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Received: 14 February 2019    Revised: 16 March 2019    Accepted: 20 March 2019

DOI: 10.1111/ijlh.13028

ORIGINAL ARTICLE

Impact of low volume citrate tubes on results of first‐line

hemostasis testing

Gian Luca Salvagno1  | Davide Demonte1 | Giovanni Poli1 | Emmanuel J. Favaloro2 |

Giuseppe Lippi1

1
Section of Clinical Biochemistry, University
of Verona, Verona, Italy
2
Department of Haematology, Sydney
Centres for Thrombosis and Haemostasis,
Institute of Clinical Pathology and
Medical Research, NSW Health
Pathology, Westmead Hospital, Westmead,
NSW, Australia
Correspondence
Giuseppe Lippi, Section of Clinical
Biochemistry, University Hospital of Verona,
Verona, Italy.
Email: giuseppe.lippi@univr.it
Abstract
Introduction: Pediatric tubes are increasingly used for drawing blood for hemostasis
testing. This study has investigated the potential impact of low volume citrate tubes
on results of first‐line hemostasis testing.
Methods: The study population comprised 34 patients on warfarin therapy and 17
ostensibly healthy volunteers. Blood was collected into five different evacuated
blood tubes from each subject. On right arm, blood was drawn directly into two
standard evacuated blood tubes (3‐mL Vacuette and 2‐mL Vacutest) and one evacu‐
ated low volume blood tube (1‐mL Vacuette) by straight needle venipuncture. On left
arm, blood was drawn using a 5‐mL syringe and then transferred within two none‐
vacuated microtubes (0.5 mL MiniCollect and 0.5 mL Micro Test). Prothrombin time
(PT), activated partial thromboplastin time (APTT), and fibrinogen were assayed on
ACL TOP 700.
Results: Spearman's correlation of PT, APTT, and fibrinogen values obtained using
different tubes was always satisfactory (ie, ≥0.93). A statistically significant bias was
frequently found by comparing values obtained in different tubes. Nevertheless, the
minimum quality specifications for bias were exceeded only by comparing data of
Vacuette 1 mL with those of all other blood tubes for PT, by comparing data of Micro
Test 0.5 mL with those of all other blood tubes for APTT, and by comparing data of
Micro Test 0.5‐mL blood tubes with those of Vacuette 3 mL and Vacuette 1.
Conclusion: First‐line hemostasis testing using low volume citrate tubes may display
differences sometimes exceeding the minimum quality specifications.

KEYWORDS
blood collection, blood tubes, coagulation testing, hemostasis testing, preanalytical variability

1 |  I NTRO D U C TI O N
Blood sample collection is essentially an unavoidable activity to
obtain suitable biological material to be used for laboratory test‐
ing.1 Laboratory hemostasis is no exception to this general rule
and indeed comprises special considerations. 2 Several lines of
evidence now attest that the so‐called preanalytical phase, and
especially blood drawing, is the leading source of variability in
laboratory diagnostics, 3,4 the largest bias being attributable to the
procedure, as well as to the materials, used for drawing venous
blood. 5
Previously published data have shown that the type6 and size7
of blood collection needle may impact on hemostasis test results.
Additional evidence has been provided that even the type,8,9
brand,10,11 and size or filling volume12 of citrated blood tubes may
comprise serious obstacles for harmonization of test results.

Int J Lab Hematol. 2019;1–6. © 2019 John Wiley & Sons Ltd |  1
wileyonlinelibrary.com/journal/ijlh  
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2       SALVAGNO et al.

The collection of blood samples that are suitable for testing may
be further challenged in selected categories of patients, additionally
magnified for clotting tests because coagulation blood tubes need
to be accurately filled, up to their nominal filling volume, to permit
an appropriate ratio (usually 9:1) between anticoagulant (typically
3.2% buffered sodium citrate) and blood. The collection of low blood
volumes may furthermore be favored to reduce unnecessary diag‐
nostic‐related blood loss such as in intensive care units (ICUs) (ie,
for preventing repeated blood drawing‐related anemia),13 but also
in patients with difficult veins (especially pediatric populations and
cancer patients). This diagnostic and clinical need has been recently
accomplished by commercialization of low volume tubes, charac‐
terized by draw volumes ≤1 mL. Although these devices have been
proven effective to decrease phlebotomy‐related blood loss, both in
pediatric and in adult populations,14 their use has been associated
with particular bias in laboratory testing, especially in results of
some immunochemistry15 and hematologic16 parameters. Notably,
recent evidence has also shown that the use of partial‐draw citrate
collection tubes (ie, 2.0 mL) may lead to underestimating unfrac‐
tionated heparin therapy assessment compared to standard volume
tubes (ie, 3.5 mL).17 However, no evidence has been provided, to the
best of our knowledge, on the impact of pediatric tubes, with draw
volumes ≤1 mL, on hemostasis testing. Therefore, the present study
was aimed to investigate the potential impact of low volume citrate
tubes on results of first‐line hemostasis testing.
2 |  M ATE R I A L S A N D M E TH O DS
The study population comprised 34 consecutive patients on oral
anticoagulant therapy (OAT; warfarin; mean age 76 ± 9 years; 13
women and 21 men) and 17 ostensibly healthy volunteers recruited
from the laboratory staff (mean age; 45 ± 11 years; 13 women and 4
men). Blood from each of these subjects was collected into five dif‐
ferent evacuated blood tubes, all containing the same sodium citrate
formulation, as shown in Table 1.
The procedure consisted of two consecutive venipunctures,
performed by the same expert phlebotomist, on both arms of the
patient. On the right arm, blood was drawn into the two standard
evacuated blood tubes (3‐mL Vacuette and 2‐mL Vacutest) and
one evacuated low volume blood tube (1‐mL Vacuette) which were
filled up to the level mark, as for normal local practice (ie, using a
19‐gauge straight needle venipuncture, with blood collected directly
into the evacuated blood collection tubes). The sequence of these
three blood tubes was randomized after each following patient. On
the left arm, blood was drawn using a 5‐mL syringe equipped with
a 19‐gauge needle. After removing the needle from the syringe, the
blood was then immediately transferred within the two nonevacu‐
ated microtubes (0.5 mL MiniCollect and 0.5 mL Micro Test), which
were filled up to the level mark.
Prothrombin time, APTT, and fibrinogen were assayed
using the same fully automated coagulation analyzer ACL
TOP 700 (Instrumentation Laboratory Bedford, MA, USA),
with RecombiPlasTin (Instrumentation Laboratory), SynthASil
(Instrumentation Laboratory) and Fibrinogen‐CXL (Instrumentation
Laboratory), respectively. The analytical performance of these tests
has been earlier described elsewhere.18 Immediately after collection,
all blood tubes were centrifuged at 1300 × g for 15 minutes at room
temperature, in accordance with the current recommendations of
the Clinical Laboratory Standards Institute (CLSI).19 The overall time
elapsed between sample collection and testing was always less than
1 hours.
The data obtained in the different blood tubes (median and in‐
terquartile range; IQR) were compared among different tubes with
Spearman's correlation. The relative (percent) bias was calculated
with Bland and Altman plots. The relative bias was also compared
with the minimum quality specifications for bias, as provided by Ricos
et al (ie, ±3.0% for PT, ±3.4% for APTT, and ± 4.8% for fibrinogen). 20
The statistical analysis was carried out with Analyse‐it (Analyse‐it
Software Ltd, Leeds, UK). Statistical significance was set at P < 0.05.
The study was based on anonymized routine samples referred for
routine testing and the study, which was part of a standard process

TA B L E 1   Blood tubes characteristics

Manufacturer Name Anticoagulant Type of tube Draw volume

Greiner Bio‐One, Kremsmünster,
Austria
Greiner Bio‐One, Kremsmünster,
Austria
Greiner Bio‐One, Kremsmünster,
Austria
Kima, Padova, Italy
Kima, Padova, Italy
Vacuette Buffered sodium citrate Evacuated, 13 × 75 mm 3.0 mL
3.2% Reference number: 454334
Lot number: A180848F
Vacuette Buffered sodium citrate Evacuated, 13 × 75 mm 1.0 mL
3.2% Reference number: 454320
Lot number: A1810395
MiniCollect Buffered sodium citrate Nonevacuated, 10 × 37 mm 0.5 mL
3.2% Reference number: 450538
Lot number: A1803QX
Vacutest Buffered sodium citrate Evacuated, 13 × 75 mm 2.0 mL
3.2% Reference number: 14074
Lot number: A2908
Micro Test Buffered sodium citrate Nonevacuated, 10 × 45 mm 0.5 mL
3.2% Reference number: 814074
Lot number: L2748

TA B L E 2   Results of prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen obtained in different citrated
blood tubes
Test Vacuette 3 mL Vacuette 1 mL
PT (s) 21.9 (15.7) 19.8 (14)
APTT (s) 35.4 (8.6) 33.7 (8.3)
Fibrinogen (g/L) 3.23 (1.26) 3.09 (1.19)
of new blood tubes validation before routine usage in the local hos‐
pital, 21 and was cleared by the local Ethical Committee (University
Hospital of Verona, n. 35747, July 25, 2016).
3 | R E S U LT S
The results of PT, APTT, and fibrinogen obtained in the different
blood tubes are shown in Table 2. As regards PT, the Spearman's
correlation of values obtained in the different tubes was always ex‐
cellent (ie, ≥0.99). Although a statistically significant bias was fre‐
quently found by comparing values obtained in the different tubes,
the minimum quality specifications for bias of PT (ie, ±3.0%) were
only exceeded when data obtained in Vacuette 1‐mL blood tubes
were compared with those obtained in the other blood tubes
(Table 3). The Spearman's correlation of APTT values obtained in the
different tubes was also satisfactory (ie, always ≥0.93). Even in this
case, a statistically significant bias was frequently found by compar‐
ing values obtained in the different tubes (Table 4). Nevertheless,
the minimum quality specifications for bias of APTT (ie, ±3.4%)
were only exceeded when data obtained in Micro Test 0.5‐mL
blood tubes were compared with those obtained in the other blood
tubes. Importantly, the bias in this tube was on average 3‐fold higher
than the minimum quality specifications. As regards fibrinogen, the
Spearman's correlation of values obtained in the different tubes was
always excellent (ie, ≥0.96). A statistically significant bias was fre‐
quently found by comparing values obtained in the different tubes
(Table 5), but the minimum quality specifications for bias of fibrino‐
gen (ie, ±4.8%) were only exceeded when data obtained in Micro
Test 0.5‐mL blood tubes were compared with those obtained in two
other blood tubes (ie, Vacuette 3 mL and Vacuette 1 mL). A suba‐
nalysis of data in OAT patients and in healthy volunteers revealed
virtually identically results.
4 | D I S CU S S I O N
Low volume blood collection tubes are a valuable resource for both
reducing unnecessary diagnostic‐related blood loss and facilitating
blood drawing in patients with unsuitable/difficult veins. However,
local validation of test results is mandatory before these tubes can
be introduced into routine phlebotomy practice, because results
21
may otherwise reflect clinically important differences.
The results of our study show that first‐line hemostasis testing
may be influenced by the use of some types of low volume, pediatric
|
      3
MiniCollect 0.5 mL Vacutest 2 mL Micro test 0.5 mL
22.2 (15.9) 22.0 (15.3) 21.2 (14.5)
33.8 (8.6) 34.2 (9.2) 30.7 (7.5)
3.28 (1.27) 3.38 (1.09) 3.38 (1.37)
tubes. Fibrinogen was overall less sensitive to low draw volume be‐
cause the minimum quality specifications for bias were only exceeded
when comparing 0.5 mL Kima Micro Test with 3.0‐mL or 1.0‐mL blood
tubes produced by the other manufacturer (ie, Grainer Bio‐One). PT
data produced using plasma collected into pediatric tubes with draw
volumes of 0.5 mL were globally comparable to those generated using
standard volume blood tubes, but were also highly intercomparable
between these two pediatric tubes (ie, main bias was 1.6%). The larg‐
est variability, always exceeding the minimum quality specifications,
was noted using 1.0‐mL Vacuette, with bias higher between 1.6‐ and
2.5‐fold that of the quality specifications. Regarding APTT, a variabil‐
ity exceeding the minimum quality specifications was only observed
using 0.5‐mL Micro Test, with bias always >2.8 than the quality spec‐
ifications. This would actually mean that results of PT obtained using
1.0‐mL Vacuette and APTT using 0.5 mL Micro Test would not be com‐
parable to those obtained with standard volume tubes and may hence
disrupt both the diagnostic reasoning and the clinical decision making,
especially when longitudinal patient data are compared using differ‐
ent tubes. This evidence further highlights the importance for hemo‐
stasis laboratories to prioritize a process for local validation of blood
collection tubes before introducing new devices. Another important
aspect emerged from this study is that, although hazardous for phle‐
botomists’ safety, blood drawing with a syringe and then transfer of
that blood into nonevacuated pediatric tubes seems a reliable practice,
as attested by the limited bias (always lower than the minimum quality
specifications) found for PT, APTT, and fibrinogen values by comparing
0.50 mL MiniCollect with the other two standards tubes (Tables 3-5).
As regards the variability of PT and APTT data observed among
the tubes we tested, two possible solution can be identified for over‐
come this drawback in facilities using both standard and pediatric
tubes. The first entails the harmonization of test results by calcu‐
lating mean normal PT (MNPT) and mean normal APTT (MNAPTT)
for both standard and low volume tubes and then defining separate
tests on the analyzer (ie, “standard volume tubes PT or APTT” and
“low volume tubes PT or APTT”). The second approach, which also
applies to fibrinogen, encompasses the use of separate reference
ranges for standard and low volume tubes.
5 | CO N C LU S I O N
Although we acknowledge that this study may have some limitations
(ie, drawing blood from different arms, using syringe versus evacu‐
ated blood tubes), our results suggest that results of first‐line hemo‐
stasis testing obtained in plasma collected into some pediatric tubes
 |

TA B L E 3   Comparison of prothrombin time (PT) test results obtained in different citrated blood tubes
4      

Tubes Vacuette 1 mL MiniCollect 0.5 mL Vacutest 2 mL Micro Test 0.5 mL

Vacuette 3 mL r = 1.00 (95% CI, 0.99‐1.00) r = 0.99 (95% CI, 0.98‐1.00) r = 1.00 (95% CI, 1.00‐1.00) r = 1.00 (95% CI, 0.99‐1.00)
Bias: −7.6% (95% CI, −8.4 to −6.8%) Bias: 0.0% (95% CI, −0.8 to Bias: −1.3% (95% CI, −1.8 to −0.8%) Bias: −2.9% (95% CI, −3.6 to −2.2%)
P < 0.001 0.8%) P < 0.001 P < 0.001
P = 0.916
Vacuette 1 mL ‐ r = 0.99 (95% CI, 0.98‐1.00) r = 1.00 (95% CI, 0.99‐1.00) r = 1.00 (95% CI, 0.99‐1.00)
Bias: 7.6% (95% CI, 6.5to Bias: 6.3% (95% CI, 5.6 to 7.0%) Bias: 4.7% (95% CI, 4.1 to 5.4%)
8.7%) P < 0.001 P < 0.001
P < 0.001
MiniCollect ‐ ‐ r = 0.99 (95% CI, 0.99‐1.00) r = 0.99 (95% CI, 0.98‐1.00)
0.5 mL Bias: −1.3% (95% CI, −2.0 to −0.5%) Bias: −2.9% (95% CI, −3.8 to −1.9%)
P = 0.002 P < 0.001
Vacutest 2 mL ‐ ‐ ‐ r = 0.99 (95% CI, 0.99‐1.00)
Bias: −1.6% (95% CI, −2.3 to −0.9%)
P < 0.001

TA B L E 4   Comparison of activated partial thromboplastin time (APTT) test results obtained in different citrated blood tubes

Tubes Vacuette 1 mL MiniCollect 0.5 mL Vacutest 2 mL Micro Test 0.5 mL

Vacuette 3 mL r = 0.99 (95% CI, 0.98‐0.99) r = 0.97 (95% CI, 0.94‐0.98) r = 0.95 (95% CI, 0.92‐0.97) r = 0.94 (95% CI, 0.90‐0.97)
Bias: −3.4% (95% CI, −4.2 to −2.8%) Bias: −2.9% (95% CI, −4.1 Bias: −1.6% (95% CI, −2.8 to −0.4%) Bias: −13.2% (95% CI, −15.0 to −11.5%)
P < 0.001 to −1.7%) P = 0.009 P < 0.001
P < 0.001
Vacuette 1 mL ‐ r = 0.97 (95% CI, 0.95‐0.98) r = 0.96 (95% CI, 0.93‐0.98) r = 0.95 (95% CI, 0.92‐0.97)
Bias: 0.6% (95% CI, −0.6 to Bias: 1.9% (95% CI, 0.6 to 3.1%) Bias: −9.8% (95% CI, −11.4 to −8.1%)
1.8%) P = 0.005 P < 0.001
P = 0.232
MiniCollect ‐ ‐ r = 0.96 (95% CI, 0.92‐0.97) r = 0.93 (95% CI, 0.88‐0.96)
0.5 mL Bias: 1.3% (95% CI, −0.2 to 2.8%) Bias: −10.4% (95% CI, −12.3 to −8.4%)
P = 0.095 P < 0.001
Vacutest 2 mL ‐ ‐ ‐ r = 0.97 (95% CI, 0.95‐0.98)
Bias: −11.6% (95% CI, −12.8 to −10.4%)
P < 0.001
SALVAGNO et al.
 |
      5

TA B L E 5   Comparison of fibrinogen test results obtained in different citrated blood tubes

MiniCollect
Tubes Vacuette 1 mL 0.5 mL Vacutest 2 mL Micro Test 0.5 mL

Vacuette r = 0.98 (95% CI, 0.96‐0.99) r = 0.97 (95% CI, r = 0.97 (95% CI, 0.95‐0.98) r = 0.98 (95% CI, 0.96‐0.99)
3 mL Bias: 0.3% (95% CI, −1.1 to 1.8%) 0.95‐0.98) Bias: 2.7% (95% CI, 1.2 to 4.1%) Bias: 7.1% (95% CI, 5.8 to 8.5%)
P = 0.653 Bias: 2.4% (95% P = 0.001 P < 0.001
CI, 0.7 to 4.1%)
P = 0.007
Vacuette ‐ r = 0.96 (95% CI, r = 0.97 (95% CI, 0.94‐0.98) r = 0.97 (95% CI, 0.94‐0.98)
1 mL 0.94‐0.98) Bias: 2.3% (95% CI, 0.5% to 4.1%) Bias: 6.8% (95% CI, 4.7 to 8.8%)
Bias: 2.0% (95% P = 0.013 P < 0.001
CI, 0.1 to 0.4%)
P = 0.036
MiniCollect ‐ ‐ r = 0.96 (95% CI, 0.93‐0.98) r = 0.97 (95% CI, 0.96‐0.99)
0.5 mL Bias: 0.3% (95% CI, −1.7 to 2.2%) Bias: 4.7% (95% CI, 3.1 to 6.4%)
P = 0.779 P < 0.001
Vacutest ‐ ‐ ‐ r = 0.97 (95% CI, 0.95‐0.98)
2 mL Bias: 4.5% (95% CI, 2.9 to 6.1%)
P < 0.001

may display differences which can sometimes exceed the minimum
quality specification, thus reinforcing the recommendation to per‐
form local validation studies before introducing new blood tubes
into routine phlebotomy practice.
AC K N OW L E D G E M E N T S
The authors wish to thank Mrs. Cristina Recchi for her technical con‐
tribution to the measurements. All blood tubes used in this experi‐
mental study were directly purchased from the manufacturers with
proprietary funding. The companies were not aware of the purposes
of this study and had no role in directing the study or influencing
the outcomes. The views in this report are those of the authors and
not necessarily those of the University Hospital of Verona or NSW
Health Pathology.
C O N FL I C T O F I N T E R E S T
The authors of this paper have no conflicts of interest, including spe‐
cific financial interests, relationships, and/or affiliations relevant to
the subject matter or materials included.
AU T H O R C O N T R I B U T I O N S
Giuseppe Lippi and Emmanuel J. Favaloro contributed to the concept,
designed the study, and wrote the manuscript; Gian Luca Salvagno and
Davide Demonte involved in data collection or processing; Giuseppe
Lippi, Emmanuel J. Favaloro, and Giovanni Poli involved in analysis or
interpretation; and Giuseppe Lippi involved in literature search.
ORCID
Gian Luca Salvagno  https://orcid.org/0000-0003-0487-9051
Giuseppe Lippi  https://orcid.org/0000-0001-9523-9054
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How to cite this article: Salvagno GL, Demonte D, Poli G,
Favaloro EJ, Lippi G. Impact of low volume citrate tubes on
results of first‐line hemostasis testing. Int J Lab Hematol.
2019;00:1–6. https://doi.org/10.1111/ijlh.13028