causes of elevated d-dimer in patients admitted to a large urban ed

8/12/2019 Causes of Elevated D-Dimer in Patients Admitted to a Large Urban ED

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

a b s t r a c ta r t i c l e i n f o

Article history:

Received 30 March 2013Received in revised form 16 July 2013

Accepted 19 July 2013

Available online 13 August 2013

Keywords:

D-dimer testing

Emergency department

Venous thromboembolism

Thrombosis

Background: Although the request for D-dimer is widespreadin emergency departments (EDs), the causes of el-

evation 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 throm-

boembolism (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 be-

tween 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 b0.001). The frequency of VTE gradually increased

from patients with values b1000 ng/mL to those with D-dimerN3000 ng/mL (4.1 vs 26.7%; p b0.001). As com-

pared with D-dimer values b 1000 ng/mL, the Odds Ratio for VTE was 8.5 for values N3000 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 (N1000 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.

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 per100,000, with a con-

stant trend of increase of approximately 26 cases per 100,000 every new

year [1]. Nearly one third of the patients with symptomatic VTE are diag-

nosed with PE, whereas two thirds are diagnosed with DVT alone [2]. Al-

thoughthe prevalenceis reportedly heterogeneous among differentracial

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 com-

pared with those aged less than 15 years. Although no denitive conclu-

sions can be drawn about gender prevalence, it has been hypothesized

that sex may not be an independent risk factor [3]. The severity of this pa-

thology 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 thata 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 lim-

itations, comprehensively reviewed elsewhere [7,8], D-dimer is now

widely recognized as the biochemical gold standard in the diagnostic ap-

proach 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 admit-

ted to the ED with a consistent suspicion of VTE, irrespective of their

pre-test probability of disease, analysis of clinical outcomes and relation-

ship 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

European Journal of Internal Medicine 25 (2014) 4548

Corresponding author at: U.O. Diagnostica Ematochimica, Azienda Ospedaliero-

Universitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy. Tel.: +39 0521 703050, +39

0521 703791.

E-mail addresses:[email protected],[email protected](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

Contents lists available atScienceDirect

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http://dx.doi.org/10.1016/j.ejim.2013.07.012http://dx.doi.org/10.1016/j.ejim.2013.07.012http://dx.doi.org/10.1016/j.ejim.2013.07.012mailto:[email protected]:[email protected]:[email protected]://dx.doi.org/10.1016/j.ejim.2013.07.012http://www.sciencedirect.com/science/journal/09536205http://www.sciencedirect.com/science/journal/09536205http://dx.doi.org/10.1016/j.ejim.2013.07.012mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.ejim.2013.07.012


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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 immu-

noassay, 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 thelaboratory information system (LIS). The nal diagnosis after ED admis-

sion 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 subse-

quently reviewed by two expert physicians for deleting wrong registra-

tions 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

suspectedDVT and/or PE aresubjected to compression ultrasonography

(CUS) and computed tomography (CT), respectively[11], which are

nally judged by an expert ultrasonographist or radiologist. Preg-

nant 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 studywas 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 sev-

enty two patients were excluded from the analysis because thenal di-

agnosis was unavailable, unclearor mixed, so thenal 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 brilla-tion. 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 frequentnal diagnosis in the whole co-

hort 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 di-

agnosed in 19 patients, accounting for 1.2% ofnal diagnoses. D-dimer

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

N3000 ng/mL (71/266; 26.7%). This difference was highly statistically

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 valueabove the diagnos-

tic cut-off of the local immunoassay.

Final diagnosis n %

Infection 257 15.6

VTE 200 12.1

Syncope 155 9.4

Heart failure 146 8.9Trauma 135 8.2

Cancer 95 5.8

Dyspnea 94 5.7

Cerebrovascular ischemia 93 5.6

ACS 92 5.6

COPD 87 5.3

Atrialbrillation 81 4.9

Anemia 22 1.3

Cirrhosis 22 1.3

Subarachnoid hemorrhage 20 1.2

Abdominal aortic aneurysm 19 1.2

Supercial thrombosis 19 1.2

Acute renal failure 18 1.1

Cholecystitis 18 1.1

Peripheral occlusive disease 16 1.0

Lymphedema 12 0.7

Epilepsy 9 0.5Intestinal ischemia 8 0.5

Arthritis 6 0.4

Hypertensive crisis 6 0.4

Baker's cyst 4 0.2

Renal colic 4 0.2

Recent surgery 3 0.2

Pancreatitis 2 0.1

Allergy 1 0.1

Amyloidosis 1 0.1

Gastric perforation 1 0.1

Inguinal hernia 1 0.1

VTE, venous thromboembolism;COPD, chronic obstructive pulmonarydisease; ACS, acute

coronary syndrome.

0

2000

4000

6000

8000

10000

12000

VTE Other

D-d

imer

(ng

/mL)

p


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signicant (Pearson's chi-square statistic 122; p b0.001). As compared

with D-dimer values b1000 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 b0.001) for those with valuesbe-

tween 2000 and 3000 ng/mL, and 8.5 (95% CI,5.4 to 13.2; p b 0.001) for

those with values N3000 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 unavoid-

able [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 proba-

bility (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 non-

thrombotic 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 lacksspecicity for diagnosing VTE, especially in elderly

patients admitted to theED, andin those with signicant co-morbidities

[7,8,14]. The relationship between D-dimer and aging was indeed pre-

dictable, 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

Heath et al.[19], we could conrm that systematic D-dimer testing, re-

gardless 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 ve-

nous thrombosis is much more likely in those with very high D-dimer

levels(i.e.,exhibiting valuesmore than 12-fold higherthan thediagnos-

tic threshold). Although we cannot obviously conclude that further

diagnostic testing can be safely omitted in patients with limited in-

crease of D-dimer at ED admission, the cost-benet of increasing

the overcrowding in the ED as well a s 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 withunlikely/likely pre-

test probability to have D-dimer above thecut-off. Moreover, it cannotbe

excluded that VTE could have developed in 3 months after hospital dis-

charge 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, sothe use of higher cut-offs may be considered.

Learning points

D-dimer was examined in ED patients with suspected venous throm-

boembolism (VTE).

A signicant correlation was found between age and D-dimer.

Infection was the most frequent diagnosis, followed by VTE and syn-

cope.

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.

Conict of interests

All authors have no actual or potential conict of interest including

anynancial, personal or other relationships with other people or orga-

nizations withinthree years of beginning thesubmitted work that could

inappropriately inuence, or be perceived to inuence, their work.

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3000ng

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VTE

Atrialfibri

lla

tion

COPD

ACS

Cere

brovascu

lar

isc

hem

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Cancer

Traum

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causes of elevated d-dimer in patients admitted to a large urban ed

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