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 is an independent correlate of increased mortality.[2]
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.[3]
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.[4]
- 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.[5]
D-Dimer in Patients with Pulmonary Embolism and Venous Thromboembolism
Metaanalyses
- Elevated D-dimer level beyond a prognostic cut-off point is associated with increased risk of short term (within a month) and 3 months adverse events and mortality in the overall population and in hemodynamically stable patients with acute PE.[6]
- 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%).[7][8][9][10][11] There was no significant between-study heterogeneity (I2=0%).[6]
- 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.[4][12][13][11] Not all the studies showed an association between elevated D-dimer level and increased mortality.[6]
- According to the previous metanalyses, the potential prognostic role of D-dimer for risk of mortality following PE has been studied mainly in hemodynamically stable patients and it may have a potential role for risk stratification and tailoring the treatment of these patients. However, D-dimer alone might not be specific to stratify patients as it may vary according to different factors such as age. Hence, D-dimer might be a better predictor of mortality if it is associated with other factors within an integrated score. In addition, it is worth mentioning that the prognostic cut-off values for D-dimer were different from usual daignostic cut-off points and were also different among the studies. These D-dimer cut-off values are hypothesis generating as they were obtained in post-hoc studies.[6]
Shown below is a table summarizing the results of all the studies included in the metaanalysis.[6]
| Article's Authors | Follow up Period | PE Related Mortality n(%) | Overall Mortality n(%) | D-Dimer Cut-Off Value | Association Between D-Dimer level and Mortality |
| Agterof et al.[7] | 10 days 3 months |
23 | 51 (11.6%) | Immunoturbidimetric Tinaquant latex test 3000 mcg/ml |
Association with mortality at 10 days |
| Singanayagam et al.[8] | 1 month | NA | 5.1% | VIDAS 4000 mcg/l |
Association with mortality |
| Aujesky et al.[4] | 3 months | 7 (1.9%) | 19 (5.2%) | VIDAS 5500ng/ml |
NO association with mortality at 3 months |
| Ghanima et al.[12] | 3 months | NA | 5 (5%) | Immunoturbidimetric STA LIA 500 ng/ml |
NO association with mortality |
| Grau et al.[13] | 3 months | 18 (3%) | 62 (10.5%) | Latex agglutination turibemtric immunoassay 5000 ng/ml |
Correlation with mortality |
| Klok et al.[9] | 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 |
| Lobo et al.[10] | 15 days | 39 (2.3%) | 72 (4.2%) | Latex agglutination Turbidimetric immunoassay 4200 ng/ml |
Association with PE related mortality |
| Bova et al.[11] | 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 |
Individual Studies of The Metaanalysis
- In a study involving 674 patients with PE followed up for 3 months, mortality was reported to be 8.2%, 20 % of which was due to recurrent PE while 80% of mortality resulted from non PE related comorbidities such as malignancy, bleeding, cardiac, infectious, pulmonary and neurological causes. Out of the 674 subjects, 262 patients with less likely clinical probability of PE had their D-dimer measured. High D-dimer level is an independent predictor of overall mortality at 3 months among patients with PE after adjustment for COPD, active malignancy, age more than 65 years, inpatient status, central embolus and congestive heart failure (OR 7·29, 95% CI: 1·4–37). This study suggested that the best cut-off level of D-dimer to predict mortality is more than 3000 ng/mL for the VIDAS and Tinaquant assay.[9] No information was provided regarding the percentage of death in patients having D-dimer levels less than the cut-off value vs those with D-dimer levels more than the cut-off value. In addition, high D-dimer level is an independent predictor of overall mortality; however, the association between D-dimer and cause of death (PE related or non PE related) was not evaluated in this study.
- Elevated D-dimer levels were associated with a higher pulmonary artery obstruction index (PAOI), an increased right ventricular/left ventricular (RV/LV) ratio, and a higher rate of thrombolysis in patients with pulmonary embolism, all of which can be of prognostic value for patients with PE. The study is a cohort of 99 patients with either first episode of PE or recurrent PE confirmed by CT. 96 out of the 99 patients received treatment for PE, such that 87% of patients were treated with LMWH and UFH while the remaining 13% were treated with systemic thrombolytics. Five patients died and one of those five did not receive treatment. D-dimer level was not found to be correlated with mortality; however, it should be taken into consideration that the population size is small.[12]
- Data results from RIETE registry, a multicenter international observational registry of 10293 subjects, 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. 1701 subjects from the RIETE registry had their blood withdrawn for D-dimer testing prior to the initiation of treatment for PE. The subjects were 765 males and 942 females for whom the diagnosis of PE was confirmed by either pulmonary angiography, lung scintigraphy or helical CT scan. The mortality after a 15 days follow up period was 4.2%; 50% of which died from the initial PE, 4.2% from recurrent PE and 1.4% from bleeding. D-dimer levels ≥ 4200 µg/L (upper quartile) were associated with 7% overall mortality within the first 15 days post-PE vs. only 2.7% mortality in patients when D-dimer levels were < 1050 µg/L (lower quartile). The detailed results are as follows:
- Patients with elevated D-dimer levels were at more risk of overall death (OR, 1.8; 95% CI, 1.1–3.2) than those with D-dimer levels below the described cut-off values after adjustment for gender], creatinine level, immobility, cancer, systolic blood pressure, heart rate and atrial fibrillation.
- Patients with elevated D-dimer levels were at more risk of fatal PE (OR, 2.0; 95% CI, 1.0–3.8) than those with D-dimer levels below the described cut-off values after adjustment for gender, immobility and systolic blood pressure.
- Patients with elevated D-dimer levels were at more risk of major bleeding (OR, 3.2; 95% CI, 1.5–7.0) than those with D-dimer levels below the described cut-off values after adjustment for gender, creatinine level and thrombolytic therapy.
- The sensitivity and specificity of D-dimer for predicting overall death were 42% (95% CI,30–56) and 76% (95% CI, 74–78) respectively; while the PPV and NPV were 7% (95% CI, 5–9) and 97%(95% CI, 96–98).
- The sensitivity and specificity of D-dimer for predicting fatal PE were 44% (95% CI, 28–59) and 75% (95% CI, 73–78) respectively; while the PPV and NPV were4% (95% CI, 2–6) and 98% (95% CI, 98–99) respectively.[10]
Shown below is a table summarizing the results of this study.
| Outcome at 15 Days | 1st Quartile | 2nd Quartile | 3d Quartile | 4th Quartile |
| Overall death | 2.7% | 3.4% | 3.7% | 7% |
| Fatal initial PE | 1% | 1.8% | 1.6% | 4% |
| Recurrent PE | 0.7% | 0 | 0.9% | 0.9% |
| Fatal recurrent PE | 0.2% | 0 | 0.5% | 0 |
| Major bleeding | 1% | 0.5% | 1.9% | 3.5% |
| Fatal bleeding | 0.5% | 0 | 0.2% | 0.7% |
- 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.[7]
- 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.[8]
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).[14]
- 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).[4]
- 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.[13]
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.[15]
- 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).[16]
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. [17] 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).[18]
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.[19]
- 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.[20]
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).[21]
D-Dimer in Sepsis
- Increased 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.[22]
References
- ↑ 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.
- ↑ Halaby R, Popma CJ, Cohen A, Chi G, Zacarkim MR, Romero G; et al. (2014). "D-Dimer elevation and adverse outcomes". J Thromb Thrombolysis. doi:10.1007/s11239-014-1101-6. PMID 25006010.
- ↑ 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.
- ↑ 4.0 4.1 4.2 4.3 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.
- ↑ 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.
- ↑ 6.0 6.1 6.2 6.3 6.4 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.
- ↑ 7.0 7.1 7.2 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.
- ↑ 8.0 8.1 8.2 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.
- ↑ 9.0 9.1 9.2 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.
- ↑ 10.0 10.1 10.2 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.
- ↑ 11.0 11.1 11.2 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.
- ↑ 12.0 12.1 12.2 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.
- ↑ 13.0 13.1 13.2 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.