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Platelets, Early Online: 1–5

! 2014 Informa UK Ltd. DOI: 10.3109/09537104.2014.963543

ORIGINAL ARTICLE

Concomitant spuriously elevated white blood cell count,

a previously underestimated phenomenon in EDTA-dependent
pseudothrombocytopenia
Yufei Xiao1 & Yang Xu2
1
Department of Laboratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and 2Department of
Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abstract Keywords
The proportion and potential risk of concomitant spuriously elevated white blood cell count Coulter LH 750, EDTA, platelet clump,
(SEWC) are underestimated in ethylenediaminetetraacetic acid (EDTA)-dependent pseudo- pseudothrombocytopenia, sodium citrate,
thrombocytopenia (PTCP). The proportion, kinetics and prevention of SEWC remain poorly spuriously elevated WBC count
understood. A total of 25 patients with EDTA-dependent PTCP were enrolled in this study. With
the hematology analyzer Coulter LH 750, we determined the time courses of WBC count, WBC History
differential and platelet count in EDTA- and sodium citrate-anticoagulated blood, respectively.
Blood smears were prepared to inspect the presence of platelet clumps using light microscopy. Received 10 June 2014
The effect of automatic instrumental correction on the extent of SEWC was evaluated. The Revised 24 July 2014
proportion of SEWC was 92% in EDTA-dependent PTCP and 73.9% of SEWCs were within the Accepted 5 September 2014
For personal use only.

normal range. The development of SEWC was time-dependent, and neutrophils and Published online 23 September 2014
lymphocytes were the main subpopulations involved in SEWC. A strong and significant
correlation (r ¼ 0.9937, p50.001) was found between the increased WBC count and the
decreased platelet count. Both corrected and uncorrected WBC counts at 15 minutes or later
after blood collection in EDTA were significantly higher than their basal counts, respectively,
p50.05. Interestingly, in citrated blood, WBC counts after blood collection were not
significantly different from its basal counts, p40.05. A high proportion of concomitant
SEWCs, which are mainly within normal range, are present in patients with EDTA-dependent
PTCP. Proper interpretation of SEWC is crucial to avoid clinic errors. SEWC develops in a time-
dependent pattern, although the Coulter LH 750 only partly mitigates the extent of SEWC,
sodium citrate is able to effectively prevent SEWC.

Introduction describe this condition as spuriously elevated WBC count

(SEWC) instead of pseudoleukocytosis, although the latter has
Ethylenediaminetetraacetic acid (EDTA), a preferred anticoagu-
been cited frequently in the literatures [6–9]. For example,
lant advocated by the Clinical and Laboratory Standards Institute,
Solanki et al. [7] found that three patients with PTCP had
is widely used for routine-automated complete blood count (CBC)
pseudoleukocytosis, and the other three patients’ WBC counts
because of its good cell preservation property and little dilution
also increased but still remained within the normal range. Unlike
bias [1]. Pseudothrombocytopenia (PTCP) is a rare laboratory
PTCP, concomitant SEWC remains poorly understood with
artifact primarily associated with, but not restricted to EDTA
respect to its proportion, characteristics and kinetics [10–14].
[2, 3]. PTCP is caused by EDTA-dependent autoantibodies that
Importantly, failure to recognize SEWC would lead to unneces-
recognize the glycoprotein GPIIb–IIIa on platelet membrane,
sary laboratory tests, wrong diagnoses and even inappropriate
trigger platelet agglutination and induce platelet clumping in vitro
treatments [7]. Effective prevention of concomitant SEWC is
[3–5]. The impedance-type hematology analyzers such as the
critical to improve the safeties of patients with PTCP in clinical
Beckman-Coulter LH 750 (Beckman Coulter, Inc., Brea, CA) are
practice.
designed to discriminate blood cells initially according to their
In this study, we aimed to investigate the proportion and
sizes, i.e. particles of 2–20 fl are considered as platelets and those
kinetics of SEWC in 25 patients with EDTA-dependent PTCP,
435 fl are recognized as white blood cells (WBC) [2]. Therefore,
and explore whether automatic correction by the Coulter LH 750
platelet clumps formed in PTCP will be included in WBC count if
(Beckman Coulter, Inc.) or use of sodium citrate has a role in
they become large enough to share similar sizes with WBCs,
SEWC prevention.
resulting in a false increase in WBC count. Because some
reported WBC counts are still within the normal range, we
Patients and methods
Correspondence: Dr Yang Xu, Department of Hematology, the Second Patients
Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou
310009, China. Tel: +86-571-87783672; Fax: +86-571-87783655. Between January 2010 and June 2013, 25 consecutive patients
E-mail: yxu@zju.edu.cn with EDTA-dependent PTCP were enrolled in this study in the
 2 Y. Xiao & Y. Xu
Second Affiliated Hospital, Zhejiang University School of
Medicine, Hangzhou, China. All patients provided written
informed consent. The study conformed to the Declaration of
Helsinki, and was approved by the Institutional Review Board
of the Second Affiliated Hospital, Zhejiang University School of
Medicine. Among the patients were 13 males and 12 females, and
the median age was 53 years (range: 18–82 years). The diagnoses
include asymptomatic healthy individuals (n ¼ 16), colorectal
cancers (n ¼ 3), rheumatic disease (n ¼ 1), fever of unknown
origin (n ¼ 1), pulmonary nodule (n ¼ 1), cataract (n ¼ 1) and
neurological dysfunction (n ¼ 2). The diagnostic criteria of
PTCP included: (i) platelet count is 5100  109/l in EDTA-
anticoagulated blood measured by automatic CBC analyzers;
(ii) lack of signs or symptoms of bleeding; (iii) flag of platelet
clumps was detected by the cell counter and platelet clumps were
observed on Wright-Giemsa stained blood smear. SEWC is
defined as a time-dependent increase of WBC count by 10%
over its basal level within 3 hours after blood collection.
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Blood cell count
CBC was performed in the Coulter LH 750 (Beckman Coulter,
Inc.). The Coulter LH750 is designed to detect platelet clumps
formed in a defined population and extract them from the count.
Hence, the reported WBC count is the corrected WBC (cWBC)
count, with the uncorrected WBC (uWBC) count displayed on the
‘‘CBC Parameter’’ tab of the ‘‘Workstation Patient Results’’
screen. Quality control procedure was run daily to ensure all
measurements were within acceptable limits.
For personal use only.
Time courses of CBC in different anticoagulants
For each PTCP patient, peripheral blood was routinely drawn
from an antecubital vein and collected in both EDTA- and 3.2% of
sodium citrate-anitcoagulated tubes, respectively. All the blood
samples were subject to WBC, differential and platelet counts
immediately (0 minute), and then stored at room temperature, and
the counts were repeated 15, 30, 60, 120 and 180 minutes after
collection. Both uWBC and cWBC counts were recorded.
Blood smear examination
Blood smear was prepared upon blood collection and was
repeated after 15, 30, 60, 120 and 180 minutes, respectively.
The smear was stained with Wright-Giemsa, and then screened
for the presence and size of platelet clumps.
Statistical analysis
The data were presented as mean ± standard deviation (SD), and
were analyzed using the software SPSS 13.0 (SPSS Inc., Chicago,
IL). The paired t-test was used for comparison of CBC parameters
between two different groups. A p50.05 was considered as
statistically significance. Statistical comparison of increase in
WBC count with decrease in platelet count was performed
by regression analysis with calculation of a coefficient of
correlation (r).
Results
Time course of platelet count in EDTA or sodium citrate
To evaluate the effect of different anticoagulants on platelet count,
we measured the time courses of platelet count in EDTA and
sodium citrate, respectively. As shown in Figure 1, both EDTA-
and citrate-induced thrombocytopenia were time-dependent.
Immediately after blood collection, the mean platelet count in
EDTA-anticogulated blood (163 ± 63  109/l) was significantly
lower than that in citrated blood (184 ± 73  109/l) (p50.05). The
Platelets, Early Online: 1–5
platelet counts dropped within 60 minutes in both anticoagulants;
however, a significant slower reduction of platelet counts was
seen in citrated blood than in EDTA-anticoagulated blood
(p50.05). On the blood smears, the number of platelet clumps
also increases in a time-dependent manner, and the platelet
aggregation was considerably more pronounced in EDTA than in
citrate (Figure 2). The platelet clumps were much smaller in
sodium citrate than in EDTA, for example, at 120 minutes after
blood collection, a clump in EDTA usually contains425 platelets,
whereas a clump in citrate is composed of 510 platelets
(Figure 2). Thus, although both anticoagulants induce time-
dependent PTCP, the extent and velocity of thrombocytopenia
were more significant in EDTA than in sodium citrate.
The proportion and kinetics of SEWC
in EDTA-dependent PTCP
To study the kinetics of SEWC following the addition of EDTA,
we determined the time course of uWBC count. The uWBC count
was 6.15 ± 2.02  109/l as its basal level, and increased to
6.85 ± 2.66  109/l at 15 minutes and continued to increase to
7.95 ± 2.73  109/l until 180 minutes after collection (Table I).
The uWBC count at 15 minutes or later was significantly higher
than the basal count, all p50.05 (Table I). The average final
uWBC count increased by 29.3% relative to its basal count.
SEWCs were present in 23 of 25 (92%) patients with PTCP.
Among the SEWCs, 17 (73.9%) uWBC counts were within the
normal range, whereas only six (26.1%) were 410  109/l.
Moreover, two leukopenias were reported as normal due to
SEWC (Table II). Thus, a high proportion of SEWC are in EDTA-
dependent PTCP, and most of them are within the normal range.
Next we sought to determine which parts of WBC differential are
spuriously elevated, the time course of WBC differential was
shown in Table I. The basal levels of neutrophil, lymphocyte,
monocyte, eosinophil and basophil counts were 3.77 ± 1.52,
1.74 ± 0.58, 0.48 ± 0.17, 0.13 ± 0.14 and 0.02 ± 0.02  109/l,
respectively. When compared with their basal levels, both
neutrophil and lymphocyte counts at 30 minutes or later were
significantly increased (p50.05), whereas the counts of mono-
cyte, eosinophil and basophil through 180 minutes were little if
any increased (p40.05). To test if SEWC was primarily caused
by platelet clumps, for each time point, the increased WBC count
(DWBC) and the decreased platelet count (DPLT) relative to their
Figure 1. Time course of platelet counts in patients with PTCP. Data
were expressed as mean ± SD. The shorter error bar indicates EDTA and
the longer one indicates sodium citrate. For each patient, the blood were
collected into both EDTA- and sodium citrate-anticogulated tubes,
respectively, and then platelet counts were measured in parallel at the
indicated time after blood collection.
 DOI: 10.3109/09537104.2014.963543 Spuriously elevated WBC in pseudothrombocytopenia 3

basal levels were calculated, respectively. A strong and significant Discussion

correlation (r ¼ 0.9937, p50.001) was found between DWBC and
DPLT (Figure 3).
The effect of automatic correction by the Coulter
LH 750 on the extent of SEWC
Whether the Coulter LH 750 was able to automatically correct
SEWC related to PTCP is unclear. To test this, the uWBC
and cWBC counts were compared in the presence of EDTA
(Table III). Both uWBC and cWBC counts at 15 minutes or later
were significantly higher than their basal counts (p50.05). The
uWBC count increased by 11.38, 19.51, 21.95, 27.47 and 29.27%
of the basal count, and the cWBC count increased by 2.44, 7.15,
8.94, 14.50 and 27.15% of the basal count at 15, 30, 60, 120 and
180 minutes after blood collection, respectively. With the
exception of basal counts, the cWBC count was significantly
lower than the uWBC count at each time point (p50.05). Taken
together, the automatic correction conferred by the Coulter
LH 750 only partly mitigates the extent of SEWC.
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The Coulter LH 750 is designed to count WBCs using the
impedance method where particles are counted and channelized
by their size [15, 16]. Any particles 35 fl are considered as
WBCs, and platelet clumps mimicking the size of WBC are
usually included in WBC count by hematology analyzer. As a
result, the reported value is often higher than its basal or true
value of WBC count in EDTA-dependent PTCP. This laboratory
artifact is better defined as SEWC so that pseudoleukocytosis and
those increased but still normal WBC count can be included. In
fact, most previous studies on PTCP did not address the issue of
SEWC [10, 12, 14, 17–19], only a few cases of SEWC were
reported in the literatures [7–9]. However, SEWC may pose
diagnostic challenge in clinical practice. SEWC exceeding the
upper limit, i.e. pseudoleukocytosis, would lead to unnecessary
admission, search for bacterial infections, profiling of tumor

Table II. The characteristics and CBC data of two patients with
leukopenia masked by SEWC.
Sodium citrate completely prevent SEWC in patients
with PTCP Time after blood collection (min)
Although sodium citrate does not fully prevent formation of Cell count 0 15 30 60 120 180
platelet clumps, whether it will lead to SEWC remains unknown. Patient no. 6, 50-year-old female, CRC
To this end, the time course of WBC count in the presence of uWBC (109/l) 3.8 3.8 3.8 4.1 4.0 4.3
sodium citrate with or without automatic correction was per- Hemoglobin (g/l) 104 105 104 106 105 108
formed (Table III). We found that uWBC and cWBC counts were Platelet (109/l) 102 80 73 72 66 70
little changed throughout 180 minutes after blood collection, Patient no. 7, 69-year-old male, CRC
although cWBC was slightly lower than uWBC, which did not uWBC (109/l) 3.7 4.6 5.6 6 6 5.6
For personal use only.

Hemoglobin (g/l) 119 118 118 119 118 119

reach statistically significance (p40.05). Therefore, sodium 9
Platelet (10 /l) 82 44 27 19 14 12
citrate completely prevents SEWC despite its limited function
on PTCP prevention. CRC, colorectal cancer.

Figure 2. Representative images of blood smears prepared at indicated time after collection in EDTA- and citrate-anticoagulated blood from a PTCP
patient. Note that the arrows showing the platelet or platelet clumps.

Table I. Time courses of uWBC count and WBC differential in EDTA-dependent PTCP.

Time after blood collection (min)

9
Cell count (10 /l) 0 15 30 60 120 180
a a a a
uWBC 6.15 ± 2.02 6.85 ± 2.66 7.35 ± 2.96 7.50 ± 2.90 7.84 ± 2.89 7.95 ± 2.73a
N 3.77 ± 1.52 3.85 ± 1.61 3.99 ± 1.73a 4.09 ± 1.78a 4.25 ± 1.88a 4.26 ± 1.93a
L 1.74 ± 0.58 1.77 ± 0.64 1.93 ± 0.75a 1.96 ± 0.78a 2.09 ± 0.86a 2.20 ± 0.87a
M 0.48 ± 0.17 0.49 ± 0.16 0.49 ± 0.17 0.52 ± 0.19 0.51 ± 0.19 0.52 ± 0.19
E 0.13 ± 0.14 0.14 ± 0.15 0.14 ± 0.15 0.14 ± 0.16 0.15 ± 0.17 0.16 ± 0.19
B 0.02 ± 0.02 0.03 ± 0.04 0.03 ± 0.03 0.04 ± 0.04 0.04 ± 0.04 0.03 ± 0.04

L, lymphocyte; M, monocyte; N, neutrophil; E, eosinophil; B, basophil.

a
As compared with basal levels (at 0 minute), all p50.05.
 4 Y. Xiao & Y. Xu
markers and even treatment of antibiotics [7]. On the other hand,
SEWC within the normal range, which occurs more frequently in
PTCP, would mask true leukopenia following chemotherapy,
resulting in delayed prevention or treatment for infections.
Therefore, it is important to properly interpret and prevent
PTCP-related SEWC to avoid undesired clinical outcome.
The overall prevalence of EDTA-dependent PTCP is
0.1–0.3% in general population, and increases in hospitalized
patients or outpatients referred for isolated thrombocytopenia [14,
20]. However, the concomitant SEWC has been readily neglected
unless leukocytosis is reported in clinical setting; the actual
proportion of SEWC in PTCP is unknown. We demonstrated that
SEWCs occur in 23/25 (92.3%) of PTCPs through time-course
analysis, and 17 of 23 (72.9%) SEWCs were within normal range
and only 6 (26.1%) were pseudoleukocytosis. Lombarts et al. [8]
found that 9 of 20 PTCP patients had at least 10% higher WBC
counts in EDTA than in acid citrate dextrose, although
time course was not done [8]. Additionally, Garcia et al. [11]
demonstrated that abnormal WBC size histograms resulting from
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platelet clumps were detected in 92.3% PTCP patients, but the
data of WBC count was lacking. To the best of our knowledge,
this is the first study suggesting that EDTA-dependent PTCP are
accompanied by a high proportion of SEWC, most of which are
within the normal range. Thus, there is a risk of masking true
leukopenia. Indeed, two leukopenias were reported as normal due
to SEWC in our study.
So far there are no definitive criteria for SEWC; we choose
relatively arbitrarily 10% as threshold to evaluate the increased
percentage over the basal WBC count in a time-dependent
manner. The average WBC count increased by 29.3% of the basal
For personal use only.
Figure 3. The relationship between the decreased platelet count (DPLT)
and the increased WBC count (DWBC) relative to their corresponding
basal levels (r ¼ 0.9937, p50.001).
Table III. Differential effect of EDTA and sodium citrate on the time course of WBC count with or without automatic correction by the Coulter LH750.
9
Cell count (10 /l) 0 15
EDTA
uWBC 6.15 ± 2.02 6.85 ± 2.66a
cWBC 6.15 ± 2.02 6.30 ± 2.14a
Citrate
uWBC 6.20 ± 2.04 6.14 ± 2.03
cWBC 6.20 ± 2.04 6.13 ± 2.03
a
When compared with basal counts at time 0 minute, p50.05. At 15, 30, 60, 120 and 180 minutes in EDTA, uWBC versus cWBC, p50.05.
Platelets, Early Online: 1–5
count, and WBC count increases mainly within 60 minutes after
blood sampling in EDTA. Similarly, Schrezenmeier et al. [9]
found that WBC count increased significantly from 7.19  109/l at
5 minutes to 10.8  109/l at 60 minutes after blood collection in
10 patients with EDTA-dependent PTCP [9]. Inspection of blood
smear revealed that time-dependent formation of platelet clumps
are featured by increase in both number and size. Consistent with
the morphological changes, the decrease in platelet count is
highly correlated with the increase of WBC count, providing
quantitative evidence for SEWC secondary to PTCP. We also
demonstrated that the major subpopulations involved in SEWC
are neutrophils and lymphocytes but not basophils or monocytes.
The Coulter LH 750 performs WBC differential by volume
conductivity scatter (VCS) technology [6], implying that the VCS
properties of platelet clumps are similar to those of neutrophils
and lymphocytes.
The practical approaches to prevent EDTA-dependent PTCP
has been extensively explored [2, 3], such as warming the sample
to 37  C, using alternative anticoagulants including heparin and
citrate, nevertheless, these might still be ineffective in 15–20%
PTCP [3]. Recently, the calcium chloride and magnesium salt
are proposed for effective estimation of correction platelet counts
[21, 22]. It is conceivable that the preventive approaches for PTCP
also help to prevent SWEC through inhibition of platelets
clumping. The Coulter LH 750 detects platelet clumps formed
in a defined population and extract them from the count, thereby
automatically correct a false increase of WBC count. Here we
explored the possibility of instrumental correction as a simple
option for SWEC prevention. We compared the time course of
cWBC with that of uWBC, and suggested that SEWC can be
partly mitigated at 15 minutes or later. The possible explanation is
that the capability of data extraction by the LH 750 decreases with
the increases in the size and number of platelet clumps, resulting
in impaired function of automatic correction.
We and others found that, the extent and velocity of
thrombocytopenia, the sizes of platelet clumps in sodium citrate
were significantly less than those in EDTA, suggesting that
sodium citrate does not completely prevent PTCP [11]. However,
it is interesting that sodium citrate is able to effectively prevent
SEWC. The Coulter LH 750 considered particles of 35 fl as
WBCs, and the citrated platelet clumps that rarely exceed 35 fl are
not large enough to be recognized as WBCs, therefore, the WBC
count is not affected.
Our study has several potential limitations. The number of
patients is relatively small; to some extent, the selection bias may
contribute to the high proportion of SEWC. The anticoagulants
other than EDTA and citrate were not tested for inducing SEWC.
Historically, acid citrate dextrose was found to give rise to the
lowest WBC count among different anticoagulants, and heparin
and EDTA had similar activities of inducing leukocytosis [8].
However, Savage et al. [23] observed that pseudoleukocytosis was
Time after blood collection (min)
30 60 120 180
7.35 ± 2.96a 7.5 ± 2.90a 7.84 ± 2.89a 7.95 ± 2.73a
6.59 ± 2.41a 6.7 ± 2.46a 7.06 ± 2.62a 7.82 ± 2.78a
6.29 ± 2.02 6.26 ± 2.06 6.26 ± 2.06 6.28 ± 2.06
6.17 ± 2.02 6.20 ± 2.05 6.15 ± 2.01 6.17 ± 2.07
 DOI: 10.3109/09537104.2014.963543
almost absent in heparinized blood. Although the role of heparin
in SEWC remains controversial, heparin should not be recom-
mended for routine SEWC prevention because of high incidence
of PTCP. Finally, our finding is solely based on the use of a
Coulter LH 750, the only blood counter available in our hospital.
Schrezenmeier et al. [9] observed that the Coulter T540 and STKS
models have different potential to detect the PTCP by error codes,
possibly due to different data processing technologies, and
pseudoleukocytosis was only present in the T540 device. It
would be tempting to determine whether SEWC occurs in other
automated blood counters.
In summary, previously the concomitant SEWC was under-
estimated in terms of its prevalence and potential risk for patients.
For the first time, we demonstrate that a high proportion of SEWC
are present in EDTA-dependent PTCP, and most SEWCs are still
within the normal range, which requires close monitoring and
proper interpretation to avoid clinical errors. Although automatic
correction by the Coulter LH 750 only partly mitigates SEWC,
sodium citrate is able to effectively prevent SEWC. Further
Platelets Downloaded from informahealthcare.com by University of Washington on 10/27/14
studies would be required to confirm our findings based on a
larger number of patients, use of different hematology analyzers
and anticoagulants.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
This study was supported by National Basic Research Program of
China (No. 2013CB911303), National Natural Science Foundation of
China (No. 30973371) and Natural Science Foundation of Zhejiang
For personal use only.
Province of China (No. Y207111).
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