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{{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:<ref name="pmid22494827">{{cite journal| author=Goldhaber SZ, Bounameaux H| title=Pulmonary embolism and deep vein thrombosis. | journal=Lancet | year= 2012 | volume= 379 | issue= 9828 | pages= 1835-46 | pmid=22494827 | doi=10.1016/S0140-6736(11)61904-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22494827  }} </ref> the degree to which the d-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in your clinical setting: most available d-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
** If the D-dimer reads high, then further testing ([[medical ultrasonography|ultrasound]] of the leg veins or lung [[scintigraphy]] or [[CTPA|CT scanning]]) is required to confirm the presence of [[thrombus]].  [[Anticoagulant]] therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation. 
In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high-probability.<ref>{{cite journal |last=Rathbun |first=SW |coauthors=TL Whitsett, SK Vesely, GE Raskob |year=2004 |title=Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings |journal=Chest |issue=125 |pages=851 |accessdate= 2007-11-17}}</ref>
===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><ref name="pmid15096330">{{cite journal| author=Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R et al.| title=D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. | journal=Ann Intern Med | year= 2004 | volume= 140 | issue= 8 | pages= 589-602 | pmid=15096330 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15096330  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15518461 Review in: ACP J Club. 2004 Nov-Dec;141(3):77] </ref><ref name="pmid20926499">{{cite journal| author=Bounameaux H, Perrier A, Righini M| title=Diagnosis of venous thromboembolism: an update. | journal=Vasc Med | year= 2010 | volume= 15 | issue= 5 | pages= 399-406 | pmid=20926499 | doi=10.1177/1358863X10378788 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20926499  }} </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>
* Among 292 hemodynamically stable patients with [[PE]], a D-dimer < 5000 was associated with no in-hospital mortality from PE (0 of 222) while a D-dimer > 5000 ng/mL was associated with a in-hospital mortality from PE of 2.9% (2 of 70)(p = 0.06).<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===
The recurrence rate within the first few months following a first episode of [[VTE]] is not negligeable.  In fact, it is estimated to be around 6% at 6 months following the first episode.<ref name="pmid12814979">{{cite journal| author=White RH| title=The epidemiology of venous thromboembolism. | journal=Circulation | year= 2003 | volume= 107 | issue= 23 Suppl 1 | pages= I4-8 | pmid=12814979 | doi=10.1161/01.CIR.0000078468.11849.66 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12814979  }} </ref> Hence, the duration of treatment with oral anticoagulation therapy must be enough to decrease the risk of recurrence and at the same time not too long to cause bleeding complications.  The prognostic role of D-dimer in predicting the rate of recurrence of [[VTE]] has been extensively studied.  The different studies seem to be consistent as their findings revealed an association between the D-dimer level and the rate of recurrence of [[VTE]]; hence, they suggest a possible role for D-dimer in tailoring the duration of treatment of oral anticoagulation following [[VTE]].<ref name="pmid19228602">{{cite journal| author=Zhu T, Martinez I, Emmerich J| title=Venous thromboembolism: risk factors for recurrence. | journal=Arterioscler Thromb Vasc Biol | year= 2009 | volume= 29 | issue= 3 | pages= 298-310 | pmid=19228602 | doi=10.1161/ATVBAHA.108.182428 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19228602  }} </ref>
* D-dimer seems to have a good prognostic role in predicting recurrence of thromboembolism.  According to the 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-dimer 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.  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>  It is important to note that the predictive value of D-dimer for recurrence of thromboembolic events depends on the time of discontinuation of oral anticoagulant as the oral anticoagulant affects D-dimer by decreasing its level; hence, the prognostic role of D-dimer is best at least a month following discontinuation of the oral anticoagulation therapy.  For instance, in this same study the percentages of patients who had abnormal D-dimer levels were 15.6%, 40.3% and 40.6% at the time of therapy discontinuation, after one month and after three months respectively.  In addition, the predictive value of D-dimer is valid in idiopathic cases of thromboembolism and not in the context of cancer or predisposing risk factors.<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>
* The predictive value of D-dimer in predicting recurrence of [[VTE]] was also investigated by Palareti and colleagues in a study involving 396 patients treated with oral anticoagulant therapy after a first episode of [[VTE]].  Patients were followed up for 21 months after discontinuation of oral anticoagulation.  The negative predictive value of D-dimer 3 months after the discontinuation of  oral anticoagulation was reported to be 95.6% (CI=95%).<ref name="pmid11848459">{{cite journal| author=Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S| title=Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. | journal=Thromb Haemost | year= 2002 | volume= 87 | issue= 1 | pages= 7-12 | pmid=11848459 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11848459  }} </ref>  Palareti et al conducted a prospective cohort study of 610 patients who suffered from their first spontaneous episode of [[VTE]]. Patients who had a D-dimer level less than 250 ng/ml had 60% less relative risk of recurrence of [[VTE]] compared to patients having higher D-dimer levels (RR=0.4; CI=95%).  The 610 patients were followed up and their D-dimer levels were measured after the discontinuation of their treatment with oral anticoagulation which had lasted for at least 3 months. The follow up period was done at a 3 months interval for the first year and at a 6 months interval for 10 years.<ref name="pmid12941680">{{cite journal| author=Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B et al.| title=D-dimer levels and risk of recurrent venous thromboembolism. | journal=JAMA | year= 2003 | volume= 290 | issue= 8 | pages= 1071-4 | pmid=12941680 | doi=10.1001/jama.290.8.1071 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12941680  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15122870 Review in: ACP J Club. 2004 Mar-Apr;140(2):50]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14709262 Review in: J Fam Pract. 2004 Jan;53(1):20, 23] </ref>  Palareti et al also investigated the predictive role of D-dimer in recuurent [[VTE]] after the discontinuation of oral anticoagulant in patients with idiopathic thromboembolic events and in patients with inherited thrombophilia.  The results of this study revealed that the D-dimer measured one month after discontinuation of oral anticoagulant has a high predictive balue for recurrence of [[VTE]] in subjects with and without inherited thrombophilia.<ref name="pmid12847064">{{cite journal| author=Palareti G, Legnani C, Cosmi B, Valdré L, Lunghi B, Bernardi F et al.| title=Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. | journal=Circulation | year= 2003 | volume= 108 | issue= 3 | pages= 313-8 | pmid=12847064 | doi=10.1161/01.CIR.0000079162.69615.0F | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12847064  }} </ref>  Palareti et al not only proved the role of D-dimer as a prognostic factor for recurrence of [[VTE]], but also further investigated the use of D-dimer to tailor the duration of oral anticoagulation to minimize the risk of recurrence.<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>
* Tosetto and colleagues evaluated the use of the DASH score in predicting the rate of recurrence of [[VTE]] in patients who recieved at least 3 months of anticoagulation following a first episode of [[VTE]].  The DASH score includes D-dimer, age and hormonal therapy.  The recurrence rates were reported as follows:
** Score ≤ 1: 3.1% (95% confidence interval [CI], 2.3-3.9)
** Score=2: 6.4% (95% CI, 4.8-7.9)
** Score ≥ 3: 12.3% (95% CI, 9.9-14.7)<ref name="pmid22489957">{{cite journal| author=Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S et al.| title=Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). | journal=J Thromb Haemost | year= 2012 | volume= 10 | issue= 6 | pages= 1019-25 | pmid=22489957 | doi=10.1111/j.1538-7836.2012.04735.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22489957  }} </ref>
* The annual rates of recurrence of [[VTE]] in patients treated with anticoagulant after their first episode of [[VTE]] were reported to be 3.5% (CI, 2.7% to 4.3%) and 8.9% (95% CI, 5.8% to 11.9%) in patients with negative D-dimer and patients with positive D-dimer respectively.  These results were based on a systematic analysis of 7 studies involving a total of 1888 patients who received oral anticoagualtion therapy for at least 3 months and were followed up for two years thereafter.<ref name="pmid18838728">{{cite journal| author=Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T et al.| title=Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. | journal=Ann Intern Med | year= 2008 | volume= 149 | issue= 7 | pages= 481-90, W94 | pmid=18838728 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18838728  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19332615 Review in: Evid Based Med. 2009 Apr;14(2):59]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19238612 Review in: Ann Intern Med. 2009 Feb 17;150(4):JC2-14] </ref>
* Another study investigated the predictive value of D-dimer for recurrence of [[VTE]] by following up 204 patients diagnosed with their first episode of [[VTE]].  Follow up was done after 3 months, 6 months, 12 months and then yearly.  D-dimer was found to have a high [[negative predictive value]] of 94.2% and 92.2% in all studied patients and in patients with unprovoked VTE respectively.  D-dimer was an independent predictor of recurrent [[VTE]] especially in the population of patients with unprovoked VTE (Hazard ratio=4.61; CI=95%; p=0.001).<ref name="pmid21847593">{{cite journal| author=Wang Y, Liu ZH, Zhang HL, Luo Q, Zhao ZH, Zhao Q| title=Predictive value of D-dimer test for recurrent venous thromboembolism at hospital discharge in patients with acute pulmonary embolism. | journal=J Thromb Thrombolysis | year= 2011 | volume= 32 | issue= 4 | pages= 410-6 | pmid=21847593 | doi=10.1007/s11239-011-0625-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21847593  }} </ref>
* A study conducted in Bologna evaluated the predictive value for recurrence of [[VTE]] of D-dimer in combination with residual venous obstruction (RVO) assessed by compression [[ultrasound]] in 400 patients 30 days (+/- 10 days) following after the discontinuation of oral anticoagulation.  Elevated levels of D-dimer more than 500 ng/ml were found to be an independent risk factor for the recurrence of [[VTE]].  The detailed results about the recurrence rates were as follows:
** Normal D-dimer without RVO: 5.7% (95% CI:2-13%)
** Normal D-dimer with RVO: 10.4% (95% CI:6-18%)
** Abnormal D-dimer without RVO: 22.9% (95% CI: 14-33%)
** Abnormal D-dimer with RVO: 25.9% (95% CI: 18-35%)<ref name="pmid16363238">{{cite journal| author=Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G| title=D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. | journal=Thromb Haemost | year= 2005 | volume= 94 | issue= 5 | pages= 969-74 | pmid=16363238 | doi=10.1160/TH05-02-0095 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16363238  }} </ref>
* D-dimer levels were evaluated in 152 patients following oral anticoagulation treatment for [[VTE]].  D-dimer levels were measured at the time of discontinuation of the treatment, after one week, after one month and after 3 months.  The D-dimer levels were elevated at the time of discontinuation in 70% of the subjects, 80% of which sustained a high D-dimer after a week. The percentage of subjects with elevated D-dimer decreased to 30% after a month and to 13% after 3 months.  Seven out of the 152 subjects developed recurrent [[VTE]] and all of them has a persistently high D-dimer levels.<ref name="pmid12574808">{{cite journal| author=Kuruvilla J, Wells PS, Morrow B, MacKinnon K, Keeney M, Kovacs MJ| title=Prospective assessment of the natural history of positive D-dimer results in persons with acute venous thromboembolism (DVT or PE). | journal=Thromb Haemost | year= 2003 | volume= 89 | issue= 2 | pages= 284-7 | pmid=12574808 | doi=10.1267/THRO03020284 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12574808  }} </ref>
* Further studies evaluated the prognostic role of D-dimer and factor VIII coagulant in the recurrence of [[VTE]] and lead to results consistent with previous studies.  In fact, the Prevention of Recurrent Venous Thromboembolism trial evaluated 508 subjects who received anticoagulation therapy for at least three months following idiopathic [[VTE]] and followed them up for any [[VTE]] recurrence for more than 2 years.  The results of this study revealed an association between recurrence of [[VTE]] and elevated level of D-dimer (>500ng/ml), and not elevated levels of factor VIII coagulant (> or = 150 IU dL).  The hazard ratio of recurrent [[VTE]] with elevated D-dimer was reported to be  2.0 (1.2-3.4; CI=95%).  This association was significant among subjects having their first episode of [[VTE]].  The annual rates of recurrence of [[VTE]] are summarized as follows:
** Elevated level of D-dimer:  10.9%
** Normal level of D-dimer: 2.9%<ref name="pmid16706961">{{cite journal| author=Shrivastava S, Ridker PM, Glynn RJ, Goldhaber SZ, Moll S, Bounameaux H et al.| title=D-dimer, factor VIII coagulant activity, low-intensity warfarin and the risk of recurrent venous thromboembolism. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 6 | pages= 1208-14 | pmid=16706961 | doi=10.1111/j.1538-7836.2006.01935.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16706961  }} </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>
===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>
===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>
According to a prospective study and metaanalysis, D-dimers level were found to correlate with [[CAD]] with an odds ratio of 1.67 (95% CI, 1.31 to 2.13; P<0.0001).<ref name="pmid11352877">{{cite journal| author=Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P et al.| title=Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. | journal=Circulation | year= 2001 | volume= 103 | issue= 19 | pages= 2323-7 | pmid=11352877 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11352877  }} </ref>  This finding can be explained by the fact that [[CAD]] might be associated with activation of the [[coagulation cascade]] and increased [[fibrin]] turnover.<ref name="pmid10605766">{{cite journal| author=Lowe GD, Rumley A| title=Use of fibrinogen and fibrin D-dimer in prediction of arterial thrombotic events. | journal=Thromb Haemost | year= 1999 | volume= 82 | issue= 2 | pages= 667-72 | pmid=10605766 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10605766  }} </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>
===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 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>
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>
===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>
In a different study investigating endothelial, platelet and coagulation factors activation, patients with [[multiple myeloma]] undergoing treatment were found to have elevated D-fimers.  In fact, 3 out of 4 patients who had elevated D-dimer levels beyond 500 mg/L developed [[DVT]].  Hence, D-dimer might play a role in stratifying patients with multiple myeloma who are at high risk of [[DVT]].<ref name="pmid15777340">{{cite journal| author=Streetly M, Hunt BJ, Parmar K, Jones R, Zeldis J, Schey S| title=Markers of endothelial and haemostatic function in the treatment of relapsed myeloma with the immunomodulatory agent Actimid (CC-4047) and their relationship with venous thrombosis. | journal=Eur J Haematol | year= 2005 | volume= 74 | issue= 4 | pages= 293-6 | pmid=15777340 | doi=10.1111/j.1600-0609.2004.00393.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15777340  }} </ref>
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>
===Normal Pregnancy===
It is well known that physiological changes in the hypercoagulable state of normal pregnancy include alterations in coagulation and fibrinolysis systems. Pregnant women are at increased risk of VTE, and consumptive coagulopathies, such as [[DIC]]. D-dimer levels gradually increase in [[pregnancy]] and are believed to reach their peak values on day one post-partum, after which steady decline is observed to reach normal pre-pregnancy values approximately 42 days after delivery.<ref name="pmid23954836">{{cite journal| author=Wang M, Lu S, Li S, Shen F| title=Reference intervals of D-dimer during the pregnancy and puerperium period on the STA-R evolution coagulation analyzer. | journal=Clin Chim Acta | year= 2013 | volume= 425C | issue=  | pages= 176-180 | pmid=23954836 | doi=10.1016/j.cca.2013.08.006 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23954836  }} </ref>  D-dimer surpasses normal range of 0.5 µg/mL in pregnant women starting the first trimester; where 79- 84% of pregnant women have normal D-dimer levels in the first trimester.  This percentage declines to reach 22-33% in the second trimester, and only 0-1% in the third trimester.  When studying D-dimer levels in 89 healthy pregnant women, Kovac and colleagues proposed in 2010 a new threshold of D-dimer levels for pregnancy to rule out VTE.  They suggested D-dimer cut-off values of 0.286 µg/mL, 0.457 µg/mL, and 0.644 µg/mL in pregnant women in their first, second and third trimesters, respectively.<ref name="pmid15764641">{{cite journal| author=Kline JA, Williams GW, Hernandez-Nino J| title=D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. | journal=Clin Chem | year= 2005 | volume= 51 | issue= 5 | pages= 825-9 | pmid=15764641 | doi=10.1373/clinchem.2004.044883 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15764641  }} </ref><ref name="pmid19804940">{{cite journal| author=Kovac M, Mikovic Z, Rakicevic L, Srzentic S, Mandic V, Djordjevic V et al.| title=The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. | journal=Eur J Obstet Gynecol Reprod Biol | year= 2010 | volume= 148 | issue= 1 | pages= 27-30 | pmid=19804940 | doi=10.1016/j.ejogrb.2009.09.005 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19804940  }} </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>
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>
===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>
* 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>
===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>
===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>
===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>
==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}}


[[Category:Laboratory Test]]
[[Category:Laboratory Test]]

Latest revision as of 12:53, 9 May 2014

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