D-dimer prognostic role in mortality

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

Overview

Elevated levels of D-dimer signify activation of the hemostastic and fibrinolytic pathways. D-Dimer has been widely evaluated in its association with adverse outcomes among patients with acute venous thromboembolism (VTE).[1] Elevated D-dimer levels are independently associated with mortality,[2] and this association is particularly strong among patients with a malignancy.[3][4]

D-Dimer in Patients Not Known to Have Either Malignancy or Cardiovascular Disease

Among 17,359 healthy subjects aged more than 35 years who were not known to have either cancer or cardiovascular diseases in the MOLI-SANI cohort and who were followed for an average of 4.2 years, elevated D-dimer was independently associated with increased risk of overall mortality. The incidence of death by quartile of D-dimer were 1.1%, 1.4%, 1.1% and 2.8% for the first, second, third and fourth quartiles respectively. A D-dimer level within the upper quartile (>221 ng/mL) was associated with a higher risk of mortality; in fact, the hazard ratio for death in patients having a D-dimer level within the upper quartile were 2.86%, 1.54% and 1.46% before adjustment for any factors, after adjustment for age and gender and after adjustment for age, gender, smoking, BMI, alcohol intake, hypertension, diabetes or dyslipidemia respectively. Following the stratification of each quartile into tertiles, the hazard ratios for increasing death for the upper three tertiles were 1.06%, 1.45% and 1.97% (p<0.0001) after adjustment for age, gender, smoking, BMI, alcohol intake, hypertension, diabetes and dyslipidemia and 1.01%, 1.38% and 1.86% (p<0.0002) after further adjustment for CRP and WBC.[5]

D-Dimer in Patients Presenting to the Emergency Room

  • Among 366 patients presenting to the emergency department (ED), mortality was higher among patients with a D-dimer > 5500 mg/L (9%) versus that among patients with a D-dimer <1,500 mg/ml (1.1%). 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.[6]
  • Elevated level of D-dimer is an independent predictor of all-cause mortality among patients presenting to the ED following a cardiac arrest outside the hospital (OR 5.7, 95% CI 1.22 to 26.69). Among 182 individuals with out-of-hospital cardiac arrest, 49% were deceased and were found to have a mean level of D-dimer of 9113.6 μg/L which was significantly higher than that of the cardiac arrest survivors who had a mean level of D-dimer of 4,597.5 μg/L.[7]

D-Dimer in Patients with Pulmonary Embolism and Venous Thromboembolism

  • Elevated D-dimer level beyond a prognostic cut-off point is associated with increased risk of short term (within a month) and 3 month adverse events and mortality in the overall population and in hemodynamically stable patients with PE.[8]
    • In a meta-analysis of 2,885 pulmonary embolism (PE) patients, elevated D-dimer was associated with short-term mortality defined as death within 30 days after PE both among all patients (OR: 2.76; 95% CI:1.83–4.14; I2 = 0%) as well as among those with hemodynamic stability (OR: 4.28; 95% CI:1.88–9.71; I2 = 0%).[9][10][11][12][13] There was no significant between-study heterogeneity (I2=0%).[8]
    • In a meta-analysis of 4 studies enrolling 1254 patients, D-dimer was associated with 3-month mortality (OR: 4.29; 95% IC: 1.70–10.79; I2 = 0%); however, the results were less consistent across studies.[6][14][15][13] Not all the studies showed an association between elevated D-dimer level and increased mortality.[8]


Shown below is a table summarizing the results of all the studies included in the metaanalysis.[8]

Article's Author Follow up Period PE Related Mortality n(%) Overall Mortality n(%) D-Dimer Cut-Off Value Association Between D-Dimer level and Mortality Mortality in D-Dimer> Cut-Off Value Mortality in D-Dimer> Cut-Off Value
Kline et al.[16] In hospital
6 months		 2 2 (1%) MDA assay
8000 mcg/ml		 Association with in-hospital adverse outcomes
Agterof et al.[9] 10 days
3 months		 23 51 (11.6%) Immunoturbidimetric Tinaquant latex test
3000 mcg/ml		 Association with mortality at 10 days
Singanayagam et al.[10] 1 month NA 5.1% VIDAS
4000 mcg/l		 Association with mortality
Klok et al.[17] 1.5 month 4 7 (6.2%) Quantitative immunoassay STA LIA
3000 ng/ml		 Association with adverse events (univariate analysis)
Aujesky et al.[6] 3 months 7 (1.9%) 19 (5.2%) VIDAS
5500ng/ml		 NO association with mortality at 3 months
Ghanima et al.[14] 3 months NA 5 (5%) Immunoturbidimetric STA LIA
500 ng/ml		 NO association with mortality
Grau et al.[15] 3 months 18 (3%) 62 (10.5%) Latex agglutination turibemtric immunoassay
5000 ng/ml		 Correlation with mortality
Klok et al.[11] 15 days
3 months		 At 15 days: 5 (1.9%) At 3 months: 55 (8.2%) VIDAS and Immunoturbidimetric Tinaquant latex test
3,000 ng/ml		 Independent association with mortality
Kabbara et al.[18] 3 months NA NA Association with PE related mortality
Lobo et al.[12] 15 days 39 (2.3%) 72 (4.2%) Latex agglutination Turbidimetric immunoassay
4200 ng/ml		 Association with PE related mortality
Bova et al.[13] In hospital
3 months		 In hospital: 1(0.9%)
At 3 months: NA		 In hospital: 4 (2%)
At 3 months: 18 (9%)		 VIDAS and Immunoturbidimetric
3000 ng/ml
1200mcg/ml		 NO association with in-hospital mortality
Association with mortality at 3 month
  • In 2008, high D-dimer levels were incorporated with other markers of PE severity, including location and size of emboli, to evaluate the relationship among various PE prognostic factors. When emboli were centrally located, D-dimer levels were shown to be higher and associated mortality was more significant. In addition, concomitant malignancy, age > 65 years, and diagnosis of in-patient PE were all associated with heightened levels of D-dimer and increased mortality risk. This study suggested that the best cut-off level of D-dimer to predict mortality is more than 3000 ng/mL (OR= 7.29, CI=95%).[11]
  • 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. According to the RIETE registry, a prospective registry of 1707 patients with acute VTE, D-dimer levels ≥ 4200 µg/L were associated with 7% mortality within the first 15 days post-VTE vs. only 2.7% mortality in patients when D-dimer levels were < 1050 µg/L. Patients with elevated D-dimer levels were at more risk of fatal PE and major bleeding than those with D-dimer levels below the described cut-off values in RIETE registry.[12]
  • According to Agterof and colleagues, D-dimer concentration ≥ 3000 µg/ml and pulse rate ≥ 100 bpm were both associated with serious adverse events in the first 10 days among patients with pulmonary embolism. Their findings suggest that it is not recommended to treat patients with PE who have high D-dimer levels or pulse rates as outpatients.[9]
  • In another retrospective study involving 411 patients, elevated D-dimer levels of median = 2947 µg/L was associated with 30-day mortality in normotensive patients vs. patients with D-dimer median value = 1464 µg/L (p=0.02). Nonetheless, neither the importance of D-dimer levels nor that of troponin, which was also studied, nor their combination could outweigh the PE severity index (PESI) score in determining mortality (p<0.0001); but addition of troponin to PESI score was helpful in predicting adequate PESI score for risk stratification.[10]

Optimal Cutpoint D-Dimer Cutpoint for Identifying Increased Risk of Mortality

  • 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).[19]
  • Among patients followed for a longer period of time (3 months), there was a 1.1% mortality in patients with median D-dimer levels < 1500 µg/L vs. 9.1% mortality in patients median D-dimer levels > 5500 µg/L (p=0.049).[6]
  • These association between elevated D-Dimer and mortality extends beyond 3 months in the RIETE registry in which a D-dimer ≥ 5000 µg/L was associated with a 2.9 fold increased risk of all cause mortality.[15]

D-Dimer in Patients with Malignancy

  • Among 300 patients with malignancy, increased D-dimer was as strong or stronger than other biomarkers in its association with higher mortality.[20]
  • Higher levels of D-dimer have a predictive value for higher risk of mortality among patients with lung cancer independently of the tumor stage or the histological grade (HR = 5.1; 95% CI, 1.015-1.19, P = 0.013).[21]

D-Dimer in Patients with Congestive Heart Failure

Among 214 patients with class II to IV congestive heart failure followed for 8.5 months, increased D-dimer was independently associated with increased mortality after adjustment for other heart failure prognostic factors such as age, gender, class of heart failure and renal failure. [22] The correlation between elevated D-dimer more than 1435 ng/ml and mortality in heart failure was also reported in a different study conducted on 174 patients (HR = 3.250, 95% CI 1.647-6.414, P = 0.001).[23]

D-Dimer in Patients with Coronary Artery Disease

  • Among 1057 subjects with known CAD, elevated D-dimer was an independently associated with cardiovascular mortality at 6.6 years of follow-up.[24]
  • Among 6,391 subjects in the Multiethnic Study of Atherosclerosis cohort, elevated D-dimer was found to be associated with cancer mortality and was independently associated with all cause mortality.[25]

D-Dimer in Acute Aortic Dissection

  • High level of D-dimer above 5.67 μg/mL was independently predictive of increased in-hospital mortality among 144 individuals with acute aortic dissection (OR=3.272; 95% CI: 1.638 to 6.535).[26]

D-dimer in Sepsis

  • 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.[27]
  • 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.[27]

References

  1. ↑ Lippi G, Franchini M, Targher G, Favaloro EJ (2008). "Help me, Doctor! My D-dimer is raised". Ann Med. 40 (8): 594–605. doi:10.1080/07853890802161015. PMID 18608117.
  2. ↑ 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.
  3. ↑ Morii T, Mochizuki K, Tajima T, Ichimura S, Satomi K (2011). "D-dimer levels as a prognostic factor for determining oncological outcomes in musculoskeletal sarcoma". BMC Musculoskelet Disord. 12: 250. doi:10.1186/1471-2474-12-250. PMC 3226444. PMID 22044610.
  4. ↑ Raj SD, Zhou X, Bueso-Ramos CE, Ravi V, Patel S, Benjamin RS; et al. (2012). "Prognostic significance of elevated D-dimer for survival in patients with sarcoma". Am J Clin Oncol. 35 (5): 462–7. doi:10.1097/COC.0b013e31821d4529. PMID 21654313.
  5. ↑ Di Castelnuovo A, de Curtis A, Costanzo S, Persichillo M, Olivieri M, Zito F; et al. (2013). "Association of D-dimer levels with all-cause mortality in a healthy adult population: findings from the MOLI-SANI study". Haematologica. 98 (9): 1476–80. doi:10.3324/haematol.2012.083410. PMC 3762106. PMID 23645692.
  6. ↑ 6.0 6.1 6.2 6.3 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.
  7. ↑ Szymanski FM, Karpinski G, Filipiak KJ, Platek AE, Hrynkiewicz-Szymanska A, Kotkowski M; et al. (2013). "Usefulness of the D-dimer concentration as a predictor of mortality in patients with out-of-hospital cardiac arrest". Am J Cardiol. 112 (4): 467–71. doi:10.1016/j.amjcard.2013.03.057. PMID 23683952.
  8. ↑ 8.0 8.1 8.2 8.3 Becattini C, Lignani A, Masotti L, Forte MB, Agnelli G (2012). "D-dimer for risk stratification in patients with acute pulmonary embolism". J Thromb Thrombolysis. 33 (1): 48–57. doi:10.1007/s11239-011-0648-8. PMID 22109384.
  9. ↑ 9.0 9.1 9.2 Agterof MJ, van Bladel ER, Schutgens RE, Snijder RJ, Tromp EA, Prins MH; et al. (2009). "Risk stratification of patients with pulmonary embolism based on pulse rate and D-dimer concentration". Thromb Haemost. 102 (4): 683–7. doi:10.1160/TH09-04-0229. PMID 19806253.
  10. ↑ 10.0 10.1 10.2 Singanayagam A, Scally C, Al-Khairalla MZ, Leitch L, Hill LE, Chalmers JD; et al. (2011). "Are biomarkers additive to pulmonary embolism severity index for severity assessment in normotensive patients with acute pulmonary embolism?". QJM. 104 (2): 125–31. doi:10.1093/qjmed/hcq168. PMID 20871127.
  11. ↑ 11.0 11.1 11.2 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.
  12. ↑ 12.0 12.1 12.2 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.
  13. ↑ 13.0 13.1 13.2 Bova C, Pesavento R, Marchiori A, Palla A, Enea I, Pengo V; et al. (2009). "Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up". J Thromb Haemost. 7 (6): 938–44. doi:10.1111/j.1538-7836.2009.03345.x. PMID 19302447.
  14. ↑ 14.0 14.1 14.2 Ghanima W, Abdelnoor M, Holmen LO, Nielssen BE, Ross S, Sandset PM (2007). "D-dimer level is associated with the extent of pulmonary embolism". Thromb Res. 120 (2): 281–8. doi:10.1016/j.thromres.2006.08.006. PMID 17030057.
  15. ↑ 15.0 15.1 15.2 Grau E, Tenías JM, Soto MJ, Gutierrez MR, Lecumberri R, Pérez JL; et al. (2007). "D-dimer levels correlate with mortality in patients with acute pulmonary embolism: Findings from the RIETE registry". Crit Care Med. 35 (8): 1937–41. doi:10.1097/01.CCM.0000277044.25556.93. PMID 17581488.
  16. ↑ Kline JA, Hernandez-Nino J, Rose GA, Norton HJ, Camargo CA (2006). "Surrogate markers for adverse outcomes in normotensive patients with pulmonary embolism". Crit Care Med. 34 (11): 2773–80. doi:10.1097/01.CCM.0000241154.55444.63. PMID 16943732.
  17. ↑ Klok FA, Van Der Bijl N, Eikenboom HC, Van Rooden CJ, De Roos A, Kroft LJ; et al. (2010). "Comparison of CT assessed right ventricular size and cardiac biomarkers for predicting short-term clinical outcome in normotensive patients suspected of having acute pulmonary embolism". J Thromb Haemost. 8 (4): 853–6. doi:10.1111/j.1538-7836.2010.03780.x. PMID 20096002.
  18. ↑ Kabbara R, Labarere J, Pernod G, Bosson JL (2008). "D-dimer level is not a prognostic biomarker specific of pulmonary embolism". Crit Care Med. 36 (2): 652–3, author reply 653. doi:10.1097/01.CCM.0000300509.75176.40. PMID 18216635.
  19. ↑ 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. ↑ Nagy Z, Horváth O, Kádas J, Valtinyi D, László L, Kopper B; et al. (2012). "D-dimer as a potential prognostic marker". Pathol Oncol Res. 18 (3): 669–74. doi:10.1007/s12253-011-9493-5. PMID 22286958.
  21. ↑ Komurcuoglu B, Ulusoy S, Gayaf M, Guler A, Ozden E (2011). "Prognostic value of plasma D-dimer levels in lung carcinoma". Tumori. 97 (6): 743–8. doi:10.1700/1018.11091. PMID 22322841.
  22. ↑ Marcucci R, Gori AM, Giannotti F, Baldi M, Verdiani V, Del Pace S; et al. (2006). "Markers of hypercoagulability and inflammation predict mortality in patients with heart failure". J Thromb Haemost. 4 (5): 1017–22. doi:10.1111/j.1538-7836.2006.01916.x. PMID 16689753.
  23. ↑ Zorlu A, Yilmaz MB, Yucel H, Bektasoglu G, Refiker Ege M, Tandogan I (2012). "Increased d-dimer levels predict cardiovascular mortality in patients with systolic heart failure". J Thromb Thrombolysis. 33 (4): 322–8. doi:10.1007/s11239-011-0635-0. PMID 21901368.
  24. ↑ Morange PE, Bickel C, Nicaud V, Schnabel R, Rupprecht HJ, Peetz D; et al. (2006). "Haemostatic factors and the risk of cardiovascular death in patients with coronary artery disease: the AtheroGene study". Arterioscler Thromb Vasc Biol. 26 (12): 2793–9. doi:10.1161/01.ATV.0000249406.92992.0d. PMID 17023678.
  25. ↑ Folsom AR, Delaney JA, Lutsey PL, Zakai NA, Jenny NS, Polak JF; et al. (2009). "Associations of factor VIIIc, D-dimer, and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality". Am J Hematol. 84 (6): 349–53. doi:10.1002/ajh.21429. PMC 2950108. PMID 19472201.
  26. ↑ Wen D, Du X, Dong JZ, Zhou XL, Ma CS (2013). "Value of D-dimer and C reactive protein in predicting inhospital death in acute aortic dissection". Heart. 99 (16): 1192–7. doi:10.1136/heartjnl-2013-304158. PMID 23813850.
  27. ↑ 27.0 27.1 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.

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