Stroke. 2006;37:1113-1115
Published online before print March 9, 2006,
doi: 10.1161/01.STR.0000209240.63821.1a
(Stroke. 2006;37:1113.)
© 2006 American Heart Association, Inc.
D-Dimer Predicts Early Clinical Progression in Ischemic Stroke
Confirmation Using Routine Clinical Assays
Mark Barber, MD, MRCP;
Peter Langhorne, PhD, FRCP;
Ann Rumley, PhD;
Gordon D.O. Lowe, MD, FRCP
David J. Stott, MD, FRCP
From the University Section of Clinical Gerontology and Vascular Medicine, Royal Infirmary, Glasgow, UK.
Correspondence to Dr Mark Barber, Academic Section of Geriatric Medicine, Room Disc 47, 3rd Floor, University Block, Royal Infirmary, Glasgow, G31 2ER. E-mail M.Barber{at}clinmed.gla.ac.uk
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Abstract
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Background and Purpose— Plasma
D-dimer levels, measured
using a research laboratory assay, independently predict progressing
ischemic stroke. We wished to confirm these findings using commercially
available assays and to provide data to allow the design of
intervention studies.
Methods— We studied 219 consecutive acute ischemic stroke admissions of whom 54 (25%) met criteria for progressing stroke.
Results— There were strong correlations between D-dimer results as measured by the Biopool AB, MDA and VIDAS assays; correlation coefficients r=0.91 to 0.94; all P<0.001. In binary logistic regression analyses, D-dimer, as measured by the 3 different assays, was an independent predictor of progressing stroke (odds ratios, 1.87 to 2.45; all P<0.001). This confirms the results of our original analysis (Biopool AB) using 2 commercial D-dimer assays, demonstrating the potential usefulness of D-dimer in providing early prognostic information after ischemic stroke in different clinical settings. We also provide information on the performance of the 3 assays in predicting progressing stroke at a variety of cutoff values.
Conclusions— Ischemic stroke patients at high risk of early progression can be identified using commercial D-dimer measurements. This could allow selection of high-risk patients for inclusion in randomized trials of early antithrombotic treatments.
Key Words: anticoagulants • cerebral infarction • coagulation • fibrin • fibrinogen • fibrinolysis • thrombin
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Introduction
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Early clinical progression of ischemic stroke is common and
is associated with poor prognosis.
1 D-dimer levels are elevated
in the acute phase of stroke and subsequently fall.
2–4 We previously demonstrated that plasma
D-dimer levels (along
with mean arterial blood pressure) independently predict progressing
ischemic stroke.
5 This measurement of
D-dimer was performed
with a commercially available ELISA from Biopool AB used in
our research laboratory. We wished to confirm our findings using
other commercially available assays commonly used by hospital
laboratories, particularly the MDA and VIDAS
D-dimer assays.
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Materials and Methods
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We studied consecutive ischemic stroke admissions.
5 Progressing
stroke was defined using a modification of the European Progressing
Stroke Study definition.
6 This requires deterioration in conscious
level, arm or leg weakness, or speech over 72 hours following
admission. Blood was taken within 24 hours of symptom onset,
and plasma samples were stored at –80°C before analysis.
The MDA
D-dimer assay is an automated latex particle-based immunoassay,
and the VIDAS
D-dimer assay is an automated enzyme-linked fluorescent
assay.
7
Univariate analysis of D-dimer levels used unpaired t tests of natural log-transformed levels. Correlations between the different assays were calculated using the Spearman rank method. Multivariate analysis was performed using a stepwise binary logistic regression procedure including variables when significance was found to be P<0.10 in univariate analysis.
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Results
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Fifty-four (25%) of the 219 patients recruited met the criteria
for progressing stroke. Results were unavailable for 7 of the
MDA
D-dimer assays and 5 of the VIDAS
D-dimer assays. There
were strong correlations between
D-dimer results as measured
by the 3 assays: correlation coefficient
r=0.94 between the
Biopool AB and MDA assays;
r=0.92 between the Biopool AB and
VIDAS assays; and
r=0.91 between the MDA and VIDAS assays (all
P<0.001). Median
D-dimer levels were higher in the progressing
stroke group compared with the group with no progression using
both the MDA assay (597 versus 348 ng/mL;
P=0.00002) and the
VIDAS assay (863 versus 407 ng/mL;
P=0.00002). The results of
the binary logistic regression analyses for the MDA and VIDAS
D-dimer assays are shown in
Table 1. These results were very
similar to those of the original analysis using the Biopool
AB ELISA.
5 Table 2 shows the sensitivity, specificity, and positive
predictive values for progressing stroke at percentile cutoffs
using the 3 assays.
View this table:
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[in a new window]
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TABLE 1. Logistic Regression Model of Independent Predictors of Progressing Ischemic Stroke, Including D-Dimer, by the MDA assay (a) and the VIDAS assay (b)
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View this table:
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[in a new window]
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TABLE 2. Sensitivity, Specificity, and Positive Predictive Values for Progressing Stroke at Percentile Cutoffs Using the 3 D-Dimer Assays
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Discussion
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We confirmed the results of our original analysis using 2 alternative
and commonly used routine
D-dimer assays. This confirms the
potential usefulness of
D-dimer in providing early prognostic
information after ischemic stroke in different clinical settings.
As a test,
D-dimer has the advantage over other measures of
thrombin generation (such as prothrombin fragment 1+2 and thrombin-antithrombin
complex levels) in that levels are resistant to ex vivo activation
and have a long half-life. The VIDAS assay has already been
recently shown to be of potential clinical value in prediction
of a high-risk group for proximal deep vein thrombosis among
patients with acute stroke.
8
We also provide information on the performance of the 3 assays at different cutoff values. It appears that the MDA and VIDAS D-dimer assays may perform marginally better than the Biopool assay as predictors of progressing ischemic stroke. This may reflect the fact that the Biopool assay we used has been set up to have greater analytical sensitivity at lower levels (important for epidemiological studies).
Strengths and weaknesses of this study are those of the original project.5 We studied a large consecutive group of subjects using few exclusion criteria. A single researcher assessed all patients. However, samples were taken within 24 hours of symptom recognition, rather than immediately, and detailed functional imaging was not performed as part of the study protocol.
Previous studies specifically designed to assess prevention of progressing stroke using anticoagulant or antiplatelet therapy have been negative9–11 (perhaps, in part, because a high-risk subgroup was not identified for recruitment). If, as we suggested previously, D-dimer is used to help target interventions aimed at preventing early neurological deterioration after acute ischemic stroke, then appropriate cutoff levels can be chosen for these different assays depending on the potential risks and benefits of the intervention used.5 For example, levels above the median (401 ng/mL for MDA; 513 ng/mL for VIDAS) identify 50% of patients in whom the risk of early progression is 33% compared with a risk of 16% in patients with below-median levels. Higher-risk groups for early (ischemic) progression, identified in this way, may merit consideration for randomized trials of early antithrombotic treatments (for example, heparins or new antiplatelet agents). Such trials of selective antithrombotic treatment should record neuroimaging data, stroke etiology, and the causes of progressing stroke. In addition, blood samples should be withdrawn earlier. These studies should ideally include, as end points, not only progressing stroke along with the modified Rankin scale and Barthel Index (the latter 2 at 3 months), but also venous thromboembolism.8
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Acknowledgments
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This study was supported by a grant from the Chief Scientist
Office of the Scottish Executive Health Department (CZG/1/72).
M.B. was an NHS Education for Scotland/Chief Scientist Office
clinical research fellow. The kits for MDA and VIDAS assays
of
D-dimer were supplied by bioMérieux.
Received November 2, 2005;
revision received January 10, 2006;
accepted January 16, 2006.
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References
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- Rödén-Jüllig Å. Progressing stroke: epidemiology. Cerebrovasc Dis. 1997; 7 (suppl 5): 2–5.
- Lip GYH, Blann AD, Farooqi IS, Zarifis J, Sagar G, Beevers DG. Sequential alterations in haemorheology, endothelial dysfunction, platelet activation and thrombogenesis in relation to prognosis following acute stroke: the West Birmingham Stroke Project. Blood Coagul Fibrinolysis. 2002; 13: 339–347.[CrossRef][Medline]
[Order article via Infotrieve]
- Haapaniemi E, Soinne L, Syrjala M, Kaste M, Tatlisumak T. Serial changes in fibrinolysis and coagulation activation markers in acute and convalescent phase of ischemic stroke. Acta Neurol Scand. 2004; 110: 242–247.[Medline]
[Order article via Infotrieve]
- Reganon E, Vila V, Martinez-Sales V, Vaya A, Lago A, Alonso P, Aznar J. Association between inflammation and hemostatic markers in atherothrombotic stroke. Thromb Res. 2003; 112: 217–221.[CrossRef][Medline]
[Order article via Infotrieve]
- Barber M, Langhorne P, Rumley A, Lowe GDO, Stott DJ. Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression. Stroke. 2004; 35: 1421–1425.[Abstract/Free Full Text]
- Barber M, Stott DJ, Langhorne P. An internationally agreed definition of progressing stroke. Cerebrovasc Dis. 2004; 18: 255–256.[CrossRef][Medline]
[Order article via Infotrieve]
- Houbouyan-Reveillard LL, Mihoubi A, Houdijk WP, Qanadli S, Joseph T, Courret JP, Page B, Goguel AF. Preliminary evaluation of two new rapid immunoturbidimetric D-dimer assays in patients with clinically suspected venous thromboembolism (VTE). Thromb Haemost. 2000; 84: 770–774.[Medline]
[Order article via Infotrieve]
- Kelly J, Rudd A, Lewis RR, Coshall C, Parmar K, Moody A, Hunt BJ. Screening for proximal deep vein thrombosis after acute ischemic stroke: a prospective study using clinical factors and plasma D-dimers. J Thromb Haemost. 2004; 2: 1321–1326.[Medline]
[Order article via Infotrieve]
- Rödén-Jüllig Å, Britton M, Malmkvist K, Leijd B. Aspirin in the prevention of progressing stroke: a randomized controlled study. J Intern Med. 2003; 254: 584–590.[CrossRef][Medline]
[Order article via Infotrieve]
- Duke RJ, Bloch RF, Turpie AG, Trebilcock R, Bayer N. Intravenous heparin for the prevention of stroke progression in acute partial stable stroke. Ann Intern Med. 1986; 105: 825–828.[Medline]
[Order article via Infotrieve]
- Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. J Am Med Assoc. 1998; 279: 1265–1272.[Abstract/Free Full Text]
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Abstract
Introduction