journal=J Ultrasound | year= 2007 | volume= 10 | issue= 1 | pages= 12-21 | pmid=23396402 | doi=10.1016/j.jus.2007.02.007 | pmc=PMC3478708 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23396402  }} </ref>  [[Platelet]] dysfunction and thrombocytopenia are frequent in liver cirrhosis, along with prolonged [[prothrombin time]] (PT) and activated partial thromboplastin time (APTT).<ref name="pmid20400681">{{cite journal| author=Lisman T, Porte RJ| title=Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. | journal=Blood | year= 2010 | volume= 116 | issue= 6 | pages= 878-85 | pmid=20400681 | doi=10.1182/blood-2010-02-261891 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20400681  }} </ref>  Elevated D-dimer level is seen in more than 75% of patients with advanced liver disease. Significant elevation correlates with worse liver outcomes, as demonstrated by Child-Pugh classification.  It demonstrates features of [[fibrinolysis]] in these patients when levels are just above 0.2 µg/mL.<ref name="pmid7615203">{{cite journal| author=Violi F, Ferro D, Basili S, Saliola M, Quintarelli C, Alessandri C et al.| title=Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis. | journal=Gastroenterology | year= 1995 | volume= 109 | issue= 2 | pages= 531-9 | pmid=7615203 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7615203  }} </ref><ref name="pmid8423044">{{cite journal| author=Violi F, Ferro D, Basili S, Quintarelli C, Musca A, Cordova C et al.| title=Hyperfibrinolysis resulting from clotting activation in patients with different degrees of cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis. | journal=Hepatology | year= 1993 | volume= 17 | issue= 1 | pages= 78-83 | pmid=8423044 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8423044  }} </ref> In a study that included 188 patients, D-dimer was considered of high specificity in patients with Child-Pugh class A or B, of cut-off values > 0.56 µg/mL and > 1.18 µg/mL respectively; whereas it was highly sensitive in patients with class C with cut-off value > 0.77 µg/mL with lower specificity in this particular class probably due to patients’ advanced state of [[liver]] dysfunction. <ref name="pmid23637275">{{cite journal| author=Zhang DL, Hao JY, Yang N| title=Value of D-dimer and protein S for diagnosis of portal vein thrombosis in patients with liver cirrhosis. | journal=J Int Med Res | year= 2013 | volume= 41 | issue= 3 | pages= 664-72 | pmid=23637275 | doi=10.1177/0300060513483413 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23637275  }} </ref>
D-dimer elevation is notably seen in patients with [[portal vein thrombosis]] (PVT) regardless of  Child-Pugh class, a complication of portal hypertension that affects approximately 0.6-26% of patients with liver cirrhosis in general and approximately 35% of patients with cirrhosis from [[hepatocellular carcinoma]] (HCC).<ref name="pmid23396402">{{cite journal| author=Sacerdoti D, Serianni G, Gaiani S, Bolognesi M, Bombonato G, Gatta A| title=Thrombosis of the portal venous system. | journal=J Ultrasound | year= 2007 | volume= 10 | issue= 1 | pages= 12-21 | pmid=23396402 | doi=10.1016/j.jus.2007.02.007 | pmc=PMC3478708 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23396402  }} </ref>  In patients with worse outcomes of chronic liver disease Child-Pugh class C, D-dimer level of ≥ 0.55 µg/mL was 100% sensitive to diagnose PVT when measured.<ref name="pmid16194685">{{cite journal| author=Fimognari FL, De Santis A, Piccheri C, Moscatelli R, Gigliotti F, Vestri A et al.| title=Evaluation of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis. | journal=J Lab Clin Med | year= 2005 | volume= 146 | issue= 4 | pages= 238-43 | pmid=16194685 | doi=10.1016/j.lab.2005.06.003 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16194685  }} </ref>
===Normal Pregnancy===
===Malignancy===
D-dimer is significantly associated with increased incidence of [[malignancy]]. The younger patient population, especially under 60 years, seem to be of particular concern for overt or occult [[cancer]] forms when D-dimer values are > 4 µg/mL .<ref name="pmid15710574">{{cite journal| author=Schutgens RE, Beckers MM, Haas FJ, Biesma DH| title=The predictive value of D-dimer measurement for cancer in patients with deep vein thrombosis. | journal=Haematologica | year= 2005 | volume= 90 | issue= 2 | pages= 214-9 | pmid=15710574 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15710574  }} </ref>  Data regarding the correlation of malignancy with D-dimer shows that increasing D-dimer values are significantly more associated with malignancy than lower, yet abnormal, values. In patients with D-dimer > 8 µg/mL, the rate of malignancy following an episode of DVT was approximately 50%.<ref name="pmid16464765">{{cite journal| author=Paneesha S, Cheyne E, French K, Delgado J, Borg A, Rose P| title=High D-dimer level at presentation in patients with venous thrombosis is a marker for malignancy. | journal=Haematologica | year= 2005 | volume= 90 | issue= 12 Suppl | pages= ELT08 | pmid=16464765 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16464765  }} </ref>  Similarly, patients with thrombosis who have low D-dimer values < 1 µg/mL are less likely to have an underlying malignancy.<ref name="pmid15175810">{{cite journal| author=Rege KP, Jones S, Day J, Hoggarth CE| title=In proven deep vein thrombosis, a low positive D-Dimer score is a strong negative predictor for associated malignancy. | journal=Thromb Haemost | year= 2004 | volume= 91 | issue= 6 | pages= 1219-22 | pmid=15175810 | doi=10.1267/THRO04061219 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15175810  }} </ref>
According to the Vienna Cancer and Thrombosis Study (CATS) that evaluated 1178 cancer patients, D-dimer was highest at a median of approximately 1.2 µg/mL in pancreatic cancer, followed by 1.08 µg/mL in gastric cancer, then 0.84 µg/mL in [[lung cancer]], 0.81 µg/mL in [[colorectal cancers]].<ref name="pmid22371182">{{cite journal| author=Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O et al.| title=High D-dimer levels are associated with poor prognosis in cancer patients. | journal=Haematologica | year= 2012 | volume= 97 | issue= 8 | pages= 1158-64 | pmid=22371182 | doi=10.3324/haematol.2011.054718 | pmc=PMC3409812 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22371182  }} </ref>  Significant association was also seen with lower D-dimer values and other malignancies, such as brain cancer (0.66 µg/mL), [[lymphoma]]s (0.61 µg/mL), [[prostate cancer]] (0.46 µg/mL) and finally [[breast cancers]] (0.46 µg/mL).<ref name="pmid22371182">{{cite journal| author=Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O et al.| title=High D-dimer levels are associated with poor prognosis in cancer patients. | journal=Haematologica | year= 2012 | volume= 97 | issue= 8 | pages= 1158-64 | pmid=22371182 | doi=10.3324/haematol.2011.054718 | pmc=PMC3409812 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22371182  }} </ref>
===Cardiovascular Diseases===
====Ischemic Heart Disease====
Since D-dimers alterations reflect thrombus turnover, levels are expected to be increased in [[ischemic heart disease]] and [[coronary angina]]. D-dimer levels are significantly associated with a 1.5 fold increase in [[coronary artery disease]] (CAD) and in subclinical [[atherosclerosis]].<ref name="pmid7805229">{{cite journal| author=Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK| title=Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk in Communities Study. | journal=Circulation | year= 1995 | volume= 91 | issue= 2 | pages= 284-90 | pmid=7805229 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7805229  }} </ref>  In patients with CAD, the median D-dimer value was 0.112 µg/mL vs. only 0.0028 µg/mL in patients without CAD.  The positive correlation between D-dimer, [[fibrinogen]], plasma viscosity, and interleukin-6 seem to be of importance in understanding the association of D-dimer with inflammatory products.<ref name="pmid11597948">{{cite journal| author=Koenig W, Rothenbacher D, Hoffmeister A, Griesshammer M, Brenner H| title=Plasma fibrin D-dimer levels and risk of stable coronary artery disease: results of a large case-control study. | journal=Arterioscler Thromb Vasc Biol | year= 2001 | volume= 21 | issue= 10 | pages= 1701-5 | pmid=11597948 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11597948  }} </ref>  The most important value that D-dimer carries is its prediction of future cardiac events in various patient age groups, in both genders, and in patients with known peripheral arterial disease and myocardial infarction.<ref name="pmid9459337">{{cite journal| author=Lowe GD, Yarnell JW, Sweetnam PM, Rumley A, Thomas HF, Elwood PC| title=Fibrin D-dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. | journal=Thromb Haemost | year= 1998 | volume= 79 | issue= 1 | pages= 129-33 | pmid=9459337 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9459337  }} </ref><ref name="pmid11304479">{{cite journal| author=Lowe GD, Yarnell JW, Rumley A, Bainton D, Sweetnam PM| title=C-reactive protein, fibrin D-dimer, and incident ischemic heart disease in the Speedwell study: are inflammation and fibrin turnover linked in pathogenesis? | journal=Arterioscler Thromb Vasc Biol | year= 2001 | volume= 21 | issue= 4 | pages= 603-10 | pmid=11304479 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11304479  }} </ref><ref name="pmid11304480">{{cite journal| author=Folsom AR, Aleksic N, Park E, Salomaa V, Juneja H, Wu KK| title=Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. | journal=Arterioscler Thromb Vasc Biol | year= 2001 | volume= 21 | issue= 4 | pages= 611-7 | pmid=11304480 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11304480  }} </ref><ref name="pmid10073948">{{cite journal| author=Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, Sharrett AR et al.| title=Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. | journal=Arterioscler Thromb Vasc Biol | year= 1999 | volume= 19 | issue= 3 | pages= 493-8 | pmid=10073948 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10073948  }} </ref><ref name="pmid8100915">{{cite journal| author=Fowkes FG, Lowe GD, Housley E, Rattray A, Rumley A, Elton RA et al.| title=Cross-linked fibrin degradation products, progression of peripheral arterial disease, and risk of coronary heart disease. | journal=Lancet | year= 1993 | volume= 342 | issue= 8863 | pages= 84-6 | pmid=8100915 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8100915  }} </ref><ref name="pmid10330382">{{cite journal| author=Moss AJ, Goldstein RE, Marder VJ, Sparks CE, Oakes D, Greenberg H et al.| title=Thrombogenic factors and recurrent coronary events. | journal=Circulation | year= 1999 | volume= 99 | issue= 19 | pages= 2517-22 | pmid=10330382 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10330382  }} </ref>  Despite obvious associations, some still question the use of D-dimer in providing informative or additional clinical data in the diagnosis or management of myocardial ischemia.<ref name="pmid17541763">{{cite journal| author=Lippi G, Filippozzi L, Montagnana M, Salvagno GL, Guidi GC| title=Diagnostic value of D-dimer measurement in patients referred to the emergency department with suspected myocardial ischemia. | journal=J Thromb Thrombolysis | year= 2008 | volume= 25 | issue= 3 | pages= 247-50 | pmid=17541763 | doi=10.1007/s11239-007-0060-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17541763  }} </ref>
In a study by Tataru et al. in 2000 that recruited 1112 male and 299 female patients, the significant association between and previous MI was further emphasized.<ref name="pmid10901512">{{cite journal| author=Tataru MC, Heinrich J, Junker R, Schulte H, von Eckardstein A, Assmann G et al.| title=C-reactive protein and the severity of atherosclerosis in myocardial infarction patients with stable angina pectoris. | journal=Eur Heart J | year= 2000 | volume= 21 | issue= 12 | pages= 1000-8 | pmid=10901512 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10901512  }} </ref>
====Atrial Fibrillation====
D-dimer levels are also elevated in patients with [[atrial fibrillation]] (AF), especially in those who are known to have established several embolism risk factors.<ref name="pmid17716992">{{cite journal| author=Cohen A, Ederhy S, Meuleman C, Di Angelantonio E, Dufaitre G, Boccara F| title=D-dimers in atrial fibrillation: a further step in risk stratification of thrombo-embolism? | journal=Eur Heart J | year= 2007 | volume= 28 | issue= 18 | pages= 2179-80 | pmid=17716992 | doi=10.1093/eurheartj/ehm170 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17716992  }} </ref>  In 2003, Somloi et al. measured D-dimer levels in 73 patients with AF prior to TEE-guided cardioversion; they concluded that although D-dimer is unspecific, D-dimer concentration < 0.06 µg/ml provides a negative predictive value of 98%.<ref name="pmid12842257">{{cite journal| author=Somlói M, Tomcsányi J, Nagy E, Bodó I, Bezzegh A| title=D-dimer determination as a screening tool to exclude atrial thrombi in atrial fibrillation. | journal=Am J Cardiol | year= 2003 | volume= 92 | issue= 1 | pages= 85-7 | pmid=12842257 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12842257  }} </ref>  Habara et al. concluded that D-dimer concentration of 0.115 µg/mL was an optimal cut-off value to detect left atrial appendange (LAA) thrombus; the NPV was 97% irrespective of co-morbidities, such as [[congestive heart failure]], or [[stroke]].<ref name="pmid17716992">{{cite journal| author=Cohen A, Ederhy S, Meuleman C, Di Angelantonio E, Dufaitre G, Boccara F| title=D-dimers in atrial fibrillation: a further step in risk stratification of thrombo-embolism? | journal=Eur Heart J | year= 2007 | volume= 28 | issue= 18 | pages= 2179-80 | pmid=17716992 | doi=10.1093/eurheartj/ehm170 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17716992  }} </ref>  Even in AF patients receiving appropriate Warfarin anticoagulation therapy, D-dimer levels remained abnormally high.<ref name="pmid15992948">{{cite journal| author=Nozawa T, Inoue H, Hirai T, Iwasa A, Okumura K, Lee JD et al.| title=D-dimer level influences thromboembolic events in patients with atrial fibrillation. | journal=Int J Cardiol | year= 2006 | volume= 109 | issue= 1 | pages= 59-65 | pmid=15992948 | doi=10.1016/j.ijcard.2005.05.049 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15992948  }} </ref>
It was further found that AF patients with D-dimer levels > 0.15 µg/mL were at a significantly greater risk of thrombo-embolic events than other patient subgroups. As such, the level 0.15 µg/mL is currently considered an accepted threshold value for increased rate of thrombo-embolic events in patients with AF.  Nonetheless, increased number of risk factors bypasses the importance of D-dimer in AF patients and thus, patients with multiple risk factors are at high risk of thrombo-embolic events regardless of D-dimer levels and anticoagulation therapy. As such, D-dimer alone in patients with AF must be coupled to clinical risk factors for adequate assessment of thrombo-embolic risk.<ref name="pmid15992948">{{cite journal| author=Nozawa T, Inoue H, Hirai T, Iwasa A, Okumura K, Lee JD et al.| title=D-dimer level influences thromboembolic events in patients with atrial fibrillation. | journal=Int J Cardiol | year= 2006 | volume= 109 | issue= 1 | pages= 59-65 | pmid=15992948 | doi=10.1016/j.ijcard.2005.05.049 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15992948  }} </ref>
According to Diego et al., elevated D-dimer level is significantly associated with increasing severity of atherosclerosis based on ultrasound detection of carotid plaques and overall cardiovascular decline.<ref name="pmid12871360">{{cite journal| author=de Maat MP, Bladbjerg EM, Drivsholm T, Borch-Johnsen K, Møller L, Jespersen J| title=Inflammation, thrombosis and atherosclerosis: results of the Glostrup study. | journal=J Thromb Haemost | year= 2003 | volume= 1 | issue= 5 | pages= 950-7 | pmid=12871360 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12871360  }} </ref><ref name="pmid12637131">{{cite journal| author=Cohen HJ, Harris T, Pieper CF| title=Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. | journal=Am J Med | year= 2003 | volume= 114 | issue= 3 | pages= 180-7 | pmid=12637131 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12637131  }} </ref>
===Stroke===
Elevated D-dimer values can also be used to predict acute cerebrovascular events and subtypes.  Levels increase remarkably during first 6 hours of [[stroke]] onset in patients with large occlusion and those being treated with intravenous [[thrombolytic]]s regardless of time of artery recanalization.<ref name="pmid19568692">{{cite journal| author=Skoloudík D, Bar M, Sanák D, Bardon P, Roubec M, Langová K et al.| title=D-dimers increase in acute ischemic stroke patients with the large artery occlusion, but do not depend on the time of artery recanalization. | journal=J Thromb Thrombolysis | year= 2010 | volume= 29 | issue= 4 | pages= 477-82 | pmid=19568692 | doi=10.1007/s11239-009-0372-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19568692  }} </ref>  D-dimer seems to have shown association with infarction volume<ref name="pmid22053225">{{cite journal| author=Park YW, Koh EJ, Choi HY| title=Correlation between Serum D-Dimer Level and Volume in Acute Ischemic Stroke. | journal=J Korean Neurosurg Soc | year= 2011 | volume= 50 | issue= 2 | pages= 89-94 | pmid=22053225 | doi=10.3340/jkns.2011.50.2.89 | pmc=PMC3206284 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22053225  }} </ref> and with cardioembolic strokes but not atherothrombotic or lacunar strokes.  According to Ageno et al. in 2002, the optimal D-dimer cut-off point for predicting cardioembolic [[stroke]] is 2 µg/mL with 93.2% specificity and 59.3% sensitivity.  In contrast, the cut-off point for predicting lacunar stroke in the same study was 0.54  µg/mL with 96.2% specificity and 61.3% [[sensitivity]].<ref name="pmid12456231">{{cite journal| author=Ageno W, Finazzi S, Steidl L, Biotti MG, Mera V, Melzi D'Eril G et al.| title=Plasma measurement of D-dimer levels for the early diagnosis of ischemic stroke subtypes. | journal=Arch Intern Med | year= 2002 | volume= 162 | issue= 22 | pages= 2589-93 | pmid=12456231 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12456231  }} </ref>  Although it is suggested as a screening test for patients presenting with acute-onset [[headache]]s,<ref name="pmid16302160">{{cite journal| author=Squizzato A, Ageno W| title=D-dimer testing in ischemic stroke and cerebral sinus and venous thrombosis. | journal=Semin Vasc Med | year= 2005 | volume= 5 | issue= 4 | pages= 379-86 | pmid=16302160 | doi=10.1055/s-2005-922484 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16302160  }} </ref>  triage for high-risk patients who require antithrombotic therapy, and evaluating progressing strokes, defined by clinical worsening of symptoms following admission, the prognostic role of D-dimer in cases of strokes is unclear and yet to be determined.<ref name="pmid16527998">{{cite journal| author=Barber M, Langhorne P, Rumley A, Lowe GD, Stott DJ| title=D-dimer predicts early clinical progression in ischemic stroke: confirmation using routine clinical assays. | journal=Stroke | year= 2006 | volume= 37 | issue= 4 | pages= 1113-5 | pmid=16527998 | doi=10.1161/01.STR.0000209240.63821.1a | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16527998  }} </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>==
===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>===
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''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. ''([[European society of cardiology#Level of Evidence|Level of Evidence: A]])'' <nowiki>"</nowiki>
|}
====Low Clinical Probability (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>====
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Normal D-dimer level using either a highly or moderately sensitive assay excludes pulmonary embolism. ''([[European society of cardiology#Level of Evidence|Level of Evidence: A]])'' <nowiki>"</nowiki>
|}
====Intermediate Clinical Probability (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>====
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Normal D-dimer level using a highly sensitive assay excludes pulmonary embolism. ''([[European society of cardiology#Level of Evidence|Level of Evidence: A]])'' <nowiki>"</nowiki>
|}
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[European society of cardiology#Classes of Recommendations|Class IIa]]
|-
|bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Further testing should be considered if D-dimer level is normal when using a less sensitive assay. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])'' <nowiki>"</nowiki>
|}
====High Clinical Probability (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>====
{|class="wikitable"
|-
|colspan="1" style="text-align:center; background:LightCoral"|[[European society of cardiology#Classes of Recommendations|Class III]]
|-
|bgcolor="LightCoral"|<nowiki>"</nowiki>'''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. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])'' <nowiki>"</nowiki>
|}
==References==
{{reflist|2}}


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Latest revision as of 12:53, 9 May 2014

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]


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