Comparison of normal d-dimer in different category in patient withpulmonary embolism

Abstract

AimQuantitative D-dimer is used to exclude pulmonary embolism in patients with low clinical probability. In this study, we aimed to compare quantitative d-dimer, age-adjusted D-dimer, and age-adjusted D-dimer suggested by the American College of Emergency Physicians (ACEP).MethodsEmergency service patients above the age of 18, whose D-dimer values were tested due to the suspicion of pulmonary thromboembo-lism were evaluated retrospectively. Quantitative d-dimer level, age-adjusted D-dimer, and age-adjusted D-dimer suggested by the ACEP levels were compared with patient data. SPSS (Statistical Package for Social Sciences) Windows 20.0 software was used for statistical analysis of all data obtained.ResultsThree different categories of D-dimer values were compared. According to ACEP, the D-dimer value skipped the least number of PE diagnosis com-pared to the other values and it was found to be the most significant in determining PE. sPESI was not significant in predicting mortality in PE patients.DiscussionD-Dimer values vary according to the devices and kits used. Today, D-dimer values are used in many clinics to exclude PE. These include the quan-titative d-dimer, age-adjusted d-dimer, and the age-adjusted d-dimer suggested by ACEP. It is identified that the cut-off value of d-dimer, calculated accord-ing to age, reduced the need for imaging tests significantly compared to quantitative d-dimer. A systemic meta-analysis found that the d-dimer test results calculated for age reduced the need for imaging by 5% compared to normal d-dimer test results when combined with Wells score.ConclusionRecommended by ACEP age-adjusted D-Dimer may be preferred for the evaluation of pulmonary embolism patients.

Keywords

Introduction

The clinical presentation can vary and the diagnosis of pulmonary embolism (PE) can be difficult to rule out on the basis of the clinical presentation alone, and it is estimated that 25% of patients who present with symptoms and signs of PE actually have the condition.¹ Many attempts have therefore been made to identify patients with suspected PE in whom the disease can be ruled out based on the combination of clinical decision rules and D-dimer testing without additional imaging. Frequently used clinical decision rules in the diagnostic management of PE include the extensively validated Wells and revised Geneva rules.^2-3
In cases with negative D-dimer test results, together with low or no clinical probability, the venous thromboembolism (VTE) risk is quite low, and advanced, specific imaging methods are not necessary. In prospective study that have supported this suggestion, the risk of VTE at a 3-month interval has been reported to be between 0-0.5%.⁴ In cases having high or intermediate probability, the D-dimer test becomes less sensitive, and imaging tests for VTE are recommended.⁵
In patients with good hemodynamics, planning should be done according to the preliminary assessment score. D-dimer test has no place because of the false positive results; if the possibility of PE is high in clinical evaluation or the risk is high according to the scoring, direct pulmonary CT angiography is recommended.⁶ If a patient is at non-high risk of PE according to one of these rules, a D-dimer below 500 μg/L can safely rule out the diagnosis in about 20% to 30% of patients without additional imaging. An important next step to improve the diagnostic management of PE was the derivation of an age-adjusted D-dimer positivity threshold, which is defined as a patient’s age times 10 μg/L in those older than 50 years.⁷ In February 2018, the American College of Emergency Physicians (ACEP) recommended the use of age-adjusted D-dimer values in appropriate patients over 50 years old.⁴ By applying this threshold, the proportion of patients in whom imaging can be safely withheld is increased by another 5% to 6%. Among patients in a large general hospital who died from pulmonary embolism, the diagnosis (confirmed at necropsy) was unsuspected in 70% of patients.⁸
Ninety three percent of these deaths occurred within 2.5 hours of the onset of symptoms, emphasising the importance of clinical suspicion and timely initiation of diagnostic testing and subsequent treatment.

Materials and Methods

Study Design Emergency services patients older than 18 years of age whose D-Dimer values were tested with the suspicion of pulmonary thromboembolism were retrospectively screened. Study Settings and Population This study was planned in the emergency department of a training and research hospital with a capacity of 1100 beds and approximately 260 thousand emergency applications. The diagnosis of patients with pulmonary embolism by emergency physicians and chest disease specialist was confirmed with CT pulmonary angiography via the detection of filling defect by specialist radiologist. Patients with known renal or blood disease, cardiovascular disease, patients diagnosed with pulmonary embolism prior to admission to the emergency room with an ongoing treatment, pregnant women, those who underwent cardiopulmonary resuscitation, patients with incomplete data and patients under 18 years of age were excluded from the study. Patient data were obtained from hospital automation system and patient record archive. Study Protocol Ethics committee approval was obtained before patient data were collected. Patients with pulmonary embolism in the ICD diagnostic code, admitted to the emergency department were retrospectively screened via electronic data base and 91 patients were identified. Thirty-nine patients who met the inclusion criteria were included in the study. The patients’ gender, age, presentation at the admission, duration of symptoms, vital signs, wells, revised genova and sPESI scores, 3-month mortality, quantitative d-dimer, age-adjusted d-dimer and age-adjusted d-dimer suggested by ACEP were recorded. Gender, presentation at the admission, admission time (<24 hours, > 24 hours), MAP positivity (> 90/60 mmHg), echocardiography (ECHO) findings (positive for normal or pulmonary embolism), the presence of mortality, patient’s age being over or under 65 and saturation (90% and above) were compared according to quantitative d-dimer positivity, age-adjusted d-dimer positivity and age-adjusted d-dimer positivity suggested by ACEP, which will be referred as three different categories of D-dimer evaluation. Measurements The D-Dimer was measured quantitatively with the ACL TOP 500 CTS-IL-Coagulation Analyzer and <243 ug/l was considered as a negative value. The d-dimer value for patients over 50 was calculated according to ACEP formula ((age × 5) – 20), and according to age-adjusted d-dimer formula (age× 10). Statistical Analysis SPSS (Statistical Package for Social Sciences) Windows 20.0 software was used for statistical analysis of all data obtained. All data are summarized in the tables during the evaluation. Frequency tests for frequency, mean and standard deviation values of the obtained data, the Mann-Whitney U test to compare the mean values of the obtained data, the Pearson Chi-Square (and exact test when necessary) to compare the nonparametric data were used. Only results with confidence interval above 95% and p<0.05 were accepted as significant.

Results

Characteristics of study subjects Of the 39 patients with PE, 46% were women and 53% were men. The mean age was 57.48 ± 11.52 (24-93) years. Main results Three different categories of D-dimer values were compared. According to ACEP, the D-dimer value skipped the least number of PE diagnoses compared to the other values and it was found to be the most significant in determining PE (Table 1). In our study, vital signs and PE scores of the patients were calculated according to three different categories of D-dimer evaluation, and the relationship among them was evaluated. While the specific score was found to be significant according to quantitative D-dimer (p <0.05), the PERC score was found to be significant according to D-dimer value and ACEP (p <0.05). Gender, admission complaint, admission time (<24 h, > 24 h), MAP positivity (> 90/60 mmHg), ECHO sign (normal or positive findings for pulmonary embolism), presence of mortality, age (above or below 65) and saturation (below 90%) were compared according to three different categories of D-dimer evaluation. There was no significant relationship between gender, admission complaint, MAP positivity, saturation status and d-dimer positivity according to these three categories of D-dimer evaluation. However when examined according to the application times, it was seen that the patients with d-dimer positivity according to ACEP had complaints for more than 24 hours (p=0.033). When ECHO findings are evaluated, a positive finding for PTE in ECHO allows patients to be detected in quantitative and age-adjusted d-dimer calculations (pkan = 0.002 and pash = 0.010, respectively), whereas d-dimer negative patients according to ACEP cannot be captured (p = 0.205). D-dimer calculation by age does not predict mortality, when D-dimer values are compared with mortality (p = 0.017) (Table 2).

Discussion

Various radiological and laboratory tests are used to diagnose PE, which vary in accuracy, have different costs, and some are associated with different levels of risk because they are invasive and others are not invasive.⁹ D-Dimer is one of the non-invasive tests and D-Dimer values vary according to the devices and kits used.¹⁰
Today, D-dimer values are used in many clinics to exclude PE. These include the quantitative d-dimer, age-adjusted d-dimer, and the age-adjusted d-dimer suggested by ACEP. There are many studies investigating the sensitivity and negative predictive values of these tests to exclude PE. Carrier et al. reported that there was a very low probability (0.41%) of occurrence of PE in the 3 month-follow-up of low- and medium-risk patients with negative d-dimer results.¹¹
Legnani et al.’s study showed 100% sensitivity and negative predictive value in PE exclusion using the same d-dimer test.¹² In a meta-analysis study conducted by Parks et al., only age-adjusted d-dimer calculation revealed that PE exclusion sensitivity was increased from 64.9% to 74.7% compared to the quantitative d-dimer value. The same study compared age-adjusted d-dimer with age-adjusted d-dimer suggested by ACEP and it was shown that the formula showed a tendency towards more sensitivity and negative predictive value while the test properties showed the potential to miss lower PEs.¹³ It is identified that the cut-off value of d-dimer calculated according to age, reduced the need for imaging tests significantly compared to quantitative d-dimer. A systemic meta-analysis found that the d-dimer test results calculated for age, reduced the need for imaging by 5% compared to normal d-dimer test results when combined with Wells score.¹⁴ In our study, when three different categories of D-dimer evaluation were compared in PE determination, it was seen that D-dimer positivity suggested by ACEP was the most significant calculation in determining PE.
Wells and Revised Geneva Scores are among the most frequently used scoring systems for PE detection and exclusion. In the literature, these scoring systems were frequently compared among themselves in the detection of PE. In a meta-analysis, it was found that Wells score was better than Revised Geneva score in PE exclusion.¹⁵ In another study, Wells score was found to be more successful in detecting PE than Revised Geneva Score in elderly patients; the use of d-dimer test together was shown to increase success rates in two scores.¹⁶ Cheng et al. reported that using Wells score with D-dimer test was more successful than Revised Geneva score with D-dimer test to determine the success of PE detection.¹⁷ In a study by Harringa et al., it was found that there was no difference between the prevalence of PE when comparing low- and medium-risk patients identified using Wells and Revised Geneva Scores; and that the negative d-dimer test alone had a 100% sensitivity and negative predictive value (even for high-risk patients), regardless of the risk classification for PE exclusion alone.¹⁸
In Di Marca et al.’s study in high-risk in-patients, Wells was found to be more successful than the Revised Geneva Score in the detection of PE.¹⁹ However, a study by Girarda et al. showed that Wells and Revised Geneva Scores were not successful in determining PE in critically ill or high-risk patients for PE.²⁰ In our study, there was no significant difference between Wells score and Revised Geneva score calculated among patients, and none of them were found to be significant in PE detection and predicting mortality. There was also no difference among three different categories of D-dimer evaluation.
PERC criteria are still used today by some clinics to exclude PE. In the study performed by Singh et al., PERC rule was stated to be used safely in clinically low probability population environments because of high sensitivity and low negative probability ratio.²¹ In addition, some studies reported that the PERC criteria had a very low sensitivity for PE alone, and was not suitable for use because it requires scoring systems and additional laboratory tests.^22-23 In our study, the use of PERC criterion with quantitative d-dimer positivity and d-dimer positivity according to ACEP increased the success in PE detection, whereas there was no significant difference in use with d-dimer value according to age.
sPESI score has been and is being investigated in many studies in the literature for PE and its effectiveness in determining mortality or serious vital effects. In the study conducted by Tamizifar et al. it was stated that sPESI score accurately predicted the mortality rate for low-risk patients, but could not predict prognosis significantly in high-risk patients.²⁴ Kılıç et al.’s study indicated that sPESI was significant in determining mortality for PE in the short and long term, and that no additional laboratory and imaging tests were required at low sPESI values.²⁵ In our study, the sPESI score was found to be high in only quantitative d-dimer negative cases. In addition, it was not significant in determining mortality in PE patients.

Limitations

The greatest limitation to our study is the low number of PE patients undergoing D-dimer examination, data losses and not being able to track patients due to referrals to other hospitals.

Conclusion

Unnecessary imaging in PE leads to a waste of time, economic losses, and unnecessary exposure of patients to the harmful effects of radiation. While attempting to cope with these losses, many early diagnosis tests or scoring systems are being investigated in order to detect or exclude PE. In our study, the evaluation of age-adjusted d-dimer suggested by ACEP is considered to be an appropriate method in the evaluation of PE.

Declarations

References

1. Crawford F, Andras A, Welch K, Sheares K, Keeling D, Chappell FM. D-dimer test for excluding the diagnosis of pulmonary embolism. Cochrane Database Syst Rev. 2016;(8).
   PubMed · Google Scholar
2. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost. 2000;83(3):416-420. doi:10.1055/s-0037-1613830
   Article · PubMed · Google Scholar
3. Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144(3):165-171. doi:10.7326/0003-4819-144-3-200602070-00004
   Article · PubMed · Google Scholar
4. American College of Emergency Physicians Clinical Policies Subcommittee; Wolf SJ, Hahn SA, Nentwich LM, et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected acute venous thromboembolic disease. Ann Emerg Med. 2018;71(5). doi:10.1016/s0196-0644(18)30401-3
   Article · PubMed · Google Scholar
5. Bilir Ö, Ersunan G, Giakoup B, Kalkan A, Yavası Ö, Kayayurt K. The diagnosis of pulmonary embolism in patients with normal D-dimer levels. Acta Med Mediterr. 2015;31(1):907-913.
   PubMed · Google Scholar
6. Douma RA, le Gal G, Söhne M, et al. Potential of an age-adjusted D-dimer cutoff value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ. 2010;340. doi:10.1136/bmj.c1475
   Article · PubMed · Google Scholar
7. Lucassen W, Geersing GJ, Erkens PM, et al. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med. 2011;155(7):448-460. doi:10.7326/0003-4819-155-7-201110040-00007
   Article · PubMed · Google Scholar
8. Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995;108(4):978-981. doi:10.1378/chest.108.4.978
   Article · PubMed · Google Scholar
9. West J, Goodacre S, Sampson F. The value of clinical features in the diagnosis of acute pulmonary embolism: systematic review and meta-analysis. QJM. 2007;100(12):763-769. doi:10.1093/qjmed/hcm113
   Article · PubMed · Google Scholar
10. Than MP, Helm J, Calder K, et al. Comparison of high specificity with standard versions of a quantitative latex D-dimer test in the assessment of community pulmonary embolism: HaemosIL D-dimer HS and pulmonary embolism. Thromb Res. 2009;124(2):230-235. doi:10.1016/j.thromres.2008.10.018
    Article · PubMed · Google Scholar
11. Carrier M, Righini M, Djurabi RK, et al. VIDAS D-dimer in combination with clinical pretest probability to rule out pulmonary embolism: a systematic review of management outcome studies. Thromb Haemost. 2009;101(5):886-892. doi:10.1160/th-08-10-0689
    Article · PubMed · Google Scholar
12. Legnani C, Cini M, Scarvelis D, Toulon P, Wu JR, Palareti G. Multicenter evaluation of a new quantitative highly sensitive D-dimer assay, the HemosIL D-dimer HS 500, in patients with clinically suspected venous thromboembolism. Thromb Res. 2010;125(5):398-401. doi:10.1016/j.thromres.2009.07.013
    Article · PubMed · Google Scholar
13. Parks C, Bounds R, Davis B, Caplan R, Laughery T, Zeserson E. Investigation of age-adjusted D-dimer using an uncommon assay. Am J Emerg Med. 2019;37(7):1285-1288. doi:10.1016/j.ajem.2018.09.035
    Article · PubMed · Google Scholar
14. van Es N, van der Hulle T, van Es J, et al. Wells rule and D-dimer testing to rule out pulmonary embolism: a systematic review and individual-patient data meta-analysis. Ann Intern Med. 2016;165(4):253-261. doi:10.7326/m16-0031
    Article · PubMed · Google Scholar
15. Shen JH, Chen HL, Chen JR, Xing JL, Gu P, Zhu BF. Comparison of the Wells score with the revised Geneva score for assessing suspected pulmonary embolism: a systematic review and meta-analysis. J Thromb Thrombolysis. 2016;41(3):482-492. doi:10.1007/s11239-015-1250-2
    Article · PubMed · Google Scholar
16. Guo DJ, Zhao C, Zou YD, Huang XH, Hu JM, Guo L. Values of the Wells and revised Geneva scores combined with D-dimer in diagnosing elderly pulmonary embolism patients. Chin Med J (Engl). 2015;128(8):1052-1057. doi:10.4103/0366-6999.155085
    Article · PubMed · Google Scholar
17. Cheng Z, Yang M, Zhang Z, et al. Predictive value of Wells score, revised Geneva score combined with D-dimer for pulmonary embolism in patients with acute exacerbation of chronic obstructive pulmonary disease. Zhonghua Yi Xue Za Zhi. 2018;98(48):3925-3929.
    PubMed · Google Scholar
18. Harringa JB, Bracken RL, Nagle SK, Schiebler ML, Pulia MS, Svenson JE. Negative D-dimer testing excludes pulmonary embolism in non-high risk patients in the emergency department. Emerg Radiol. 2017;24(3):273-280. doi:10.1007/s10140-017-1478-6
    Article · PubMed · Google Scholar
19. Di Marca S, Cilia C, Campagna A, et al. Comparison of Wells and revised Geneva rule to assess pretest probability of pulmonary embolism in high-risk hospitalized elderly adults. J Am Geriatr Soc. 2015;63(6):1091-1097. doi:10.1111/jgs.13459
    Article · PubMed · Google Scholar
20. Girardi AM, Bettiol RS, Garcia TS, et al. Wells and Geneva scores are not reliable predictors of pulmonary embolism in critically ill patients: a retrospective study. J Intensive Care Med. 2020;35(10):1112-1117. doi:10.1177/0885066618816280
    Article · PubMed · Google Scholar
21. Singh B, Mommer SK, Erwin PJ, Mascarenhas SS, Parsaik AK. Pulmonary embolism rule-out criteria in pulmonary embolism revisited: a systematic review and meta-analysis. Emerg Med J. 2013;30(9):701-706. doi:10.1136/emermed-2012-201730
    Article · PubMed · Google Scholar
22. Buchanan I, Teeples T, Carlson M, Steenblik J, Bledsoe J, Madsen T. Pulmonary embolism testing among emergency department patients who are pulmonary embolism rule-out criteria negative. Acad Emerg Med. 2017;24(11):1369-1376. doi:10.1111/acem.13270
    Article · PubMed · Google Scholar
23. Theunissen J, Scholing C, van Hasselt WE, van der Maten J, Ter Avest E. A retrospective analysis of the combined use of PERC rule and Wells score to exclude pulmonary embolism in the emergency department. Emerg Med J. 2016;33(10):696-701. doi:10.1136/emermed-2016-205687
    Article · PubMed · Google Scholar
24. Tamizifar B, Fereyduni F, Esfahani MA, Kheyri S. Comparing three clinical prediction rules for primarily predicting the 30-day mortality of patients with pulmonary embolism: the simplified revised Geneva score, the original PESI, and the simplified PESI. Adv Biomed Res. 2016;5:137. doi:10.4103/2277-9175.187372
    Article · PubMed · Google Scholar
25. Kilic T, Gunen H, Gulbas G, Hacievliyagil SS, Ozer A. Prognostic role of simplified Pulmonary Embolism Severity Index and the European Society of Cardiology Prognostic Model in short- and long-term risk stratification in pulmonary embolism. Pak J Med Sci. 2014;30(6):1259-1264. doi:10.12669/pjms.306.5737
    Article · PubMed · Google Scholar

Tables

Additional Information

Publisher’s Note
Bayrakol MP remains neutral with regard to jurisdictional and institutional claims.

Rights and Permissions