D-dimer

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Editor(s)-In-Chief: C. Michael Gibson, M.S., M.D. [1], The APEX Trial Investigators; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

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 (CHF), myocardial infarction (MI) and malignancy. False-negative values may occur in patients with prolonged symptoms of venous thromboembolism (≥14 days), patients on therapeutic 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.[1][2]

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

Fibrin degradation products (FDPs) are formed whenever fibrin is broken down by enzymes (e.g. 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.

Plasmin is a 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.

Principles of D-dimer testing


D-Dimer Test

D-dimer assays rely on 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:[3]
    • A negative D-dimer test will virtually rule out thromboembolism: the degree to which the d-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in your clinical setting: most available d-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%
    • If the D-dimer reads high, then further testing (ultrasound of the leg veins or lung scintigraphy or CT scanning) is required to confirm the presence of thrombus. Anticoagulant therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation.

In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This would reduce the need for unnecessary tests in those who are high-probability.[4]

Reference Range

Most sampling kits have 0-300 ng/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.[5][6][7]

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.[8]

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

Plasma D-dimer levels > 500 ng/mL are abnormal.[9]

Sensitivity and Specificity

Sensitivity[9]

ELISA (p=0.020), quantitative rapid ELISA (p=0.016) and semi-quantitative ELISA (p=0.047) are shown to be statistically superior to whole-blood agglutination.

Specificity[9]

Qualitative rapid ELISA has shown to be statistically superior to ELISA (p=0.004), quantitative rapid ELISA (p=0.002), semi-quantitative rapid ELISA (p=0.001), quantitative (p=0.005) and semi-quantitative latex agglutination assays (p=0.019).


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

Hemodynamically Stable Patients

Incidence of Thromboembolic Events in Hemodynamically Stable Patients

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

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

 
 
 
Patients with suspection of Pulmonary embolism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically Low or Moderate
 
 
 
 
Clinically High
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer Positive
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D-Dimer Negative
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No treatment
 
Further Tests
 
Further Tests


A new D-Dimer (DDMR) analyzer has shown to be more accurate in excluding patients with a low clinical pre-test probability.[14]

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.[15]
  • 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.[16]
  • 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.[17]
  • 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 with higher risk of major bleeding.[18]
  • The prognostic role of D-dimer in hemodynamically stable patients does not have a solid ground. In fact, mixed results are present regarding the association between D-dimer and mortality. According to a study conducted on 292 stable patients with PE, high levels of D-dimer more than 5000 ng/mL were not associated with a higher mortality.[19]

Recurrence of Thromboembolism

  • D-dimer seems to have a good prognostic role in predicting recurrence of thromboembolism. According to PROLONG study, normal levels of D-dimers 1 month following discontinuation of anticoagulation were associated with a decreased level of thromboembolism recurrences.[20]
  • PROLONG II study investidated the association between the levels of D-dimers more than one month after anticoagulation suspension for unprovoked venous thromboembolism. The results of this study showed that patients who have high levels of D-dimers at 3 months after anticoagulation suspension have higher thromboembolism recurrences risks than patients who have normal levels of D-dimers. Hence, these studies suggest that the measurement of D-dimer levels at several months intervals following anticoagulation suspension in patient suffering from a first episode of VTE might be beneficial in triaging patients and targeting their therapies.[19]

Sepsis and Mortality

  • 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.[21]

D-Dimer and Non Thromboembolism Conditions

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.[22]

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%.[23]

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,[24] 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.[25] Nevertheless, the increase of hemostatic markers, such as D-dimer in renal disease, are considered risk factors for VTE in patients with renal disease.[26]

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.[27][28][25]

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.[29][30][31]

Surgery

Sickle Cell Disease

ESC 2008 Guideline Recommendations [32]

Suspected Non High-risk PE Patients (DO NOT EDIT)[32]

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

Low Clinical Probability (DO NOT EDIT)[32]

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

Intermediate Clinical Probability (DO NOT EDIT)[32]

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

High Clinical Probability (DO NOT EDIT)[32]

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

References

  1. ↑ Bruinstroop E, van de Ree MA, Huisman MV (2009). "The use of D-dimer in specific clinical conditions: a narrative review". Eur J Intern Med. 20 (5): 441–6. doi:10.1016/j.ejim.2008.12.004. PMID 19712840.
  2. ↑ Agnelli G, Becattini C (2010). "Acute pulmonary embolism". N Engl J Med. 363 (3): 266–74. doi:10.1056/NEJMra0907731. PMID 20592294.
  3. ↑ Wells PS, Anderson DR, Rodger M; et al. (2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". N. Engl. J. Med. 349 (13): 1227–35. doi:10.1056/NEJMoa023153. PMID 14507948.
  4. ↑ Rathbun, SW (2004). "Clinical utility of D-dimer in patients with suspected pulmonary embolism and nondiagnostic lung scans or negative CT findings". Chest (125): 851. Unknown parameter |coauthors= ignored (help); |access-date= requires |url= (help)
  5. ↑ Schouten HJ, Geersing GJ, Koek HL, Zuithoff NP, Janssen KJ, Douma RA; et al. (2013). "Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis". BMJ. 346: f2492. doi:10.1136/bmj.f2492. PMC 3643284. PMID 23645857.
  6. ↑ van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T; et al. (2012). "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". Thromb Haemost. 107 (1): 167–71. doi:10.1160/TH11-08-0587. PMID 22072293.
  7. ↑ Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A; et al. (2010). "Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts". BMJ. 340: c1475. doi:10.1136/bmj.c1475. PMID 20354012.
  8. ↑ 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.
  9. ↑ 9.0 9.1 9.2 Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK (2004). "D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review". Annals of Internal Medicine. 140 (8): 589–602. PMID 15096330. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  10. ↑ 10.0 10.1 Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL; et al. (2005). "Multidetector-row computed tomography in suspected pulmonary embolism". N Engl J Med. 352 (17): 1760–8. doi:10.1056/NEJMoa042905. PMID 15858185. in: J Fam Pract. 2005 Aug;54(8):653, 657
  11. ↑ 11.0 11.1 van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW; et al. (2006). "Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography". JAMA. 295 (2): 172–9. doi:10.1001/jama.295.2.172. PMID 16403929.
  12. ↑ Gupta RT, Kakarla RK, Kirshenbaum KJ, Tapson VF (2009). "D-dimers and efficacy of clinical risk estimation algorithms: sensitivity in evaluation of acute pulmonary embolism". AJR Am J Roentgenol. 193 (2): 425–30. doi:10.2214/AJR.08.2186. PMID 19620439.
  13. ↑ Bounameaux H, de Moerloose P, Perrier A, Reber G (1994). "Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview". Thromb. Haemost. 71 (1): 1–6. PMID 8165626.
  14. ↑ Gosselin RC, Wu JR, Kottke-Marchant K, Peetz D, Christie DJ, Muth H; et al. (2012). "Evaluation of the Stratus® CS Acute Care™ D-dimer assay (DDMR) using the Stratus® CS STAT Fluorometric Analyzer: A prospective multisite study for exclusion of pulmonary embolism and deep vein thrombosis". Thromb Res. doi:10.1016/j.thromres.2011.12.015. PMID 22245223.
  15. ↑ Sanchez O, Planquette B, Roux A, Gosset-Woimant M, Meyer G (2012). "Triaging in pulmonary embolism". Semin Respir Crit Care Med. 33 (2): 156–62. doi:10.1055/s-0032-1311794. PMID 22648488.
  16. ↑ Aujesky D, Roy PM, Guy M, Cornuz J, Sanchez O, Perrier A (2006). "Prognostic value of D-dimer in patients with pulmonary embolism". Thromb Haemost. 96 (4): 478–82. PMID 17003925.
  17. ↑ Klok FA, Djurabi RK, Nijkeuter M, Eikenboom HC, Leebeek FW, Kramer MH; et al. (2008). "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". Br J Haematol. 140 (2): 218–22. doi:10.1111/j.1365-2141.2007.06888.x. PMID 18028485.
  18. ↑ Lobo JL, Zorrilla V, Aizpuru F, Grau E, Jiménez D, Palareti G; et al. (2009). "D-dimer levels and 15-day outcome in acute pulmonary embolism. Findings from the RIETE Registry". J Thromb Haemost. 7 (11): 1795–801. doi:10.1111/j.1538-7836.2009.03576.x. PMID 19691481.
  19. ↑ 19.0 19.1 Stein PD, Janjua M, Matta F, Alrifai A, Jaweesh F, Chughtai HL (2011). "Prognostic value of D-dimer in stable patients with pulmonary embolism". Clin Appl Thromb Hemost. 17 (6): E183–5. doi:10.1177/1076029610395129. PMID 21288930.
  20. ↑ Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A; et al. (2006). "D-dimer testing to determine the duration of anticoagulation therapy". N Engl J Med. 355 (17): 1780–9. doi:10.1056/NEJMoa054444. PMID 17065639. Review in: ACP J Club. 2007 Mar-Apr;146(2):29 Review in: Evid Based Med. 2007 Apr;12(2):45
  21. ↑ Rodelo JR, De la Rosa G, Valencia ML, Ospina S, Arango CM, Gómez CI; et al. (2012). "D-dimer is a significant prognostic factor in patients with suspected infection and sepsis". Am J Emerg Med. 30 (9): 1991–9. doi:10.1016/j.ajem.2012.04.033. PMID 22795996.
  22. ↑ Der Sahakian G, Claessens YE, Allo JC, Kansao J, Kierzek G, Pourriat JL (2010). "Accuracy of D-Dimers to Rule Out Venous Thromboembolism Events across Age Categories". Emerg Med Int. 2010: 185453. doi:10.1155/2010/185453. PMC 3195346. PMID 22046531.
  23. ↑ Sodeck G, Domanovits H, Schillinger M, Ehrlich MP, Endler G, Herkner H; et al. (2007). "D-dimer in ruling out acute aortic dissection: a systematic review and prospective cohort study". Eur Heart J. 28 (24): 3067–75. doi:10.1093/eurheartj/ehm484. PMID 17986466.
  24. ↑ Shlipak MG, Fried LF, Stehman-Breen C, Siscovick D, Newman AB (2004). "Chronic renal insufficiency and cardiovascular events in the elderly: findings from the Cardiovascular Health Study". Am J Geriatr Cardiol. 13 (2): 81–90. PMID 15010654.
  25. ↑ 25.0 25.1 Sexton DJ, Clarkson MR, Mazur MJ, Plant WD, Eustace JA (2012). "Serum D-dimer concentrations in nephrotic syndrome track with albuminuria, not estimated glomerular filtration rate". Am J Nephrol. 36 (6): 554–60. doi:10.1159/000345475. PMID 23221061.
  26. ↑ Dubin R, Cushman M, Folsom AR, Fried LF, Palmas W, Peralta CA; et al. (2011). "Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis". BMC Nephrol. 12: 3. doi:10.1186/1471-2369-12-3. PMC 3037849. PMID 21269477.
  27. ↑ Chen TY, Huang CC, Tsao CJ (1993). "Hemostatic molecular markers in nephrotic syndrome". Am J Hematol. 44 (4): 276–9. PMID 8238000.
  28. ↑ Singhal R, Brimble KS (2006). "Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management". Thromb Res. 118 (3): 397–407. doi:10.1016/j.thromres.2005.03.030. PMID 15990160.
  29. ↑ Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A; et al. (2001). "Efficacy and safety of recombinant human activated protein C for severe sepsis". N Engl J Med. 344 (10): 699–709. doi:10.1056/NEJM200103083441001. PMID 11236773.
  30. ↑ Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A; et al. (2004). "Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]". Crit Care. 8 (2): R82–90. doi:10.1186/cc2459. PMC 420030. PMID 15025782.
  31. ↑ Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S; et al. (2006). "Severe sepsis and septic shock: review of the literature and emergency department management guidelines". Ann Emerg Med. 48 (1): 28–54. doi:10.1016/j.annemergmed.2006.02.015. PMID 16781920.
  32. ↑ 32.0 32.1 32.2 32.3 32.4 Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur. Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870. Retrieved 2011-12-07. Unknown parameter |month= ignored (help)

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