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]
Mortality and Thromboembolism
- A 2012 meta-analysis of 5 studies that enrolled 2,885 patients evaluated the association of D-dimer with mortality among patients with pulmonary embolism (PE).[5] There was a significant association between elevated D-dimer levels and short-term mortality both in the overall population and among those with hemodynamic stability (OR: 2.76 and OR: 2.5 post-bias adjustment).[5][6][7][8][9][10] Short term mortality was defined according to the meta-analysis as death within 15 or 30 days after VTE. There was no significant between-study heterogeneity (I2=0%).[5]
- Similarly, Becattini demonstrates that 4 studies in 1254 patients also showed that D-dimer levels were significantly associated with 3-month mortality as well (OR: 4.29); but results were less consistent.[5][11][12][13][10] In their study, for instance, Bova and colleagues failed to conclude that D-dimer levels were prognostic markers in predicting in-hospital PE-related adverse events or mortality after 3 months of VTE. The authors of the study commented that only clinical scores and troponin I independently predicted 3-month all-cause mortality.[10]
- 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.[11]
- In 2008, high D-dimer levels were incorporated with other markers of PE severity, including location and size of emboli, to understand the exact relationship between 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%).[8]
- One study that recruited 99 patients confirmed that high D-dimer levels were associated with mortality even after adjusting for important factors, such as age gender, and duration of symptoms. Furthermore, increased D-dimer levels were significantly associated with higher pulmonary artery obstruction index (PAOI), increased right ventricular/left ventricular (RV/LV) ratio, and higher rate of thrombolysis in patients with PE.[12]
- 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.[9]
- 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.[6]
- 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.[7]
- 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]
- In 2006, a more prolonged outcome period of 3 months was studied by Aujesky and colleageues. Similar to the previous studies with shorter outcome time frame, 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).[11] These findings were confirmed by results from the RIETE registry that showed D-dimer ≥ 5000 µg/L after 3 months of VTE follow-up correlated with 2.9 times more risk of overall mortality.[13]
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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 5.0 5.1 5.2 5.3 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.
- ↑ 6.0 6.1 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.
- ↑ 7.0 7.1 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.
- ↑ 8.0 8.1 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.
- ↑ 9.0 9.1 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.
- ↑ 10.0 10.1 10.2 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.
- ↑ 11.0 11.1 11.2 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.
- ↑ 12.0 12.1 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 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.