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A Latex D-Dimer Reliably Excludes Venous Thromboembolism
Shannon M. Bates, MD, CM;
Anne Grand'Maison, MD;
Marilyn Johnston, ART;
Ivy Naguit, MLT;
Michael J. Kovacs, MD;
Jeffrey S. Ginsberg, MD
Arch Intern Med. 2001;161:447-453.
ABSTRACT
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Background D-Dimer, a cross-linked fibrin degradation product, has a high sensitivity
in patients with suspected venous thrombosis. Traditional latex D-dimer assays,
however, have not been sufficiently sensitive to exclude venous thromboembolism.
Methods To determine the clinical utility of a latex D-dimer assay (MDA D-Dimer;
Organon Teknika Corporation, Durham, NC) in patients with suspected venous
thromboembolism, we conducted a retrospective cohort study involving 595 unselected
patients at 4 tertiary care hospitals. Patients had blood drawn for performance
of the D-dimer assay and underwent objective testing for venous thromboembolism.
Pretest probability was determined using validated models in 571 patients.
Patients were classified as venous thromboembolism positive or negative according
to results of objective tests and 3-month follow-up. The sensitivities, specificities,
predictive values, and negative likelihood ratios of the assay were calculated
for all patients and for subgroups of patients with known cancer or a low,
moderate, or high pretest probability of venous thromboembolism.
Results The prevalence of venous thromboembolism was 19.0% (113/595). Of those
who had a pretest probability assessment, 35.9% had a low pretest probability,
49.7% a moderate pretest probability, and 14.4% a high pretest probability.
Using a discriminant value of 0.50 µg fibrinogen equivalent units per
milliliter, the assay showed an overall sensitivity of 96%, a negative predictive
value of 98%, a specificity of 45%, and a negative likelihood ratio of 0.09.
In patients with a low or moderate pretest probability, the sensitivity, negative
predictive value, and negative likelihood ratio were 97%, 99%, and 0.07, respectively.
Conclusions The MDA D-Dimer assay is the first latex agglutination assay with sufficient
sensitivity to be clinically useful in the exclusion of venous thromboembolism.
A negative result has the potential to be used as the sole test to exclude
venous thromboembolism in patients with a low or moderate pretest probability
of disease.
INTRODUCTION
DEEP VEIN thrombosis (DVT) and pulmonary embolism, collectively termed
venous thromboembolism, are common causes of morbidity and mortality.1 It is important that venous thromboembolism be accurately
diagnosed because if left untreated it can be fatal,1
and treatment with anticoagulants may cause serious complications.1 Clinical diagnosis alone of venous thromboembolism
is inaccurate, and most patients with suspected venous thromboembolism do
not have the disease.2, 3
Although objective tests have been developed for the diagnosis of venous
thromboembolism, several problems remain. Many of these tests are not available
during the night and weekends and, therefore, patients who present with suspected
venous thromboembolism during these times are often treated with empiric anticoagulants
until diagnostic testing can be performed. This frequently results in unnecessary
exposure to anticoagulant therapy because, in most cases, venous thromboembolism
is ruled out.2, 3 The reference
standard tests, venography and pulmonary angiography, are expensive, invasive,
and have associated morbidity.1, 2, 4, 5, 6, 7
Noninvasive tests for DVT, such as impedance plethysmography (IPG) and compression
ultrasonography (CUS), while sensitive and specific for occlusive proximal
DVT, have a low sensitivity for calf vein thrombosis, which make up approximately
15% of thrombi.1, 2, 8, 9, 10
Therefore, if the initial results are normal, these tests must be performed
serially to exclude proximal extension of isolated calf DVT, which occurs
in 20% to 30% of patients with isolated calf thrombus and predisposes them
to pulmonary embolism.1, 2, 8, 9, 10, 11
This is an inconvenient and costly strategy.
Although radionuclide ventilation-perfusion ( / ) lung scanning
is useful in patients with clinically suspected pulmonary embolism; the results
are inconclusive in 40% to 60% of patients.12, 13
The management of cases with such nondiagnostic scans is problematic because
the prevalence of pulmonary embolism in this population is approximately 25%.12, 13, 14 This necessitates
the performance of pulmonary angiography for definitive diagnosis or investigation
of the legs for DVT with contrast venography14
or serial IPG or CUS.15 The diagnosis of recurrent
DVT also remains problematic because the results of venography,16
CUS,17 and less frequently, IPG18
may be abnormal as a result of the previous DVT, which makes the diagnosis
of new thrombosis difficult.
D-Dimer, a specific cross-linked fibrin degradation product, has a high
sensitivity and negative predictive value (NPV) in patients with suspected
venous thromboembolism.19, 20, 21, 22, 23, 24, 25, 26, 27, 28
Three techniques are available to quantitate D-dimer.19
The clinical utility of the whole red-cell agglutination assay (SimpliRED;
Agen Biomedical Ltd, Brisbane, Australia) has been the most extensively evaluated.20, 21, 22, 23, 24
Although a number of studies suggest that this assay has a high sensitivity
for venous thromboembolism,20, 21, 22, 23
not all centers have demonstrated similar results.24
Moreover, a normal SimpliRED D-dimer result only reliably excludes DVT in
patients with a low pretest probability or a normal noninvasive test,22 and is not useful in patients with cancer.25 The time-consuming nature and low specificities19 of traditional enzyme-linked immunosorbant assays
(ELISAs) have limited their use. Although more rapid ELISAs have been developed,
the latter problem still remains.26, 27, 28
Manual nonquantitative latex D-dimer assays are rapidly performed and their
specificities have traditionally been higher than those of ELISA.19 In the past, however, these latex assays have not
been sufficiently sensitive to exclude venous thromboembolism.19
The MDA D-Dimer (Organon Teknika Corporation, Durham NC) is a quantitative
immunoassay that uses photo-optics to detect agglutination of latex microparticles
as an index of binding of a specific monoclonal antibody to D-dimer and seems
to be more sensitive than traditional visual latex assays. We therefore performed
a retrospective cohort study to determine whether this D-dimer assay has a
high sensitivity and NPV for venous thromboembolism, and if the specificity
is sufficiently high to make the test clinically useful.
PATIENTS, MATERIALS, AND METHODS
The study was performed between September 1997 and January 1999. Four
university-affiliated tertiary care hospitals participated, 2 in Hamilton,
Ontario (Henderson General Hospital and McMaster University Medical Centre,
both of the Hamilton Health Sciences Corporation), and 2 in London, Ontario
(University Hospital and Victoria Hospital, both of the London Health Sciences
Centre). The study conformed to the guidelines set forth by each center's
research ethics board, and all patients provided informed consent.
PATIENTS
The study population consisted of unselected outpatients with clinically
suspected DVT or pulmonary embolism referred to the thromboembolism service
at the 2 Hamilton centers and the emergency department at the London centers.
At the 2 Hamilton sites, more than 95% of outpatients with suspected venous
thromboembolism were referred to the thromboembolism service for consultation.
CLINICAL INTERVENTION
Patients with suspected DVT or pulmonary embolism had their history
taken and underwent physical examination. Prior to diagnostic testing, patients
were assigned a pretest probability of venous thromboembolism using previously
validated models that include an assessment of clinical symptoms and signs,
risk factors for venous thromboembolism, and the presence of an alternative
diagnosis.29, 30 Patients were
evaluated with appropriate objective tests per the consulting physician. Ascending
venography, IPG, or CUS were performed on all patients with suspected DVT,
as previously described,4, 31, 32
except for some of those with a low pretest probability and negative findings
on the whole red-cell agglutination D-dimer assay. Patients with normal initial
IPG or CUS results underwent serial testing approximately 1 week later, unless
they had a negative red-cell agglutination D-dimer assay or a low pretest
probability of venous thromboembolism. The safety of these latter approaches
has been validated by previous clinical trials (personal communication, C.
Kearon, November 1999).22
Ventilation-perfusion lung scans were performed on all patients with
suspected pulmonary embolism, as previously described,14
except for some who had a low pretest probability and negative findings on
the red-cell agglutination D-dimer assay. A previous study23
has demonstrated that the NPV of this combination of findings in patients
with suspected pulmonary embolism is 99%. Patients with a nondiagnostic lung
scan (segmental perfusion defects with matched ventilation defects, subsegmental
perfusion defects with or without ventilation defects, or perfusion defects
with corresponding abnormalities on chest radiograph) and normal initial CUS
findings underwent serial CUS testing approximately 1 week later, unless they
had negative results on the red-cell agglutination D-dimer assay. A previous
study23 found patients with the combination
of a nondiagnostic / scan, negative results on a red-cell agglutination
D-dimer assay, and normal findings on initial CUS to have an NPV of 99%. Patients
with high or moderate pretest probability of pulmonary embolism and a high-probability
/ scan finding (segmental or greater perfusion defect with normal ventilation)
were diagnosed with pulmonary embolism. Those with high-probability /
scan results and a low pretest probability underwent either bilateral ascending
venography or pulmonary angiography to confirm the diagnosis of pulmonary
embolism; previous studies have shown that only about one half of such patients
have pulmonary embolism.12, 13
Anticoagulant therapy was withheld in all patients with negative objective
test results, and these patients were observed for 3 months for symptomatic
venous thromboembolism. Patients in whom DVT or pulmonary embolism was diagnosed
at presentation or during follow-up were treated with anticoagulants per local
practice.
OUTCOME MEASURES
Patients were classified as venous thromboembolism positive or negative
according to the results of objective testing and 3-month follow-up. Patients
were considered DVT positive when 1 of the following occurred: (1) presence
of an intraluminal filling defect evident in 2 or more views on ascending
venography; (2) absence of compressibility of the common femoral vein and/or
popliteal vein on CUS; or (3) symptomatic venous thromboembolic event verified
by objective testing within 3 months of presentation with suspected DVT. Patients
were considered DVT negative when 1 of the following results occurred along
with an absence of symptomatic venous thromboembolism within 3 months of follow-up:
(1) normal venography findings; (2) normal serial CUS results; (3) normal
CUS or IPG results in the presence of a low pretest probability of DVT or
negative red-cell agglutination D-dimer assay findings; (4) normal serial
IPG results; or (5) low pretest probability and a negative D-dimer result.
Pulmonary embolism was diagnosed in the presence of 1 of the following:
(1) a pulmonary angiogram with an intraluminal filling defect present on 2
or more views; (2) a high-probability / scan in patients with a moderate
or high pretest probability of disease; (3) a nondiagnostic lung scan and
either abnormal CUS findings or ascending venography results; (4) a high-probability
/ scan and abnormal ascending venography or CUS results in patients
with a low pretest probability of pulmonary embolism; or (5) symptomatic venous
thromboembolism verified by objective testing within 3 months of presentation
with suspected pulmonary embolism. Pulmonary embolism was excluded if 1 of
the following occurred along with an absence of symptomatic venous thromboembolism
within 3 months of follow-up: (1) normal pulmonary angiography results; (2)
normal perfusion lung scan findings; (3) a nondiagnostic lung scan without
evidence of DVT; or (4) a low pretest probability and negative results on
red-cell agglutination D-dimer assay. Patients were considered venous thromboembolism
positive if DVT or pulmonary embolism was diagnosed according to the above
criteria and venous thromboembolism negative if DVT and pulmonary embolism
were excluded according to the above criteria.
LABORATORY INTERVENTION
At the time of referral, venous blood was collected in 5-mL Vacutainer
tubes (BC Vacutainers; Becton Dickinson Co, Mountain View Calif) prefilled
with 0.5 mL of 3.2% (0.105 mol/L) trisodium citrate-didihydrate. Specimens
were centrifuged at 1700g for 15 minutes at room
temperature. Platelet-poor plasma was then aliquotted into polystyrene tubes
that were maintained at -70°C until assayed in batches. D-Dimer
assays were performed according to manufacturer's instructions on the MDA
180 automated coagulometer (Organon Teknika Corporation) using a commercial
kit (MDA D-Dimer).
DETERMINATION OF D-DIMER DISCRIMINANT VALUE
The optimal discriminant value for the D-dimer assay was determined
by receiver-operator curve analysis using the first 150 patients. A value
of 0.50 µg fibrinogen equivalent units (FEU) per milliliter was chosen
because it provided the highest sensitivity with a specificity approximating
50%. For the purposes of analysis, results were expressed as either negative
(<0.50 µg FEU/mL) or positive ( 0.50 µg FEU/mL).
ANALYSIS AND STATISTICS
In the primary analysis, the accuracy indices (sensitivity, specificity,
NPV, positive predictive value [PPV], and negative likelihood ratio) of the
D-dimer assay were calculated for all patients with suspected venous thromboembolism.
Because previous studies have shown that a number of D-dimer assays have similar
sensitivity and specificity in patients with suspected DVT and in patients
with suspected pulmonary embolism,33 we reasoned
that combining these patient populations was reasonable. In the secondary
analysis, the same indices were calculated for the following subgroups: patients
with suspected DVT; patients with suspected pulmonary embolism; patients with
a high, moderate, or low pretest probability of disease; and patients with
known cancer at the time of presentation. Where indicated, the corresponding
95% confidence intervals (CIs) for the accuracy indices were calculated according
to the binomial distribution.
AVOIDANCE OF BIAS
The technologists performing and interpreting the D-dimer assays were
unaware of the results of the diagnostic tests for venous thromboembolism.
Results of the D-dimer assays were not disclosed to clinicians caring for
the patients, and the results were not used to make management decisions.
Bias in the interpretation of IPG, CUS, ascending venography, lung scans,
and pulmonary angiography was avoided by having these tests interpreted by
physicians who were unaware of the results of the D-dimer assay.
RESULTS
Of 595 patients (352 women) enrolled in the study, 317 had suspected
DVT and 278 had suspected pulmonary embolism. The prevalence of venous thromboembolism
in the total study population was 19.0% (113/595). Sixty-five (20.5%) of the
317 patients with suspected DVT were classified as DVT-positive, while 48
(17.3%) of the 278 patients with suspected pulmonary embolism were classified
as pulmonary embolism positive.
The distribution of D-dimer results is shown in Figure 1. The mean and median D-dimer levels were 6.81 µg
FEU/mL and 2.28 µg FEU/mL, respectively, in those with confirmed venous
thromboembolism and 1.14 µg FEU/mL and 0.54 µg FEU/mL, respectively,
in those without venous thromboembolism. Duplicate precision for the patient
samples for the D-dimer assay was calculated for all the samples and for those
around the clinical discriminant value (0.40-0.60 µg FEU/mL). The standard
deviation and coefficient of variation were 0.06 and 6.79%, respectively,
for all samples and 0.02 and 3.98%, respectively, for those with results between
0.40 and 0.60 µg FEU/mL.
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Distribution of MDA D-Dimer (a quantitative latex D-dimer assay)
(Organon Teknika Corporation, Durham, NC) results in the study population.
VTE indicates venous thromboembolism; DVT, deep vein thrombosis; and PE, pulmonary
embolism. The horizontal line specifies the discriminant value of 0.50 µg
fibrinogen equivalent units per milliliter (FEU/mL).
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The sensitivity, specificity, NPV, and PPV of the D-dimer assay in the
150 patients used to determine the discriminant value were 97%, 51%, 99%,
and 26%, respectively. Because these values were similar to those obtained
in the remainder of the study population, these patients were included in
the overall analysis.
The accuracy indices and corresponding 95% CIs of the D-dimer assay
for the total study population are summarized in Table 1. The sensitivity and NPV are sufficiently high to reliably
rule out venous thromboembolism. The corresponding values for the subgroups
containing patients with suspected DVT and those with suspected pulmonary
embolism are also given in Table 1.
As expected, the results in these 2 patient populations are similar.
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Table 1. Accuracy Indices of the D-Dimer in Patients With Suspected
Venous Thromboembolism*
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Of the 595 patients, 205 (34.5%) had a low pretest probability of venous
thromboembolism, while 284 (47.7%) and 82 (13.8%) had a moderate or high pretest
probability of venous thromboembolism, respectively. A priori determination
of the pretest probability was not performed in 24 patients. The prevalence
of venous thromboembolism was 5.9%, 16.9%, and 56.1% in the low, moderate,
and high pretest probability populations, respectively. The accuracy indices
and 95% CIs for the D-dimer in the various pretest probability subgroups are
summarized in Table 2. While the
sensitivity and NPV of this assay are high in patients with a low or moderate
pretest probability of venous thromboembolism, they are lower in those with
a high pretest probability of venous thromboembolism. When the low or moderate
pretest probability categories are combined, the D-dimer has a sensitivity
of 97% (95% CI, 89%-100%), a specificity of 46% (95% CI, 41%-51%), an NPV
of 99% (95% CI, 96%-100%), and a PPV of 20% (95% CI, 16%-25%). The likelihood
ratio of a negative test in this population is 0.07. Therefore, a D-dimer
result of less than 0.50 µg FEU/mL essentially excludes venous thromboembolism
in patients with a low or moderate pretest probability of venous thromboembolism;
these patients made up 85.6% of the study population who had a pretest probability
assessment.
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Table 2. Accuracy Indices of the D-Dimer According to Pretest Probability*
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Thirty patients with suspected DVT (14 with a low or moderate pretest
probability of DVT) and 36 patients with suspected pulmonary embolism (28
with a low or moderate pretest probability of pulmonary embolism) were known
to have active cancer (diagnosed within 6 months, receiving treatment at the
time of the study or within the previous 6 months, or receiving palliative
treatment only at the time of the study) at presentation. The prevalence of
DVT in the first group was 53% (16/30), while the prevalence of pulmonary
embolism in the second group was 36% (13/36). Overall, in those with cancer,
the D-dimer assay had a sensitivity of 97% (95% CI, 82%-100%), a specificity
of 46% (95% CI, 30%-63%), an NPV of 94% (95% CI, 73%-100%), and a PPV of 58%
(95% CI, 43%-72%). The accuracy indices and 95% CIs for the assay in the various
subgroups of patients with cancer are given in Table 3. The NPV and sensitivity of the assay remained high in patients
with cancer and a low or moderate pretest probability of venous thromboembolism.
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Table 3. Accuracy Indices of the D-Dimer in Patients With Cancer and
Suspected Venous Thromboembolism*
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In total, 5 patients with suspected venous thromboembolism (2 with a
moderate pretest probability and 3 with a high pretest probability) had false-negative
D-dimer results when a discriminant value of 0.50 µg FEU/mL was used.
D-Dimer levels in these patients ranged from 0.23 to 0.43 µg FEU/mL.
The duration of patient symptoms was between 1 and 4 days, and prior treatment
with anticoagulants (heparin for 12 hours) was confirmed in only 1 patient.
COMMENT
This study is one of the first to demonstrate that a D-dimer assay has
the potential to be used as the sole diagnostic test to exclude venous thromboembolism.
Although other D-dimer assays have proven useful, most reliably exclude venous
thromboembolism only in certain patient subgroups; for example, a negative
SimpliRED D-dimer result has been shown to exclude DVT only in those patients
with a normal IPG finding or a low pretest probability22
and pulmonary embolism in the subgroup of patients with nondiagnostic lung
scan and a normal CUS result, and in patients with a low probability of pulmonary
embolism.23 The Instant 1A D-Dimer (Diagnostica
Stago, Snieres, France) has been demonstrated to exclude DVT only in the presence
of a normal CUS finding.28 When used with a
discriminant value of 0.50 µg FEU/mL, the MDA D-Dimer assay, an automated
test with a turnaround time of less than 30 minutes (including 15 minutes
for plasma preparation), has a sensitivity of 96% and an NPV of 98% in patients
with suspected venous thromboembolism. This NPV compares favorably with that
of ascending venography,5 serial IPG,9, 10 and serial CUS,33, 34
3 widely accepted diagnostic strategies for DVT, as well as pulmonary angiography,
the reference standard for pulmonary embolism,13
all of which approximate 98% to 99%. In our study, 37% of the population had
a negative D-dimer result.
In patients with a low or moderate pretest probability of DVT or pulmonary
embolism, the NPV of this assay is 99%. More than 80% of patients in our study
had a low or moderate pretest probability of venous thromboembolism, and approximately
40% of these patients had a D-dimer result of less than 0.50 µg FEU/mL.
The relatively low NPV (77%) of this assay in patients with a high pretest
probability of venous thromboembolism is noteworthy. This observation is almost
certainly the result of the high prevalence of venous thromboembolism in this
subgroup (56.1%), as the sensitivity (93%) is not inconsistent with that in
the other subgroups, and NPV is critically dependent on both sensitivity and
prevalence. For example, in a population with a prevalence of venous thromboembolism
of 50%, a D-dimer assay with a sensitivity of 98% and a specificity of 50%
would have an NPV of only 96%. Conversely, an assay like the SimpliRED D-Dimer,
which has a sensitivity of approximately 90% and a specificity of approximately
75%, would be expected to have an NPV of only 76% in a patient subgroup with
a prevalence of venous thromboembolism of 50%. Therefore, in patients with
a high pretest probability of venous thromboembolism, we do not recommend
obviating further testing in those with a negative D-dimer result.
In support of this finding, a previous study has reported that the NPV
of a whole-blood agglutination D-dimer test is significantly lower in patients
with cancer than in those without cancer, again almost certainly because the
prevalence of venous thromboembolism in patients with cancer is high (approximately
50%).25 However, in a relatively small subgroup
analysis of patients with known cancer at presentation, the NPV and sensitivity
of the MDA D-Dimer assay remained high in patients with a low or moderate
pretest probability of venous thromboembolism, albeit with wide 95% CIs. This
observation should be verified in larger studies.
The results of our study are valid for this assay and cannot be extrapolated
to other assay systems. The results obtained should be generalizable to other
patient populations because unselected patients were evaluated and the prevalence
of venous thromboembolism is consistent with that reported in other studies.9, 20, 21, 22, 23, 27, 28, 29, 30
Although the assays were performed on frozen rather than fresh samples, stable
results have been obtained with this D-dimer assay in samples frozen for up
to 2 months at -20°C or lower (data not shown). The potential for
bias was eliminated by having objective tests interpreted by clinicians unaware
of the D-dimer results and assays performed by technologists unaware of the
clinical status of the patients. Although the reference standard tests of
venography and pulmonary angiography were not performed in all patients with
suspected DVT and pulmonary embolism, respectively, the classification of
patients in this study as venous thromboembolism positive and venous thromboembolism
negative was corroborated by long-term clinical outcome. This approach has
successfully been used to validate the use of serial IPG9, 10
and CUS23, 24 in patients with
suspected DVT, as well as in those with suspected pulmonary embolism and nondiagnostic
/ lung scans.15 However, it is still
likely that a small proportion of patients who truly had calf DVT or small
pulmonary emboli were misclassified as DVT negative and pulmonary embolism
negative, respectively.
While the sensitivity and NPV of the MDA D-Dimer assay are similar to
those of ELISA, the specificity of this latex assay seems somewhat higher.
Based on these promising results, further clinical trials should be performed
to determine the safety of withholding anticoagulant therapy in patients with
a low or moderate pretest probability of venous thromboembolism and an MDA
D-Dimer result of less than 0.50 µg FEU/mL. If this approach is safe,
it would reduce health care costs by allowing many patients who present with
suspected DVT or pulmonary embolism to be discharged without further expensive
and invasive testing.
AUTHOR INFORMATION
Accepted for publication August 31, 2000.
The MDA D-Dimer kits used in this study were supplied by Organon Teknika
Corporation, Durham, NC. This study was funded by an unrestricted grant from
Organon Teknika Corporation.
Shannon M. Bates, MD, CM, and Anne Grand'Maison, MD, are both recipients
of a Research Fellowships from the Heart and Stroke Foundation of Ontario,
Ottowa. Michael J. Kovacs, MD, is a University of Western Ontario (London)
Department of Medicine Scholar. Jeffrey S. Ginsberg, MD, is a recipient of
a Career Investigator Award from the Heart and Stroke Foundation of Ontario,
Toronto.
The authors would like to thank Nicola Booker, RN; Jo-ann Bennett; Sue
Smale; Pamela Stevens, RN; Jody Joval, RN; Joanne McGiniss, RN; Karen MacKinnon,
MLT; and Andrea Willoughby, RN, for their help collecting plasma samples and
clinical information. We thank Terri Finch, BA, and Donna McCarty, BA, as
well for additional assistance in collecting clinical information.
From the Department of Medicine, McMaster University (Drs Bates, Grand'Maison,
and Ginsberg), and the Hamilton Civic Hospitals Research Centre (Mss Johnston
and Naguit and Dr Ginsberg), Hamilton, Ontario; and the Department of Medicine,
University of Western Ontario, London (Dr Kovacs).
Corresponding author: Shannon M. Bates, MD, CM, McMaster University
Medical Centre, Thromboembolism Unit, HSC 3W15, 1200 Main St W, Hamilton,
Ontario, Canada L8V 1C3 (e-mail: batesm{at}mcmaster.ca).
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