Combined D-Dimer and Clinical Probability Are Usefulfor Exclusion of Recurrent Deep Venous Thrombosis

Carlos Aguilar1* and Valentin del Villar2

1 Department of Haematology, Hospital General Santa Barbara, Soria, Spain2 Department of Internal Medicine, Hospital General Santa Barbara, Soria, Spain

It is estimated that up to one-third of patients with a history of deep venous thrombosis

(DVT) present with symptoms of recurrent DVT. Our objective was to investigate both the

diagnostic value of D-dimer (DD) and safety of a standard diagnostic algorithm including

clinical assessment, plasma DD levels, and compression venous ultrasound as diagnostic

tools in outpatients presenting with clinically suspected acute recurrent DVT of the lower

limbs. We have enrolled 105 outpatients with a previous history of confirmed DVT and clini-

cally suspected recurrent DVT. A 3-month follow-up period was carried out for patients in

whom DVT was initially excluded. Prevalence of DVT in our study population was 44.8%

(47/105). DD was negative in 17.1% of cases (18/105) and DVT could be ruled out in 15.2% of

patients evaluated (16/105) on the basis of an unlikely clinical probability and a negative DD

result. Only one false negative DD result in a patient scored as likely for DVT was found.

Sensitivity, specificity, positive and negative predictive value of DD for the diagnosis of DVT

were 97.9% (95% CI 88.9–99.6%), 29.3% (95% CI 19.2–42.0%), 52.9% (95% CI 42.5–63.0) and

94.4% (95% CI 74.2%–99.0), respectively. Sensitivity was 100% (95% CI 75.7–100) in the

group of patients in whom DVT was considered unlikely. A diagnostic strategy combining

clinical evaluation and DD has proved to be useful for the exclusion of DVT in subjects with

clinically suspected recurrent DVT, especially in patients included in the lower clinical pre-

test probability group. Am. J. Hematol. 82:41–44, 2007. VVC 2006 Wiley-Liss, Inc.

Key words: D-dimer; deep venous thrombosis; diagnosis

INTRODUCTION

It is estimated that up to one-third of patientswith a history of deep venous thrombosis (DVT)present with symptoms of recurrent DVT [1]. As itis the case for first ever clinical suspicions only insome 30% of such patients a diagnosis of recurrentDVT can be made [2].Diagnostic tests may have serious limitations for

the diagnosis of this condition. In particular, com-pression venous ultrasound (CVU), which is the cur-rent mainstay of DVT diagnosis, can be problem-atic, since abnormalities (thickening and increasedechogenicity of the vessel wall, resistance to com-pression) may be detected in up to 70% of patientsdespite no evidence of recurrent disease in the yearfollowing a DVT and even remain as a permanentsequel in an area of previous thrombus [3]. Addi-tionally, recurrent thrombotic episodes have beenadvocated to be more likely in those cases in whichCVU abnormalities persist several months after theinitial episode [4].

A single recently published trial concluded that anegative D-dimer (DD) test alone is a useful toolfor ruling out acute recurrent DVT [5]. Diagnosticalgorithms using combined DD and clinical evalua-tion have proved to be useful and safe for exclusionof DVT in outpatients with a suspected first episodeof venous thrombosis [6–8]. Whether this approachcan be applied to outpatients with symptoms ofrecurrent DVT is currently unknown.We have carried out a prospective evaluation of a

cohort of outpatients presenting with clinically sus-pected acute recurrent DVT of the lower limbs who

*Correspondence to: Dr. C. Aguilar, Department of Haematol-ogy, Hospital General Santa Barbara, Paseo Santa Barbara s/n,42002-Soria, Spain. E-mail: caraguilar@excite.com

Received for publication 22 February 2006; Accepted28 June 2006

Published online 31 August 2006 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.20754

American Journal of Hematology 82:41–44 (2007)

VVC 2006 Wiley-Liss, Inc.

underwent a simple diagnostic algorithm includingclinical assessment, plasma DD levels and CVU asdiagnostic tools. Our objective was to test both thediagnostic value of DD in these cases as well as thesafety of our standard diagnostic strategy.

PATIENTS AND METHODS

Study Design

We performed an observational prospective studyaimed to investigate the diagnostic accuracy andclinical safety of a diagnostic algorithm using clinicalevaluation, DD and CVU for the diagnosis of acuterecurrent DVT of the lower limbs in outpatients.

Study Population

Patients enrolled were all consecutive individualsover 18 years of age, with a history of objectivelyconfirmed DVT, who were presented at the Emer-gency Department of the Santa Barbara GeneralHospital (Soria, Spain) between January 2004 andNovember 2005 showing clinical symptoms suggest-ing a possible diagnosis of DVT of either leg. Sub-jects on ongoing oral anticoagulant treatment andpregnant women were considered ineligible.

Diagnostic Approach

An initial clinical assessment by the attending phy-sician was performed using the modified Wells’ scorefor suspected DVT [8]. Patients scored as \DVT

likely" or \DVT unlikely" were managed accordingto the diagnostic algorithms showed in Fig. 1.

Diagnostic Procedures

We used an immunoturbidimetric quantitative DDassay (STA Liatest D-Di1; Diagnostica Stago,Asnieres sur Seine, France). A STA-Compact1 ana-lyzer (Diagnostica Stago) was used for sample test-ing. Any plasma concentration of DD < 0.4 mg/mlwas regarded as a negative result as previously vali-dated [9,10].Lower-limb Doppler CVU was performed within

three hours of admission to the Emergency Depart-ment by a Senior Radiologist who was aware of anyprevious ultrasonographic investigations, if available;compression was performed at standard 1-cm inter-vals all along the longitudinal axis of the venoussystem of the leg (common femoral vein, superficialfemoral vein, and popliteal vein) up to the poplitealtrifurcation [11,12]. Acute recurrent DVT was diag-nosed if evidence of noncompressibility in a venoussegment previously known to be free of disease oran increase in compressed venous diameter greaterthan 4 mm from baseline study were elicited [3].Both physicians clinically assessing the patients

and radiologists performing ultrasonographic studiescarried out an independent blinded evaluation of DDlevels, CVU results, and clinical scores of each patient.

Follow-up Period

Patients in whom DVT was ruled out were giveninstructions to return to hospital if symptoms per-

Fig. 1. Diagnostic algorithm followed in our patients.

42 Aguilar and del Villar

American Journal of Hematology DOI 10.1002/ajh

sisted or aggravated and were contacted everymonth for an overall period of three months inorder to record any episode of DVT that might havebeen initially missed. Medical records were alsoreviewed at the end of that period in order to ascer-tain any new episodes of DVT, intercurrent disor-ders, thrombotic risk factors or death.All patients who returned to hospital underwent

CVU irrespective of their clinical probability. Diag-nostic criteria for DVT were similar to those men-tioned above.

Statistical Analysis

All statistical parameters included in our studyand their 95% confidence intervals (95% CI) werecalculated according to binomial distribution usingEpidat (version 2.1) and Statgraphic Plus (version2.1) software.

RESULTS

We enrolled 105 outpatients in our study. Ofthese patients, 47 (44.8%) had DVT objectively con-firmed; confirmation rates in patients scored asunlikely and likely to have DVT were 21.2% (13/61)and 77.2% (34/44), respectively. Demographic char-acteristics and associated risk factors for thrombosisof patients with both suspected and confirmed DVTare summarized in Table I.Following clinical evaluation, DVT was deemed

to be likely or unlikely in 44 (41.9%) and 61(58.1%) individuals, respectively. A normal DDconcentration was elicited in 18 cases (17.1%) over-all. Patients scored as unlikely to have DVT andwith a normal DD test (this is those in whom DVTwas initially excluded without any further investiga-tions) accounted for 15.2% (16/105) of the entire se-ries and 24.6% (15/61) of cases included in thelower probability group. With only two exceptions,all patients in whom DVT was considered to belikely showed elevated DD plasma concentrations.Sensitivity of DD for the diagnosis of DVT was

97.9% (95% CI 88.9–99.6%), specificity 29.3%(95% CI 19.2–42.0%), positive predictive value 52.9%(95% CI 42.5–63.0%) and negative predictive value94.4% (95% CI 74.2–99.0%). These values were 100%(95% CI 75.7–100%), 30.6% (95% CI 19.5–44.5%),26.1% (95% CI 15.6–40.3%), and 100% (95% CI79.6–100%), respectively, for patients included in the\unlikely" group. Positive and negative likelihoodratios were 1.38 (95% CI 1.17–1.64) and 0.07 (95% CI0.01–0.52) for the whole series of patients enrolled.An appropriate follow-up period could be per-

formed in all patients; only one diagnosis of DVT(1/18–5.5%) and two deaths due to cancer were

recorded during this period. This diagnosis wasmade in a woman regarded as likely to have DVTand with initially normal both DD (0.18 mg/ml) andCVU; actually this was the only false negative DDresult elicited. Also this was the only DVT con-firmed among the 12 patients (1/12–8.3%) whoreturned to hospital for recurrent symptoms.

DISCUSSION

Our preliminary results show that a diagnosticapproach including clinical evaluation, DD andCVU is useful for exclusion of DVT, especially inpatients presenting with a low clinical probability.These conclusions are similar to those reported foroutpatients without any previous history of DVT byother research groups [6–8]; only one false negativeDD result was elicited in a patient scored as likelyfor the diagnosis of DVT, consistent with the higherrate of false negative DD results previously des-cribed in that group [8].Our study differs in its design from that by Rathbun

et al. [5] in several aspects. First, both inpatientsand individuals on oral anticoagulant treatment(OAT) were considered ineligible, given the lowerdiagnostic value of DD in those subsets of patients[13]; patients on warfarin made up 46% of subjectsenrolled in the study mentioned above, but a highrate of false negative DD results in this setting hasbeen reported [12]. Second, clinical evaluation wasnot part of the diagnostic approach and DVT exclu-sion was solely based on a negative DD result; eventhough, only a minority of patients likely to haveDVT show normal DD concentrations, and clinicalassessment may help not to miss potential DVTcases with a normal DD result in this probability

TABLE I. Demographic Characteristics and Associated

Risk Factors for Thrombosis

Patient characteristic All patients DVT confirmed

Age (SD) 69 (14) 71 (14)

Sex (M/F) 52/53 27/20

Risk factorsa 46 (43.8) 17 (36.1)

Cancer 4 (3.8) 2 (4.2)

Chemotherapy 3 (2.8) 1 (2.1)

Limb immobilization 2 (1.9) 1 (2.1)

Cava filter 2 (1.9) 2 (4.2)

Local trauma 1 (0.95) 0 (0)

Surgeryb 3 (2.8) 2 (4.2)

Varicose veins 7 (6.6) 1 (2.1)

Thrombophilia 6 (5.7) 1 (2.1)

Immobilizationc 5 (4.8) 3 (6.3)

Venous insufficiency 13 (12.4) 4 (8.4)

an(%).bRequiring general or regional anaesthesia in the previous 12 weeks.cPermanent or �3 days over the last 4 weeks.

43D-Dimer and Clinical Probability for DVT

American Journal of Hematology DOI 10.1002/ajh

group that would be overlooked should only DD beconsidered. Additionally, our 5.5% rate of DVTevents diagnosed during the follow-up period mightsuggest that CVU repeated a week after the initialprocedure should be recommended to all patients inwhom a diagnosis of DVT was considered likelyand initially excluded. It ensues from these findingsthat DD should only be ordered for patients inwhom DVT is deemed unlikely, since DD results donot alter the diagnostic approach in the rest.The number of patients enrolled is limited but

close to that reported by Rathbun et al. [5] assum-ing individuals on warfarin would not have beenconsidered; prevalence of DVT in our series ishigher (44.8 vs. 33%), but exclusion of patients onOAT with lower confirmation rates (about 13%[13]) might partly justify these differences.Overall sensitivity of DD for the diagnosis of

DVT was high (98%), but reached 100% in thoseoutpatients for whom DVT was considered clinicallyunlikely. Some 15% of patients (24.6% of this laterclinical probability group) could be safely dis-charged without the need of any diagnostic tests;the follow-up period was uneventful in all of them.This proportion is clearly lower to that reported byRathbun et al. [5] (45%); even if patients using oralanticoagulants had been excluded it would havebeen 36%. To a good extent the remarkably highermean age of our series of patients (71 vs. 55) mightbe responsible for these differences, since DD levelstend to increase with aging [14].Our study population was limited but we think

our results are interesting and clearly applicable toclinical practice; however as we mentioned abovethey must be regarded as preliminary and furtherstudies including more patients should be carriedout in order to define more clearly the accuracyof our standard diagnostic approach in this clinicalsetting.To sum up a diagnostic strategy combining clini-

cal evaluation and DD is useful for exclusion ofDVT in outpatients with a previous history of DVTpresenting with a low clinical probability and a neg-ative DD result; all the rest of patients shouldundergo CVU. DD should not be ordered whenDVT is judged to be clinically likely, since its result

is not followed by any change in the diagnosticstrategy.

REFERENCES

1. Koopman MM, Buller HR, ten Cate JW. Diagnosis of recur-

rent deep vein thrombosis. Haemostasis 1995;25:49–57.

2. Hull RD, Carter CJ, Jay RM, et al. The diagnosis of acute

recurrent deep venous thrombosis: A diagnostic challenge. Cir-

culation 1983;67:901–906.

3. Prandoni P, Cogo A, Bernardi E, et al. A simple ultrasound

approach for detection of recurrent proximal-vein thrombosis.

Circulation 1993;88:1730–1735.

4. Prandoni P, Lensing AW, Prins MH, et al. Residual venous

thrombosis as a predictive factor of recurrent venous throm-

boembolism. Ann Intern Med 2002;137:955–960.

5. Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer

result to exclude recurrent deep venous thrombosis: A manage-

ment trial. Ann Intern Med 2004;141:839–845.

6. Kearon C, Ginsberg JS, Douketis J, et al. Management of sus-

pected deep venous thrombosis in outpatients by using clinical as-

sessment and D-dimer testing. Ann Intern Med 2001;135:108–111.

7. Schutgens PE, Ackermark P, Haas FJ, Nieuwenhuis HK,

Peltenburg HG, Pjilman AH. Combination of a normal

D-dimer concentration and a non-high pretest clinical probabil-

ity score is a safe strategy to exclude deep venous thrombosis.

Circulation 2003;107:593–597.

8. Wells PS, Anderson DR, Rodger M, et al. Evaluation of

D-dimer in the diagnosis of suspected deep-vein thrombosis.

N Engl J Med 2003;349:1227–1235.

9. van der Graaf F, van den Borne H, van den Kolk M, de Wild

PJ, Janssen GW, van Uum SH. Exclusion of deep venous

thrombosis with D-dimer testing. Comparison of 13 D-dimer

methods in 99 outpatients suspected of deep venous thrombosis

using venography as reference standard. Thromb Haemost

2000;83:191–198.

10. Aguilar C, Martinez A, Martınez A, del Rıo C, Vazquez M,

Rodrıguez FJ. Diagnostic value of D-dimer in patients with a mod-

erate pretest probability of deep venous thrombosis. Br J Haematol

2002;118:275–577.

11. Lensing AW, Prandoni P, Brandjes D, et al. Detection of deep-

vein thrombosis by real-time B-mode ultrasonography. N Engl

J Med 1989;320:342–345.

12. Cogo A, Lensing AW, Wells P, Prandoni P, Buller HR. Noninva-

sive objective tests for the diagnosis of clinically suspected deep-

vein thrombosis. Haemostasis 1995;25:27–39.

13. Schutgens PE, Essebom EU, Haas FJ, Nieuwenhuis HK,

Biesma DH. Usefulness of a semi-quantitative D-dimer test for

the exclusion of deep venous thrombosis. Am J Med 2002;112:

617–621.

14. Aguilar C, del Villar V. Diagnostic performance of D-dimer is

lower in elderly outpatients with suspected deep venous throm-

bosis. Br J Haematol 2005;130:803–804.

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American Journal of Hematology DOI 10.1002/ajh