(Stroke. 1996;27:1516-1520.)
© 1996 American Heart Association, Inc.
Articles |
Deep Vein Thrombosis in Stroke
The Use of Plasma D-Dimer Level as a Screening Test in the Rehabilitation Setting
Northwestern University Medical School (R.L.H., E.J.R., P.R.Y., J.R.D., D.G.), the Rehabilitation Institute of Chicago (R.L.H., E.J.R., D.G.), and Northwestern Memorial Hospital (J.R.D.), Chicago, Ill.
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Abstract |
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Background and Purpose Venous thromboembolism is a leading cause of morbidity and mortality during the acute recovery period after stroke. This study investigated the utility of plasma D-dimer level as a diagnostic test for deep vein thrombosis (DVT) in patients hospitalized for stroke rehabilitation.
Method Plasma samples were drawn from 105 nonambulatory rehabilitation patients with recent ischemic or hemorrhagic stroke and assayed for D-dimer with an enzyme-linked immunosorbent method. Samples were drawn within 24 hours of venous duplex ultrasound (VDU) screening for DVT. Optimal discriminant analysis was used to determine whether plasma D-dimer level, age, sex, days after stroke onset, stroke etiology, National Institutes of Health Stroke Scale score, and ambulatory status could correctly classify patients' DVT status.
Results Fourteen of 105 patients had DVT identified by VDU scan. Of all attributes, only D-dimer level had significant ability to discriminate between patients with or without DVT (P<.0001). The optimal cut point for predicting DVT was D-dimer=1591 ng/mL, resulting in 79% sensitivity, 78% specificity, 35% positive predictive value, and 96% negative predictive value. Reducing the D-dimer cut point to 1092 ng/mL improved both sensitivity and negative predictive value to 100% but reduced specificity to 66% and positive predictive value to 31%.
Conclusions A D-dimer level 
1092 ng/mL can exclude the presence of DVT in stroke rehabilitation patients. When a D-dimer level >1092 ng/mL occurs, further diagnostic testing is necessary to confirm DVT. Plasma D-dimer level is a simple and inexpensive screening test for DVT during stroke rehabilitation.
Key Words: diagnosis • dimers • rehabilitation • venous thrombosis
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Venous thromboembolism is a common and serious medical complication after acute stroke and is a leading cause of morbidity and mortality during the acute recovery period. Limb paralysis, physical immobility, and blood hypercoagulability are important factors that have been related to the development of DVT. The incidence of stroke-related venous thromboembolism ranges from 23% to 75% in patients who do not receive prophylactic measures such as early mobilization, subcutaneously injected heparin, or externally applied intermittent pneumatic compression to the lower limbs.1 2 3 4 5 6 7 8 9 10 Even with prophylaxis the incidence of DVT remains 2% to 22%.2 3 7 The incidence of occult DVT found among patients with stroke on admission to rehabilitation is as high as 33%,10 with 11% of patients developing DVT during rehabilitation care.11 Because prophylactic measures can fail, early detection of venous thrombus formation is critical for prevention of respiratory compromise or death from pulmonary embolism.
Clinical signs and symptoms are unreliable for detection of DVT.12 Although contrast venography is the gold-standard diagnostic test, it is invasive and expensive. VDU is a safe, noninvasive alternative that has proven reliable for detection of DVT in symptomatic pa-tients,13 14 15 16 17 but it is costly to perform and requires expertise for interpretation.
A novel diagnostic approach to DVT uses plasma levels of coagulation markers such as D-dimer, a cross-linked fibrin degradation product that is generated during thrombus formation. Several studies indicate that the D-dimer assay can be applied as a simple, inexpensive screening test for venous thromboembolism. Using meta-analysis, Bounameaux et al18 showed that plasma D-dimer level has an overall diagnostic sensitivity of 97% and a specificity of 47% in various patient populations suspected of having DVT who were referred for venography. Such studies have not been performed in the acute stroke population or in the rehabilitation setting.
The purpose of this study was to evaluate whether plasma D-dimer level could identify patients with DVT referred for VDU screening during acute inpatient stroke rehabilitation. We assumed a priori that the standard normal D-dimer value for healthy adults (<500 ng/mL) may not be the best cut point for discriminating DVT in this population. Therefore, we also sought to define the optimal plasma D-dimer level cut point for discriminating DVT status in patients with stroke.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
Stroke rehabilitation inpatients were recruited from the Rehabilitation Institute of Chicago's Center for Stroke Rehabilitation. Patients were included if they had an acute (<3 months) ischemic or hemorrhagic stroke as confirmed by clinical examination and cranial CT or MRI scan. Since ambulatory patients are at low risk for developing DVT, only those ambulating <100 feet on rehabilitation admission, with or without an assistive device, were included. Patients with renal failure, cancer, or a filter through the vena cava or those receiving warfarin anticoagulation were excluded from the study. Also excluded were those patients unable or unwilling to sign informed consent. This study was approved by the institutional review board of Northwestern University.
Procedures
Age, sex, date of stroke, and date of admission to rehabilitation were documented for each patient. Using clinical examination and review of available laboratory tests, we classified stroke etiology as ischemic or hemorrhagic for each subject. The method of DVT prophylaxis used before and during rehabilitation hospitalization and use of antiplatelet medications were noted.
A physical examination to assess neurological status on admission was performed by a physician investigator (R.L.H.) and scored according to the NIHSS.19 FIM score on admission,20 as assessed by a certified nurse evaluator using Uniform Data System criteria, was recorded retrospectively from each patient's chart.
All study patients underwent VDU scanning and blood sampling for D-dimer during inpatient rehabilitation. VDU scans were performed by an experienced vascular technologist using an Ultra Mark 4 Duplex instrument (Advanced Technology Laboratories) and interpreted by a vascular surgeon (J.R.D.). Studies were positive for DVT if thrombus was visualized on B-mode ultrasound or if noncompressibility was noted in proximal deep veins including the femoral, superficial femoral, and popliteal veins. Altered respiratory variation on venous Doppler distal to the occlusion was confirmatory.
Within 24 hours of the VDU scanning, a single (5-mL) plasma sample was drawn in a 3.2% citrated evacuated tube from each subject. Each sample was centrifuged immediately at 3000 rpm for 10 minutes and stored at -70°C for later assay. Plasma D-dimer assays were performed in a blinded manner with the Asserachrom D-Di enzyme immunoassay kit (Diagnostica Stago). All samples were run in duplicate at 1:200 and 1:400 dilutions because of the elevated D-dimer concentrations found in study patients. D-Dimer levels were determined by spectrophotometry at a wavelength of 492 nm (Reader 400, SLT Lab Instruments).
Analysis
Because the purpose of this study was to assess the diagnostic utility of plasma D-dimer level as a screening test for DVT, the data were analyzed from the perspective of the ODA para-digm.21 22 23 24 ODA is ideal for this purpose because it explicitly maximizes weighted or unweighted classification accuracy rather than variance or likelihood functions. Univariate analysis treated DVT status as the class variable. Attributes included plasma D-dimer level (nanograms per milliliter), subject age (years), sex, number of days since stroke, stroke etiology, admission NIHSS score, and FIM score for ambulatory status on admission. Weighting by prior odds was used because of differing numbers of patients in the two class categories, and permutation probabilities were estimated with data from 10 000 Monte Carlo experiments.21 22 Hypothesizing that plasma D-dimer levels would be higher in patients with DVT, we used a one-tailed analysis; other univariate analyses were two-tailed. We estimated cross-generalizability of each univariate model in discriminating DVT status for independent random samples using a "leave-one-out" (jackknife) validity analysis, in which each patient is classified using a model created on the basis of data from all patients except the one being classified. Multivariate analysis was unable to identify a statistically reliable multiattribute model for predicting DVT status.23 24 25 26 27
The preceding analysis produced an optimal D-dimer cut point to maximize model accuracy while minimizing both false-positives and false-negatives. Since classification accuracy was <100% and because misidentifying the presence of DVT would be contradictory to the goals of a screening test, a second optimal discriminant analysis was conducted that evaluated a model in which false-negative errors were minimized.
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Results |
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One hundred forty-eight patients were recruited for the study. A total of 43 patients were excluded by the preestablished criteria: 25 (58%) were receiving warfarin anticoagulation, 9 (21%) could not provide informed consent, 4 (9%) had a filter through the vena cava, 4 (9%) had renal failure, and 1 (2%) had cancer. Descriptive statistics for study attributes from the remaining 105 patients, dichotomized by VDU scanning results, are provided in Table 1
. Fourteen patients had DVT identified by VDU scan. Positive VDU scan results were confirmed by ascending venography in 2 patients (14%) after blood samples were obtained; no patients with negative scans underwent venography. Use of heparin prophylaxis before or during rehabilitation did not significantly differ between patients with and without DVT. When univariate ODA was used, for the entire sample plasma D-dimer level showed a statistically significant ability to identify the presence or absence of DVT in nonambulatory patients admitted for acute inpatient rehabilitation (P<.0001). All other univariate models tested failed to discriminate DVT status: age (P=.85), days after stroke (P=.61), NIHSS score (P=.90), FIM score for ambulation on admission (P=.64), stroke etiology (P=.64), and sex (P=.79).
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The optimal D-dimer level cut point for discriminating the presence or absence of DVT was determined to be 1591 ng/mL by ODA. The model predicts that patients with D-dimer level 1591 ng/mL are free of DVT and patients with D-dimer level >1591 ng/mL have DVT. When applied to the total sample, this model correctly classified 81% of the patients (Table 2). However, jackknife analysis indicated marginal instability, with cross-generalizability of overall accuracy estimated to be 78% (Table 3). The jackknife values for sensitivity (79%), specificity (78%), positive predictive value (35%), and negative predictive value (96%) indicate that this model shows good utility for excluding the presence of DVT in stroke survivors within the rehabilitation setting. The overall effect strength is expressed on a scale of 0 to 1, in which 0 represents chance and 1 represents perfect classification performance. The plasma D-dimer cut point value of 1591 ng/mL for patients with stroke has a jackknife effect strength of 0.44, indicating that the model provides moderate ability to identify patients with or without DVT.
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If plasma D-dimer is to be used as a screening test to primarily exclude the presence of DVT, thereby preventing the need for further diagnostic evaluation, the plasma D-dimer cut point should provide perfect sensitivity for DVT and eliminate risk for false-negatives. Accordingly, the data were reanalyzed to determine a new cut point for plasma D-dimer that maximizes test sensitivity and negative predictive value. The resulting ODA model predicts that patients with plasma D-dimer level 1092 ng/mL are free of DVT, yielding 100% sensitivity and negative predictive value in both total sample and jackknife analyses (P<.0001). However, this model shows reduced test specificity (66%) but a slightly improved overall effect strength (0.48) relative to the former model (Tables 4 and 5).
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Discussion |
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Medical complications during recovery from stroke can interrupt the rehabilitation process and adversely affect functional outcome. Pulmonary embolism is the fourth leading cause of death acutely after stroke and the most common cause of sudden death during the period of acute rehabilitation.28 29 Prevention of pulmonary embolism is dependent on both appropriate use of prophylaxis and early detection and treatment of DVT. Absent clinical signs and symptoms do not accurately exclude venous thrombosis,12 and venography is too invasive to use routinely for screening. VDU is a good screening alternative that is quite accurate in symptomatic patients, with sensitivity of 93% to 95% and specificity of 96% to 100% compared with venography,30 but it is technically complicated, expensive, and not readily available at night or on weekends. Plasma D-dimer testing is equally noninvasive but has the additional advantage of being simple and inexpensive to perform.
In the present study we tested whether several clinical factors could correctly classify patients with or without DVT as detected by VDU during acute inpatient stroke rehabilitation. Age and time since stroke were not predictive of DVT. Level of neurological impairment and ambulatory status also had no reliable predictive value, possibly as a result of sample bias since only patients with limited ambulatory skills were selected.
As hypothesized, we found that D-dimer level was significantly elevated in patients with either ischemic or hemorrhagic stroke who had DVT. A diagnostic cut point of 1591 ng/mL was determined with the aid of an ODA classification model that provided maximum test accuracy for discriminating the DVT status of patients. Using a second model, we showed that a cut point value of 1092 ng/mL reduced overall classification accuracy but correctly identified all patients with DVT. The clinical implications of this finding are extremely important. A D-dimer value 1092 ng/mL can exclude the presence of DVT with the same level of confidence as a normal VDU. However, further diagnostic testing with VDU or venography is necessary to confirm the presence of DVT in patients with D-dimer values >1092 ng/mL (Figure). Future research with larger samples should test the reliability of these D-dimer cut points over multiple replications. Multiattribute models yielding greater overall accuracy may also be identified by the use of additional clinical and hematologic factors that are predictive of DVT.
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Clinical use of the D-dimer immunoassay could result in considerable cost reduction in the care of patients with stroke. At our institution the charge for D-dimer immunoassay is $75, whereas bilateral lower limb VDU is $550, including physician interpretation. Fifty-seven percent of the present study sample could have had DVT ruled out with D-dimer assay alone. For our study sample, the screening model presented in the Figure
would reduce total charges by 44%. Avoiding transportation costs to outside vascular laboratories could also provide additional savings for freestanding rehabilitation facilities.
Based on this model, we suggest that plasma D-dimer level, measured by ELISA technology, is a simple and inexpensive initial screening test for DVT in the stroke rehabilitation setting. Our data indicate that a majority of physically impaired patients with stroke who are typically considered at risk can have DVT safely excluded by plasma D-dimer level and avoid the need for further diagnostic testing.
These findings are similar to results from other studies that have evaluated the use of plasma D-dimer level for detection of thromboembolism. For DVT, the range of diagnostic sensitivity with D-dimer assay is 92% to 100% with a specificity of 21% to 51% compared with VDU in various hospitalized and outpatient populations.31 32 33 34 35 When compared with venography, D-dimer level shows similar results: 95% to 100% sensitivity and 6% to 65% specificity.36 37 38 39 40 Sensitivity for pulmonary embolism confirmed by nuclear scanning or pulmonary angiography is 93% to 100%, with specificity of 19% to 100%.41 42 43 44 45 46 47 In general, plasma D-dimer level has proven to be a sensitive but nonspecific indicator of thromboembolic disease.
The poor test specificity found in this and other studies is an indication that plasma D-dimer level might be elevated in any condition in which intravascular thrombosis may occur, such as trauma, surgery, or severe illness. The present study involved patients with recent stroke, including some with intracerebral hemorrhage, craniotomy, recent gastric tube placement, and other medical comorbidities. A further explanation for the low specificity is that many patients examined in this study were asymptomatic for DVT. The sensitivity of VDU in asymptomatic postoperative neurosurgical patients was <70% in one study.48 This raises the possibility that some patients harbored venous thrombi that were undetected by VDU and yet were reflected by high levels of plasma D-dimer.
The use of the ELISA technique in the present study is important when the application of plasma D-dimer assays is considered. Most clinical laboratories use a latex agglutination technique that yields results in a matter of minutes, whereas the ELISA method requires approximately 4 hours. Unfortunately, the diagnostic sensitivity of the latex agglutination method remains controversial and has not been recommended over the ELISA method.* Therefore, the model presented in this study can only be applied when the ELISA technique is used. A newer whole blood D-dimer test that can be rapidly performed at bedside has recently been developed and shows some promise as a clinical tool, but further testing is needed.52
We conclude that D-dimer immunoassay is a simple method to exclude the presence of DVT in patients with stroke during inpatient rehabilitation and is a cost-effective initial screening tool for diagnostic use in this population. It is particularly valuable for freestanding rehabilitation facilities that have laboratory services but lack more elaborate diagnostic testing, such as duplex ultrasound or venography. Further clinical studies with diagnostic decision trees that incorporate the D-dimer assay as an initial screen are warranted.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the American Heart Association, Metropolitan Chicago affiliate; National Research Service Award (Department of Health and Human Services) grant 1-T32-HD07418-01; and the Women's Board of the Rehabilitation Institute of Chicago.
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Footnotes |
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Reprint requests to Richard L. Harvey, MD, Rehabilitation Institute of Chicago, 345 E Superior St, Chicago, IL 60611. E-mail r-harvey@nwu.edu.
*References 31, 32, 36, 38, 39, 44, 46, 49-51.
Received April 9, 1996; revision received May 23, 1996; accepted May 23, 1996.
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