European Journal of Internal Medicine 25 (2014) 4548

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original article

Causes of elevated D-dimer in patients admitted to a large urban emergency department

Giuseppe Lippi a,, Laura Bonfanti b, Carlotta Saccenti b, Gianfranco Cervellin b
a b

Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy Emergency Department, Academic Hospital of Parma, Parma, Italy

a r t i c l e

i n f o

a b s t r a c t
Background: Although the request for D-dimer is widespread in emergency departments (EDs), the causes of elevation and their relationship with D-dimer levels in patients with diagnostic values are uncertain. Methods: In this retrospective investigation, the study population consisted of all patients who visited our large urban ED in the year 2012, for whom a D-dimer test was requested for excluding or diagnosing venous thromboembolism (VTE). Only patients with D-dimer values N 243 ng/mL were included, regardless of their pre-test clinical probability for VTE. Results: The nal study population consisted of 1647 patients. A signicant positive correlation was found between age and D-dimer. Infection was the most frequent diagnosis (15.6%), followed by VTE (12.1%), syncope (9.4%), heart failure (8.9%), trauma (8.2%) and cancer (5.8%). D-dimer was higher in patients with VTE than in those with other diagnoses (2541 ng/mL vs 1030 ng/mL; p b 0.001). The frequency of VTE gradually increased from patients with values b 1000 ng/mL to those with D-dimer N 3000 ng/mL (4.1 vs 26.7%; p b 0.001). As compared with D-dimer values b 1000 ng/mL, the Odds Ratio for VTE was 8.5 for values N 3000 ng/mL. Conclusions: These results show that D-dimer lacks specicity for diagnosing VTE, especially in elderly patients admitted to the ED with signicant co-morbidities. In older patients, elevated values (N 1000 ng/mL) are more frequently associated with VTE, so the use of higher cut-offs may be advantageous. 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Article history: Received 30 March 2013 Received in revised form 16 July 2013 Accepted 19 July 2013 Available online 13 August 2013 Keywords: D-dimer testing Emergency department Venous thromboembolism Thrombosis

1. Introduction Venous thromboembolism (VTE), which comprehends deep venous thrombosis (DVT) and/or pulmonary embolism (PE), is an important cause of death and disability worldwide. According to recent statistics, the overall prevalence of VTE is around 422 cases per 100,000, with a constant trend of increase of approximately 26 cases per 100,000 every new year [1]. Nearly one third of the patients with symptomatic VTE are diagnosed with PE, whereas two thirds are diagnosed with DVT alone [2]. Although the prevalence is reportedly heterogeneous among different racial or ethnic cohorts, the frequency seems higher in Blacks, intermediate in Caucasians, and lower in Asians. The prevalence is also age-dependent, with an approximately 90-fold increase in patients older than 80 as compared with those aged less than 15 years. Although no denitive conclusions can be drawn about gender prevalence, it has been hypothesized that sex may not be an independent risk factor [3]. The severity of this pathology is conrmed by studies showing that mortality can be as high as 6% in patients with DVT and 12% in those with PE, respectively [2].

Several lines of evidence attest that a consistent number of emergency department (ED) visits are made by patients with a primary diagnosis of VTE [4], thus emphasizing the need to obtain an early and accurate diagnosis in order to establish appropriate care, optimize outcome and decrease overcrowding in emergency room. It has now been clearly established that the appropriate use of laboratory resources, along with clinical prediction rules, has greatly improved the diagnostic workout in patients presenting with suspected VTE [5,6]. Despite some inherent limitations, comprehensively reviewed elsewhere [7,8], D-dimer is now widely recognized as the biochemical gold standard in the diagnostic approach of VTE among the various diagnostic biomarkers that have been proposed and tested over the past decades [9,10]. Although the request of D-dimer testing has thus become commonplace in all patients admitted to the ED with a consistent suspicion of VTE, irrespective of their pre-test probability of disease, analysis of clinical outcomes and relationship with D-dimer levels in large number of patients with diagnostic values is still limited, to the best of our knowledge [5]. As such, the aim of this study was to analyze D-dimer values and causes of an elevated D-dimer in patients admitted to a large urban emergency department. 2. Materials and methods In this retrospective investigation, the study population consisted of all patients who visited the ED of the academic hospital of Parma in the

Corresponding author at: U.O. Diagnostica Ematochimica, Azienda OspedalieroUniversitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy. Tel.: +39 0521 703050, +39 0521 703791. E-mail addresses: glippi@ao.pr.it, ulippi@tin.it (G. Lippi).

0953-6205/$ see front matter 2013 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.07.012

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G. Lippi et al. / European Journal of Internal Medicine 25 (2014) 4548 Table 1 Frequency of different diagnoses in the entire cohort of patients (n = 1647) admitted to the emergency department (ED), for whom a D-dimer test was requested for excluding or diagnosing venous thromboembolism (VTE), and displaying a value above the diagnostic cut-off of the local immunoassay. Final diagnosis Infection VTE Syncope Heart failure Trauma Cancer Dyspnea Cerebrovascular ischemia ACS COPD Atrial brillation Anemia Cirrhosis Subarachnoid hemorrhage Abdominal aortic aneurysm Supercial thrombosis Acute renal failure Cholecystitis Peripheral occlusive disease Lymphedema Epilepsy Intestinal ischemia Arthritis Hypertensive crisis Baker's cyst Renal colic Recent surgery Pancreatitis Allergy Amyloidosis Gastric perforation Inguinal hernia n 257 200 155 146 135 95 94 93 92 87 81 22 22 20 19 19 18 18 16 12 9 8 6 6 4 4 3 2 1 1 1 1 % 15.6 12.1 9.4 8.9 8.2 5.8 5.7 5.6 5.6 5.3 4.9 1.3 1.3 1.2 1.2 1.2 1.1 1.1 1.0 0.7 0.5 0.5 0.4 0.4 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1

year 2012, for whom a D-dimer test was requested by an emergency physician in order to exclude or reinforce a diagnostic suspicion of VTE according to clinical signs and symptoms (i.e., prediction rule based on Revised Geneva score or on Wells score), and displaying a value above the 243 ng/mL diagnostic cut-off for VTE of the local immunoassay, regardless of their pre-test clinical probability for VTE. The ED of the Academic Hospital of Parma is a large urban ED, with nearly 90,000 accesses per year, serving the hospital with 1300 beds and specialized wards. Results of D-dimer testing were retrieved from the laboratory information system (LIS). The nal diagnosis after ED admission according to each specic International Classication of Diseases-9 (ICD-9) code and related diagnostic terms were systematically searched for all patients in the local hospital records, and information was subsequently reviewed by two expert physicians for deleting wrong registrations or missing information. According to our local protocol and as part of the diagnostic workout adapted from the American College of Chest Physicians (ACCP) guidelines [10], all patients with D-dimer values above the diagnostic cut-off of the method (i.e., 243 ng/mL) and suspected DVT and/or PE are subjected to compression ultrasonography (CUS) and computed tomography (CT), respectively [11], which are nally judged by an expert ultrasonographist or radiologist. Pregnant women are excluded from this protocol, since we consider that D-dimer testing may be unreliable in pregnancy [12]. In all patients, D-dimer testing has been performed in the core laboratory, using HemosIL D-dimer HS for ACL TOP (Instrumentation Laboratory, Bedford, MA). This test is a latex enhanced turbidimetric immunoassay, characterized by an imprecision comprised between 2.3 and 6.6%, a detection limit of 21 ng/mL, and a diagnostic cut-off for VTE of 243 ng/mL [13]. The quality of laboratory results was validated throughout the study period by regular internal quality control (IQC) procedures and participation in an External Quality Assessment Scheme (EQAS). Results of D-dimer testing were nally expressed as median and interquartile range (IQR). The signicance of differences was assessed by MannWhitneyWilcoxon test (for continuous variables) and chi-squared test with Yates' correction for continuity (for categorical variables), using Analyse-it for Microsoft Excel (Analyse-it Software Ltd., Leeds, UK). The Odds Ratio (OR) was calculated using MedCalc Version 12.3.0 (MedCalc Software, Mariakerke, Belgium). The study was performed in agreement with the Declaration of Helsinki and under the terms of all relevant local legislation. 3. Results Overall, data about 1819 patients with a D-dimer value measured upon ED admission and exceeding the 243 ng/mL diagnostic cut-off for VTE were retrieved throughout the study period. One hundred seventy two patients were excluded from the analysis because the nal diagnosis was unavailable, unclear or mixed, so the nal study cohort was represented by 1647 patients (mean age = 77 15 years, range = 25102 years; 756 men and 891 women). The leading reasons for ED admission were suspected pneumonia and/or dyspnea, syncope, heart failure, trauma, cerebrovascular disorder, chest pain and atrial brillation. A highly signicant correlation was observed between age and D-dimer values in the entire cohort of patients (r = 0.08; p = 0.010), as well as in those with (n = 200; r = 0.23; p = 0.001) or without (n = 1447; r = 0.08; p = 0.005) a nal diagnosis of VTE. As shown in Table 1, infection was the most frequent nal diagnosis in the whole cohort of ED patients for whom D-dimer measurement was requested (n = 257; 15.6% pneumonia in nearly two thirds of cases), followed by VTE (n = 200; 12.1%), cardiogenic syncope (n = 155; 9.4%), heart failure (n = 146; 8.9%), trauma (n = 135; 8.2%) and cancer (n = 95; 5.8%, with colorectal and lung malignancies representing more than two-thirds of cases). As regards to patients with VTE, 88 (44%) were diagnosed with PE and 112 (56%) with isolated DVT (26 cases distal, 23%; 86 cases proximal, 77%). Supercial vein thrombosis was only diagnosed in 19 patients, accounting for 1.2% of nal diagnoses. D-dimer

VTE, venous thromboembolism; COPD, chronic obstructive pulmonary disease; ACS, acute coronary syndrome.

values in patients with VTE (2541 ng/mL, IQR = 11333309 ng/mL) were nearly three-times higher than in those with other diagnoses (1030 ng/mL, IQR = 6962413 ng/mL; p b 0.001) (Fig. 1). The concentration of D-dimer was slightly but not signicantly higher in patients with PE (2748 ng/mL, IQR = 15473494 ng/mL) than in those with DVT alone (2240 ng/mL, IQR = 10553122 ng/mL; p = 0.11). When the entire patient cohort was stratied according to D-dimer values at ED admission, the frequency of VTE consistently increased from the class of patients with values lower than 1000 ng/mL (33/800; 4.1%), to those with D-dimer values between 1000 and 1999 ng/mL (44/344; 12.8%), between 2000 and 3000 ng/mL (52/237; 21.9%) and N 3000 ng/mL (71/266; 26.7%). This difference was highly statistically
12000 10000 8000 6000 4000 2000 0 VTE Other
p<0.001

Fig. 1. Distribution of D-dimer values in patients admitted to the emergency department (ED), for whom a D-dimer test was requested for excluding or diagnosing venous thromboembolism (VTE), and displaying a value above the diagnostic cut-off of the local immunoassay. VTE, venous thromboembolism; Other, diagnosis other than VTE.

D-dimer (ng/mL)

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signicant (Pearson's chi-square statistic 122; p b 0.001). As compared with D-dimer values b 1000 ng/mL, the OR for VTE was 3.4 (95% CI 2.1 to 5.5; p b 0.001) for patients with values between 1000 and 1999 ng/mL, 6.5 (95% CI 4.1 to 10.4; p b 0.001) for those with values between 2000 and 3000 ng/mL, and 8.5 (95% CI, 5.4 to 13.2; p b 0.001) for those with values N 3000 ng/mL, respectively (Fig. 2). 4. Discussion The incorporation of D-dimer testing in the diagnostic approach of patients admitted to the ED with suspected VTE is now almost unavoidable [79]. According to current ACCP guidelines, D-dimer testing should be preferentially used over diagnostic imaging (CUS and/or TC) for the initial assessment of patients with suspected VTE, when pre-test probability (assessed either with the Revised Geneva score or the Wells score) is low. A non-diagnostic value of D-dimer in patients with low to moderate pretest probability does not require further testing, whereas a value exceeding the diagnostic threshold for VTE should be followed by diagnostic imaging to denitely assess or rule out DVT and/or PE [11]. Considering the well-known limitations of D-dimer testing [79], it is not surprising that the diagnostic performance of this test may be lower in hospitalized and other acutely ill patients suffering from nonthrombotic disorders, due to the high prevalence of false-positive results due to activation of hemostasis in a variety of non-thrombotic disorders [7]. The results of this epidemiological study in a large urban ED have some practical implications. First, our data support the hypothesis that D-dimer testing lacks specicity for diagnosing VTE, especially in elderly patients admitted to the ED, and in those with signicant co-morbidities [7,8,14]. The relationship between D-dimer and aging was indeed predictable, as already reported in previous investigations [1518], and the adoption of age-specic cut-offs may hence be a reasonable approach to increase its diagnostic specicity. In agreement with recent data of
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Heath et al. [19], we could conrm that systematic D-dimer testing, regardless of pre-test clinical probability, is of limited value for assessing thrombotic burden in patients admitted to the ED with a suspect of VTE, since a nal diagnosis of venous thrombosis could only be made in a minority of patients (i.e., 12.1%). Although in our investigation very high values of D-dimer were not necessarily exclusive markers of VTE, it is noteworthy that the frequency of VTE remarkably increased (by more than 6-fold) between patients with D-dimer values b 1000 ng/mL and those with values N 3000 ng/mL, corresponding to an OR of 8.5. This is an important nding for the clinical decision making in the ED, wherein the emergency physicians should consider the hypothesis that the likelihood of VTE may be very low in elderly patients with D-dimer values exceeding the diagnostic cut-off but lower than 1000 ng/mL (i.e., a value 4-fold higher than the diagnostic threshold), whereas venous thrombosis is much more likely in those with very high D-dimer levels (i.e., exhibiting values more than 12-fold higher than the diagnostic threshold). Although we cannot obviously conclude that further diagnostic testing can be safely omitted in patients with limited increase of D-dimer at ED admission, the cost-benet of increasing the overcrowding in the ED as well as the risk of radiation exposure should be carefully weighted in patients with moderate elevations of D-dimer, i.e., in those displaying values lower than 1000 ng/mL. It is also conceivable that the use of age-specic cut-offs, higher than the traditional diagnostic thresholds, may be advantageous for diagnosing VTE in older patients admitted to the ED with co-morbidities. We also acknowledge here that the retrospective design of the study, which led to the exclusion of 172 out of 1819 patients (9.5%) for missing a nal diagnosis, may be a limitation in our investigation, along with the lack of data regarding the proportion of subjects with unlikely/likely pretest probability to have D-dimer above the cut-off. Moreover, it cannot be excluded that VTE could have developed in 3 months after hospital discharge in patients with elevated D-dimer values. 5. Conclusions D-dimer lacks specicity for diagnosing VTE, especially in elderly patients admitted to the ED with signicant co-morbidities. In older patients, elevated values are more 35 frequently associated with VTE, so the use of higher cut-offs may be considered. Learning points

25

Frequency (%)

20 15 10 5 0 Infection Others Syncope Heart Failure Trauma

Cancer

D-dimer was examined in ED patients with suspected venous thromboembolism (VTE). A signicant correlation was found between age and D-dimer. Infection was the most frequent diagnosis, followed by VTE and syncope. As compared with values b 1000 ng/mL, the OR for VTE was 8.5 for D-dimer N 3000 ng/mL. D-dimer lacks specicity for diagnosing VTE in elderly patients with comorbidities.
Dyspnea Cerebrovascular ischemia >3000 ng/mL ACS COPD 1000-1999 ng/mL 2000-3000 ng/mL Atrial fibrillation

VTE

Conict of interests All authors have no actual or potential conict of interest including any nancial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately inuence, or be perceived to inuence, their work. References
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Fig. 2. Frequency of nal diagnoses in the entire cohort of patients (n = 1647), stratied according to D-dimer values at admission to the emergency department (ED). Other diagnoses include, in decreasing order, anemia, cirrhosis, subarachnoid hemorrhage, abdominal aortic aneurysm, supercial thrombosis, acute renal failure, cholecystitis, peripheral occlusive disease, lymphedema, epilepsy, intestinal ischemia, arthritis, hypertensive crisis, Baker's cyst, renal colic, recent surgery, pancreatitis, allergy, amyloidosis, gastric perforation and inguinal hernia.

<1000 ng/mL

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