Assessment of blood sample stability for complete blood count using the Sysmex XN-9000 and Mindray BC-6800 analyzers

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revbrashematolhemoter.2016;38(3):225–239

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Original

article

Assessment

of

blood

sample

stability

for

complete

blood

count

using

the

Sysmex

XN-9000

and

Mindray

BC-6800

analyzers

Sabrina

Buoro

a,∗

_,

_Tommaso

_Mecca

a

_,

_Michela

_Seghezzi

a

_,

_Barbara

_Manenti

a

_,

Lorenzo

Cerutti

a

_,

_Paola

_Dominoni

a

_,

_Gavino

_Napolitano

a

_,

_Stefano

_Resmini

a

_,

Alberto

Crippa

a

_,

_Cosimo

_Ottomano

b

_,

_Giuseppe

_Lippi

c

a_Hospital_Papa_Giovanni_XXIII,_Bergamo,_Italy b_CAM_Centro_Analisi_Monza,_Monza,_Italy c_Universitaà_degli_Studi_di_Verona,_Verona,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received4April2016 Accepted30May2016 Availableonline23June2016

Keywords: XN-9000 BC-6800 Samplestability Completebloodcount Pre-analyticalphase

a

b

s

t

r

a

c

t

Background:Differenthematologicalanalyzershavedifferentanalyticalperformancesthat areoftenreﬂectedinthecriteriaforsamplestabilityofthecompletebloodcount.Thisstudy aimedtoassessthestabilityofseveralhematologicalparametersusingtheXN-9000Sysmex andBC-6800Mindrayanalyzers.

Methods:Theimpactofstorageatroomtemperatureand4◦Cwasevaluatedafter2,4,6, 8,24,36and48husingtennormaland40abnormalbloodsamples.Thevariationfrom thebaselinemeasurementwasevaluatedbytheSteel–Dwass–Critchlow–Flignertestandby Bland–Altmanplots,usingqualityspeciﬁcationsandcriticaldifferenceasthetotalallowable variation.

Results:Red bloodcells andreticulocyteparameters (i.e. hematocrit,mean corpuscular volume,mean corpuscularhemoglobinconcentration,redbloodcelldistributionwidth, immaturereticulocytefractions,low-fluorescencereticulocytes,middle-fluorescence retic-ulocytes,highfluorescencemononuclearcells)showedlessstabilitycomparedtoleukocyte andplateletparameters(exceptformonocytecountandmeanplateletvolume).Thebias forhematocrit,meancorpuscularvolume,meancorpuscularhemoglobinconcentration andredbloodcelldistributionwidthcoefficientofvariationwashigherthanthecritical differenceafter8husingbothanalyzers.

Conclusion: Bloodsamplesmeasuredwithbothanalyzersdonotshowanalytically signiﬁ-cantchangesinupto2hofstorageatroomtemperatureand4◦C.However,themaximum timeforanalysiscanbeextendedforupto8hwhenthebiasiscomparedtothecritical difference.

©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

∗ _{Corresponding}_author_at:_Clinical_Chemistry_Laboratory,_Papa_Giovanni_XXIII_Hospital,_Square_OMS,₁_-24127_Bergamo,_Italy. E-mailaddress:sbuoro@asst-pg23.it(S.Buoro).

http://dx.doi.org/10.1016/j.bjhh.2016.05.010

1516-8484/©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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226 Introduction

Modern hematological analyzers not only enable accurate quantitativeandqualitativeassessmentofbloodcells,butalso provideavastarrayofhematologicalparametersthatmaybe usefulforthediagnosticandprognosticassessmentofmany bloodcelldisorders.Thevastmajorityoflaboratoryerrors(up to70%)emergefromthepre-analyticalphase.1_This_phase_is inﬂuencedbyanumberofvariables,includingthepreparation ofthepatientbeforetesting,theproceduresusedtocollect andtransportthebiologicalspecimens,aswell asthetime andstorageconditionsofbloodsamplesbeforeanalysis.In particular,itwasrecentlyproventhatthestabilityofmany hematologicalparametersisstronglyinﬂuencedbythe stor-agetemperatureofthesampleandthetimeelapsedbetween collectionandanalysis.2–4

Anotherfactorthatmayhaveaninfluenceonthe stabil-ityofhematologicalparametersisthetechnologyusedbythe differenthematologicalanalyzers.3_Basically,_the_instruments currentlyavailableonthemarketusedifferentmethodsand technologies toassess basicparameters such asred blood cell (RBC), platelet (PLT), total leukocyte (WBC) and leuko-cytesubclass[neutrophils(NE),lymphocytes(LY),monocytes (MO),eosinophils(EO),basophils(BA)]counts.5Itisforthis reason that a more profound knowledge of the potential impactoftime and storagetemperatureofsamples before analysisshould be regarded asa mainstaytoincrease the qualityofhematologicaltestingandtoimprovetheclinical interpretationofdataobtainedwithdifferentanalyzersand techniques.2–4_Notably,_the_latest_generation_of_{hematological} analyzersprovidesanumberofinnovativequantitativeand qualitativeparameters,suchastheenumerationofhigh fluo-rescencemononuclearcells(HFC)5–7_and_nucleated_red_blood cell(NRBC)count,7_and_the_RBC_distribution_width_expressed asastandarddeviation(RDW-SD)orcoefficientofvariation (RDW-CV).8_Moreover,_they_may_provide_platelet_distribution width(PDW),plateletcrit(PCT),meanplateletvolume(MPV), percentage of large platelet (P-LCR) parameters,5,9,10 _along withthereticulocytecount(RET)andimmaturereticulocyte fractions[IRF, high-fluorescence (HFR), middle-fluorescence (MFR)andlow-fluorescencereticulocytes(LFR)],allofwhich areusefulforthediagnosisandclassificationofanemiaorfor monitoringbonemarrowerythropoiesis.11,12

Theimportanceofverifyingthestabilityofthe aforemen-tionedparametersisnowunquestionableandpublisheddata aboutbloodsamplestabilitybeforeanalysisisscarceforthe newgeneration ofhematological analyzers.Therefore, this studyaimedtoassessandcomparethe stabilityofa num-ber of hematological parameters in normal and abnormal bloodsamplesmeasuredusingtwonovelanalyzers,XN-9000 (SysmexCo.,Kobe,Japan)andBC-6800(Mindray,Shenzhen, China),accordingtotheGuidelinesoftheInternational Coun-cilforStandardizationofHaematology(ICSH)4_and_the_Clinical andLaboratoryStandardsInstitute(CLSI)DocumentH26-P2.13 Bloodsamples

The study population consisted of ten adult and osten-sibly healthy volunteers recruited from the laboratory

staff (five women, mean age 37.5±0.8 years and five males, mean age 35.0±7.4 years). All subjects were Cau-casian,hadnodiabetesmellitus,hypertensionandhadnot taken any medication for onemonthbefore the study.Six venous blood samplesfrom each subjectwere collected in K3-ethylenediaminetetraaceticacid(K3-EDTA)tubes(Becton Dickinson, Franklin Lakes, NJ). All samples were analyzed immediatelyaftervenipuncture(i.e.,within30min).The anal-ysisoftheimpactofdifferentstoragetemperatureswasthen carriedoutbystoringthreebloodtubesfromeachindividualat roomtemperature(RT)andthreebloodtubesweredividedin sixaliquotsandstored(refrigerated)at4◦C.Repeated meas-ureswerethenperformedoneachsampleafter2h,4h,6h, 8h,24h,36hand48hofstorage.Anadditionalstudywas per-formedusing40routinesampleswithabnormalvalues,that is, containingatleastoneabnormalityofhemoglobin(Hb), platelet(PLT)orwhitebloodcell(WBC)countsor morpholog-icalalterations(i.e.,atleastonemorphologicalflagforWBC). CountabnormalitiesincludedHblowerthan70g/dL,PLTlower than100×109_/L_or_higher_than₄₀₀_×₁₀9_/L;_WBC_lower_than 1.00×109/Lorhigherthan12.00×109/L.Hematological test-ingwasperformedimmediatelyuponarrivalinthelaboratory (i.e.,within30min)andtheneachsamplewasdividedinto8 aliquots,fourwerestoredat4◦CandfourwerestoredatRT. Thetestswererepeatedafter4h,8h,24h36hand48hof stor-age.Allmeasures(i.e.,thebaselineandtherepeatedanalyses) wereperformedinduplicateandthefinalvaluewasexpressed asthemeanofthetwoanalysesateachtimepoint.

Studydesign

Thefollowingparameterswereassessedtocheckblood sam-ple stability: extended complete blood count (CBC) profile parameters, including all basic CBC parameters [RBC, Hb, hematocrit(HT)],meancorpuscularvolume(MCV),mean cor-puscularhemoglobin(MCH), mean corpuscularhemoglobin concentration (MCHC),RDW-SD, RDW-CVand NRBC. More-over,theextendeddifferentialcounts(DIFF)(includingWBC, NE,LY,MO,EO,BAandHFC),PLTprofileparameters(including PLT,PCT,MPV,PDWandP-LCR)andtheRETprofile(including RET,IRF,LFR,MFRandHFR)wereevaluated.

Themeasurementsatthedifferenttimepointswere con-comitantly performed withboth the XN-9000 and BC-6800 analyzers. The mean analytical characteristics of the two analyzers are summarized in Table 1. Briefly, the XN-9000 andtheBC-6000analyzersperforma5-partDIFF,RETcount, NRBCcount,withflagsappearinginthepresenceofabnormal results.7,14,15_Both_analyzers_use_a_combination_of_flow cytom-etryandfluorescencewithlysingbuffersforleukocyteDIFF andidentification ofabnormalcells.Aseparatechannelfor NRBCassessmentisalsoavailableintheBC-6800.

The between-run imprecision ofboth the XN-9000 and BC-6800wasevaluatedaccordingtotheCLSIdocument EP5-A3,16 _by_analysis_in_duplicate_of_three_levels_(i.e., _level_1,₂ and 3) ofcontrolmaterials(XN-CHECK;StreckLaboratories Inc.,Omaha,NE,USAandBC-6D,BC-BC-RETandNRBC; Shen-zhenMindrayBio-MedicalElectronics,Shenzhen,China)for 40 consecutive workingdays.Thestudy wascarried outin accordwiththeDeclarationofHelsinki,underthetermsofall

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227

Table1–XN-9000andBC-6800parameterswithoptimalperformanceBias%andCriticalDifference%(CD).

Parameters XN-9000 BC-6800 Optimal performance Bias% Critical Difference% onXN-9000 Critical Difference%on BC-6800

Redbloodcell RBC RBC 0.9 9.1 9.3

Hemoglobin HGB HGB 0.9 7.9 8.1

Hematocrit HCT HCT 0.9 8.4 9.5

Meanvolume,redbloodcells MCV MCV 0.6 4.2 5.3

Meancorpuscularhemoglobin MCH MCH 0.7 5.0 5.4

Meancorpuscularhemoglobinconcentration MCHC MCHC 0.4 5.8 6.7

RBCdistributionwidth RDW-CV RDW-CV 0.9 9.8 9.9

RDW-SD RDW-SD NA NA NA

Nucleatedredbloodcell NRBC NRBC NA NA NA

Whitebloodcells WBC WBC 2.8 30.5 30.6

Neutrophil NEUT Neu 4.6 45.4 45.2

Lymphocyte LYMPH Lym 3.7 30.2 30.4

Monocyte MONO Mon 6.6 53.7 57.4

Eosinophil EO Eos 9.9 62.0 58.9

Basophil BASO Bas 7.7 77.9 88.1

Highﬂuorescencecells HFLC HFC NA NA NA

Platelet PLT PLT 3.0 26.1 26.2

Meanvolumeplatelet MPV MPV 1.2 12.3 12.6

PLTdistributionwidth PDW PDW NA NA NA

Plateletcrit PCT PCT NA NA NA

PLTlargercellratio P-LCR P-LCR NA NA NA

Reticulocyte RET RET 3.9 31.7 31.1

Immaturereticulocytefraction IRF IRF NA NA NA

Low-ﬂuorescencereticulocyte LFR LFR NA NA NA

Medium-ﬂuorescencereticulocyte MFR MFR NA NA NA

High-ﬂuorescencereticulocyte HFR HFR NA NA NA

NA:notavailable.

relevantlocallegislationandwithpriorapprovaloftheLocal EthicsCommittee.

Statisticalanalysis

Thesignificanceofthedifferenceoftheparametersobtained in paired samples measured with the two analyzers was estimated according to the Steel–Dwass–Critchlow–Fligner test,withassessmentbytheHodges–Lehmannlocationshift formultiple comparisons of means and medians between differentgroups,afterverificationofvaluedistributionbythe Shapiro–Wilktest.Statisticalsignificancewassetforp-values

<0.05. The results were then reported as delta variations from baselineanalysis immediately aftercollection, asX (TX−T0), where “X” isthe different timing and “0” is the baselineresult.Percentagevariationsfromthebaselineresult (T0)insampleswithstatisticallysigniﬁcantdifferenceswere then analyzedusing Bland–Altmanplots (Bias%)and com-paredwiththecurrentqualityspeciﬁcationsforoptimalbias (OP-Bias%),17_that_is_calculated_using_{intra-individual} biolog-icalvariability(CVi)andinter-individualbiologicalvariability (CVg)followingtheequation:OP-Bias%=0.250(CVi+CVg)1/2_. Bias%wasalsocomparedwiththereferencechangevalues orcriticaldifference(CD)18,19_when_these_indices_were avail-able. The CD percentage is the highest relative difference betweentwo consecutive measurements,that, ata chosen levelofprobability, maystillbeduetothecombinedeffect oftheanalytical(Va)andbiological(Vi)variations.Itisgiven bythe followingequation: CD%=K×(Va2₊_Vi2₎1/2_, _where _K

dependsonthechosenprobability.Thecomparisonbetween Bias% and CD% was performed only forthose parameters exhibitingastatisticallysigniﬁcantdifferencebetweenBias% and OP-Bias% throughoutthe study period. The statistical analysis was performed using Analyse-it software version 3.90.1(Analyse-itSoftwareLtd.;Leeds,UK).

Results

Overall, 2480measurements were performed withthe XN-9000andBC-6800analyzers.Allresultsobtainedinthenormal samples group were included in the statistical analysis, whereas160measurementswereperformedintheabnormal samplesgroup. Unfortunately,severalmeasurements could notbeperformedduetothelowresidualsamplevolumein this second groupofsamples. Theresultsofthese studies andtherelativevariationsaccordingtothedifferentstorage conditionsareshowninTables2–5.

Redbloodcellparameters

Themedianvaluesobtainedatbaseline(i.e.,T0)inthenormal sample group did not signiﬁcantly differ between the two analyzersforalltheparameterstested,exceptforMCHand MCHC(Table2).Inthisgroupofnormalsamples,thevalues ofWBC,RBC,HB,MCHandNRBCwerefoundtobestableup to48hatRTand4◦Cusingbothanalyzers.Conversely,theHT valuesdisplayedastatisticallysigniﬁcantincrease48hafter

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rev bras hema tol hemoter. 2 0 1 6; 3 8(3) :225–239

Table2–SamplesstabilityofgroupofnormalsamplesforCBCandRETproﬁlesparameters.MedianHodges–Lehmannlocationshift(X);Bias%(B%)betweenbaseline (T0)andthetimepoint(2hupto48h)at4◦Candroomtemperature(RT)comparisonofOP-Bias%toCriticalDifference%(CD).

Temp T0

medianvalue (95%CI)

X(TX−T0)Hodges–Lehmannlocationshift Xwith

p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 2h 4h 6h 8h 24h 36h 48h WBC (109_/L) XN-9000 RT 7.67(5.91to9.40) 0.03 0.05 −0.03 0.06 0.07 −0.08 −0.10 NS 1.4(−1.0to3.7); p=0.2192;48h NE 4◦C 0.13 0.02 0.22 0.14 0.08 0.10 −0.03 NS 3.0(−1.4to7.5); p=0.9109;48h NE BC-6800 RT 7.15(5.60to7.95) 0.02 0.00 0.04 0.14 0.16 0.19 0.01 NS −0.2(−2.5to2.0); p=0.0105;48h NE 4◦C 0.01 0.16 0.02 0.03 0.03 0.04 −0.03 NS 0.2(−1.0to1.5); p=0.0013;48h NE RBC (1012_/L) XN-9000 RT 4.60(4.23to5.22) −0.01 −0.01 −0.02 0.01 0.02 0.01 0.00 NS −0.1(−0.6to0.5) p<0.0001;48hb NE 4◦C 0.12 0.10 0.13 0.15 0.11 0.16 0.15 NS 2.7(0.9to4.5) p=0.0522;48h NE BC-6800 RT 4.57(4.20to4.89) 0.00 0.09 0.05 −0.08 −0.06 −0.04 −0.04 NS −0.6(−3.9to2.7); p=0.3477;48h NE 4◦C 0.06 0.08 0.06 0.09 0.09 0.08 0.09 NS 1.6(0.4to2.9); p=0.2163;24h NE Hb(g/L) XN-9000 RT 142(126to151) 0.10 0.20 0.10 0.20 0.30 0.20 0.10 NS 1.0(0.6to1.4) p=0.5780;48h NE 4◦C 0.40 0.35 0.40 0.30 0.35 0.35 0.40 NS 3.7(2.0to5.4); p<0.0001c −0.6(−1.4to0.6); p<0.0001;48hd BC-6800 RT 146(134to151) 0.00 0.00 0.00 −0.20 −0.15 −0.20 −0.10 NS −1.4(−4.3to1.5); p=0.1119;48h NE 4◦C 0.20 0.20 0.10 0.20 0.20 0.20 0.20 NS 1.3(0.9to1.6); p=0.0640;48h NE HT (%) XN-9000 RT 41.6(37.2to43.7) −0.37 −0.63 −0.56 −0.40 2.11 3.25 6.12 48h 0.9(−1.6to3.5); p=0.9747;8h 4.9(2.2to7.6); p<0.0001;24hd 4◦C 0.25 0.25 0.40 0.80 0.95 1.35 1.90 NS 2.3(0.8to3.9); p=0.0740;24h 4.7(3.3to6.4); p<0.0001;48hd BC-6800 RT 41.4(40.2to44.1) −0.05 0.35 0.20 −0.60 2.15 3.90 6.00 48h 1.9(−1.0to4.8); p=0.4791;8h 4.9(1.9to8.0) p<0.0001;24hd 4◦C 0.20 0.40 0.00 0.50 0.90 1.30 2.00 NS 1.6(0.7to2.6); p=0.1300;24h 4.1(3.2to5.0); p<0.0001;48hd

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229

Table2–(Continued) Temp T0 medianvalue (95%CI)

p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 2h 4h 6h 8h 24h 36h 48h MCV (fL) XN-9000 RT 87.45(86.2to90.5) −0.42 −1.24 −1.02 −1.27 3.51 6.10 13.1 24h 0.5(0.2to0.7); p=0.3676;2h −1.5(−2.1to −0.8); p<0.0001;8hd 4◦C −1.25 −1.30 −1.40 −1.00 0.10 0.50 2.00 NS 0.3(−0.2to0.8); p=0.2932;24h 2.0(1.3to2.7); p<0.0001;48hd BC-6800 RT 89.8(88.2to92.7) −0.25 −0.45 −0.50 −0.35 5.70 8.80 13.4 24h −0.2(−0.8to0.5); p=0.1688;8h −0.2(−0.8to0.5); p<0.0001;8hd 4◦C −1.50 −1.40 −1.55 −1.10 −0.15 0.70 1.55 NS 0.8(0.3to1.4); p=0.3793;36h 2.1(1.3to2.9); p<0.0001;48hd MCHa (pg) XN-9000 RT 30.0(29.0to30.6) 0.30 0.40 0.50 0.40 0.50 0.30 0.30 NS 1.1(0.6to1.6); p=0.1069;48h NE 4◦C 0.40 0.40 0.40 0.30 0.20 0.10 0.20 NS 0.6(0.1to1.1); p=0.7434;48h NE BC-6800 RT 31.4(30.7to32.3) −0.20 −0.30 −0.30 −0.30 −0.30 −0.50 −0.30 NS 0.9(0.2to1.6); p=0.5672;48h NE 4◦C −0.30 −0.30 −0.10 −0.30 −0.30 −0.30 −0.30 NS 0.8(0.1to1.8); p=0.8085;48h NE MCHCa (g/dL) XN-9000 RT 34.2(33.4to34.4) 0.60 0.80 1.00 0.90 −0.80 −1.90 −4.20 4h 1.7(1.1to2.6); p<0.0001c −2.4(−3.5to −1.3); p<0.0001;8hd 4◦C 1.10 0.90 1.10 0.80 0.40 0.10 −0.50 2h 3.1(2.5to3.7); p<0.0001c 1.4(0.6to2.2); p<0.0001;48hd BC-6800 RT 35.6(33.4to36.2) −0.10 −0.30 −0.10 −0.20 −2.30 −3.50 −4.90 24h −0.7(−1.2to−0.2); p=0.2126;8h −0.7(−1.2to −0.2); p<0.0001;8hd 4◦C 0.20 0.10 0.30 0.00 −0.40 −0.60 −1.10 48h 0.9(0.3to1.4); p=0.1027;24h 2.9(2.1to3.7); p<0.0001;48hd RDW-CV (%) XN-9000 RT 12.9(12.7to13.1) 0.00 0.00 0.10 0.10 0.70 1.20 1.50 24h 0.9(0.4to1.4); p=0.9785;8h 8.7(7.6to9.8); p<0.0001;48hd 4◦C −0.10 −0.10 −0.10 −0.10 −0.30 −0.30 −0.30 24h 0.9(0.6to1.3); p=0.8055;8h 2.3(1.4to3.1); p<0.0001;48hd BC-6800 RT 12.9(12.4to13.2) 0.00 0.20 0.30 0.30 1.20 1.60 1.90 24h 0.5(0.1to0.8); p<0.0001;2hb 2.7(2.0to3.3); p<0.0001;8hd 4◦C 0.10 0.20 0.20 0.20 −0.10 0.00 −0.10 NS 0.3(−0.3to1.0); p=0.0912;48h NE RDW-SD (fL) XN-9000 RT 41.4(39.4to43.2) −0.10 −0.70 −0.25 −0.55 4.40 7.00 12.0 24h 10.2(8.6to11.8) CD%datanot available 4◦C −1.10 −1.20 −1.10 −1.10 −1.20 −1.10 −0.50 NS 0.9(−0.4to2.2) BC-6800 RT 40.5(39.5to41.5) 0.00 0.50 0.70 0.90 7.15 10.1 12.8 24h 14.9(12.5to17.4) 4◦C −0.15 0.00 0.00 0.10 −0.20 0.50 0.50 NS 0.9(0.0to1.9)

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rev bras hema tol hemoter. 2 0 1 6; 3 8(3) :225–239 Table2–(Continued) Temp T0 medianvalue (95%CI)

p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 2h 4h 6h 8h 24h 36h 48h NRBC (109_/L) XN-9000 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 20.0(−31.7to71.7) 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 0.0(−42.9to42.9) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 0.0(0.0to0.0) 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 0.0(0.0to0.0) RETa (109_/L) XN-9000 RT 48.1(35.1to60.3) 0.63 −0.89 −1.05 −1.50 −3.71 −0.59 −1.77 NS 2.5(−1.5to6.6); p=0.4964;48h NE 4◦_C _1.01 _1.15 _0.36 _0.08 _−0.07 _0.27 _−0.11 _NS _0.3₍_−3.9_to_4.4); p=0.0840;48h NE BC-6800 RT 37.4(26.8to44.4) 0.85 1.55 0.30 −1.10 0.45 −1.20 −2.60 NS 6.1(0.3to12.0); p=0.4344;36h 9.8(4.5to15.1); p<0.0001;48hd 4◦C 0.00 0.50 −1.30 0.25 1.30 1.65 3.45 NS 5.0(1.2to8.8); p=0.5394;36h 10.7(6.2to15.2); p<0.0001;48hd IRFa (%) XN-9000 RT 9.3(6.9to10.3) −0.81 −0.49 −1.08 −1.37 −1.94 −1.85 −2.07 24h −25.1(−38.7to−11.5) CD%datanot available 4◦C 0.15 −0.98 −0.42 −0.96 −0.64 −0.66 0.45 NS 4.0(−5.3to13.4) BC-6800 RT 3.4(2.5to4.3) 0.20 0.20 0.20 −0.20 −0.85 −1.35 −2.00 36h −90.2(−110.8to−69.6) 4◦_C _0.0 _−0.80 _−0.60 _−0.70 _0.10 _0.50 _0.90 _NS _22.1_(4.4_to_39.6) LFRa (%) XN-9000 RT 90.7(89.7to93.1) 0.81 0.48 1.08 1.37 1.94 1.85 2.07 24h 2.1(1.0to3.2) 4◦C −0.16 0.98 0.42 0.96 0.64 0.66 −0.45 NS −0.5(−1.4to0.4) BC-6800 RT 96.5(95.7to97.5) −0.20 −0.20 −0.20 0.20 0.85 1.35 2.00 36h 2.1(1.5to2.7) 4◦C 0.00 0.80 0.60 0.70 −0.10 −0.50 −0.90 NS −0.8(−1.3to−0.2) MFRa (%) XN-9000 RT 8.4(6.5to8.9) −0.72 −0.43 −1.02 −1.20 −1.58 −1.70 −1.68 24h −23.7(−37.6to−9.7) 4◦C 0.15 −0.78 −0.48 −0.82 −0.77 −0.66 0.04 NS −0.9(−11.2to9.5) BC-6800 RT 3.4(2.5to4.3) 0.20 0.20 0.20 −0.20 −0.85 −1.35 −2.00 36h −90.2(−67.9to−35.5) 4◦C 0.00 −0.80 −0.60 −0.70 0.10 0.50 0.90 NS 22.0(4.4to39.7) HFRa (%) XN-9000 RT 0.9(0.6to1.3) 0.00 0.00 −0.10 −0.10 −0.30 −0.10 −0.30 NS −51.1(−79.2to−23.0) 4◦C 0.10 −0.15 0.10 −0.10 0.10 0.10 0.40 NS 46.8(21.2to72.4) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 0.0(0.0to0.0) 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 0.0(0.0to0.0)

WBC:whitebloodcells;RBC:redbloodcell;RT:Roomtemperature;Hb:hemoglobin;HT:hematocrit;MCV:meancorpuscularvolume;MCH:meancorpuscularhemoglobin;MCHC:meancorpuscular hemoglobinconcentration;RDW-CV:distribution-coefficientofvariation;RDW-SD:RBCdistributionwidth-standarddeviation;NRBC:nucleatedredbloodcell;RET:reticulocyte;IRF:immature reticulocytefraction;LFR:low-fluorescencereticulocyte;MFR:medium-fluorescencereticulocyte;HFR:high-fluorescencereticulocyte;NS:Xnotsignificantthroughoutthestudyperiod;NE:not evaluated;Temp:Temperature.

a _Parameters_with_median_value_a_T0_signiﬁcant_difference_between_two_analyzer_in_the_same_samples_with_p_<_0.0001. b _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_OP-Bias%.

c _Bias%_(between_baseline_T0_and_the_time_point_X)_is_always_higher_than_OP-Bias%. d _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_CD%.

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Table3–Samplesstabilityongroupofpathologicalsamplesfor:CBCandRETproﬁlesparameters.Median

Hodges–Lehmannlocationshift(X);Bias%(B%)betweenbaseline(T0)andthetimepoint(4hupto8h)at4◦Candroom temperature(RT)comparisonofOP-Bias%toCriticalDifference%(CD).

Temp T0medianvalue (95%CI) X(TX−T0) Hodges–Lehmann locationshift Xwith p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 4h 8h WBC (109_/L) XN-9000 RT 5.3(4.3to7.2) 0.00 −0.10 NS −0.8(−6.8to5.2); p=0.2229;8h NE 4◦C 8.6(6.5to10.1) 0.06 0.04 NS 0.6(−4.5to5.6); p=0.37625;8h NE BC-6800 RT 5.4(4.1to7.1) 0.05 −0.10 NS 2.3(−0.9to5.5); p=0.3274;8h NE 4◦C 8.5(6.4to9.9) 0.20 −1.22 NS 1.8(0.7to2.9); p=0.0774;4h 18.4(7.2to29.7); p<0.0001;8ha RBC (1012_/L) XN-9000 RT 4.8(3.8to5.6) 0.01 −0.16 NS −4.0(−17.8to9.8); p=0.4582;8h NE 4◦C 3.6(3.5to3.9) −0.02 −0.02 NS −0.4(−2.1to1.2); p=0.1161;8h NE BC-6800 RT 4.6(3.7to5.3) −0.02 −0.01 NS 0.3(−1.1to1.8); p=0.4194;8h NE 4◦C 3.5(3.3to3.8) −0.01 0.26 NS 8.5(−0.5to17.5); p=0.0945;8h NE Hb (g/L) XN-9000 RT 141.0(123.0to152.0) 0.10 −0.70 NS −5.2(−19.7to9.2); p=0.3370;8h NE 4◦C 113.0(101.0to116.0) 0.00 0.00 NS 0.5(−0.4to1.3); p=3067;8h NE BC-6800 RT 141.0(123.0to154.0) −0.10 −0.20 NS −0.8(−4.3to2.7); p=0.3108;8h NE 4◦C 111.0(103.0to117.0) 0.00 1.30 NS 1.6(0.07to3.12); p=0.3546;8h NE HT (%) XN-9000 RT 40.7(35.3to46.5) 0.40 −1.40 NS −3.5(−17.4to10.3); p=0.5044;8h NE 4◦C 33.9(31.5to35.5) 0.00 0.00 NS 0.1(−0.7to0.9); p=0.0614;8h NE BC-6800 RT 39.7(34.5to44.3) 0.00 0.00 NS 1.3(−0.3to2.9); p=0.5982;8h NE 4◦C 32.6(30.6to34.4) 0.00 0.02 NS 8.6(−0.5to17.7); p=0.0921;8h NE MCV (fL) XN-9000 RT 84.8(84.0to88.4) 0.60 0.30 NS 0.5(0.1to0.8); p=0.4860;8h NE 4◦C 89.9(87.7to92.5) 0.40 0.40 NS 0.5(−0.3to1.4); p=0.8606;8h NE BC-6800 RT 85.8(84.5to88.7) 0.60 0.80 NS 0.5(0.4to0.7); p=0.3379;4h 1.0(0.8to1.2); p<0.0001;8ha 4◦C 92.4(87.1to93.5) 0.20 0.10 NS 0.1(0.0to0.3); p<0.0001;8hb NE MCH (pg) XN-9000 RT 28.9(27.3to29.8) 0.07 −0.33 NS 1.2(0.1to2.4); p=0.3425;8h NE 4◦C 29.6(27.2to30.9) 0.20 0.00 NS −0.1(−1.0to0.8); p=0.0961;8h NE BC-6800 RT 30.3(28.9to31.4) 0.00 0.10 NS −1.1(−4.0to1.8); p=0.2119;8h NE 4◦C 31.3(28.2to32.4) 0.10 0.85 NS 0.20(−0.07to0.05); p=0.1530;4h 3.9(2.8to5.4) p<0.0001;8ha

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Table3–(Continued)

Temp T0medianvalue (95%CI) X(TX−T0) Hodges–Lehmann locationshift Xwith p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 4h 8h MCHC (g/dL) XN-9000 RT 33.6(32.5to34.5) −0.10 −0.60 NS 0.5(−0.3to1.2); p=0.8634;4h NE 4◦C 32.9(32.4to33.5) 0.02 −0.20 NS 0.6(0.3to0.9); p=0.1932;8h NE BC-6800 RT 35.3(34.7to35.6) −0.35 −0.40 NS _p−2.1₌_0.812;(−5.0₈to_h0.8); NE 4◦C 34.1(33.7to34.3) 0.10 0.85 8h 0.0(−0.3to0.3); p<0.0001b_;₄_h 3.8(1.6to6.1); p<0.0001;8ha RDW-CV (%) XN-9000 RT 13.3(13.1to15.9) 0.20 0.35 NS 2.8(−9.7to15.4); p<0.7469;8h NE 4◦C 14.2(13.4to14.6) 0.10 0.10 NS 0.7(0.1to1.2); p=0.4190;8h NE BC-6800 RT 13.4(13.0to15.6) 0.30 0.50 NS 2.1_p_<_0.0001(1.8toc2.4); 3.6(2.9to4.2); p<0.0001;8ha 4◦_C _13.7_(13.4_to_14.1) _0.10 _0.25 _NS _0.9_(0.5_to_1.2); p=0.9609;4h 2.1(1.2to2.9); p<0.0001;8ha RDW-SD (fL) XN-9000 RT 42.3(41.1to44.3) 1.00 1.85 NS 3.6(−9.0to16.2); p=0.6544;8h CD%datanot available 4◦C 44.2(43.1to48.4) 0.50 0.60 NS 1.2(−0.2to2.5); p=0.6629;8h BC-6800 RT₄_◦_C 41.5_42.7_(41.9(40.3to_to43.3)_47.8) _0.401.20 _0.902.00 _NS8h 4.3_2.0(3.6_(1.0to_to5.1)_2.9) NRBC (109_/L) XN-9000 RT₄◦_C 0.0_0.0_(0.0(0.0_toto_0.0)0.0) 0.00_0.01 _0.020.01 ₄8_hh 103.3_129.9(41.9_(95.5to_to164.8)_164.4) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 NS 78.6(26.4to130.8) 4◦C 0.0(0.0to0.0) 0.00 0.02 8h 124.0(78.5to169.6) RET (109_/L) XN-9000 RT 53.1(46.3to72.1) 0.11 −3.39 NS −4.4(−24.8to16.1); p=0.3996;8h NE 4◦C 54.0(46.0to68.1) 1.20 1.50 NS 3.0(−0.1to6.1); p=0.5427;8h NE BC-6800 RT 41.5(31.9to55.2) 2.30 3.55 NS _p7.3₌_0.0912;(3.3to11.4);₈_h NE 4◦C 52.2(41.1to60.1) 1.14 3.45 NS 5.4(−5.2to16.0); p=0.7652;8h NE IRF (%) XN-9000 RT 6.6(4.1to7.9) 0.00 0.60 NS 6.1(−28.3to40.5) CD%datanot available 4◦C 15.5(11.5to20.5) 0.20 0.10 NS −0.1(−6.5to6.3) BC-6800 ₄RT_◦_C 1.7_8.4(0.9_(5.0to_to_12.9)2.5) −0.20 −0.30 NS −8.5(−28.5to11.5) −0.60 −0.80 NS −21.5(−44.7to1.7) LFR (%) XN-9000 RT₄_◦_C 93.4_84.6_(79.5(92.1_toto95.9)_88.5) _−0.200.00 _−0.10−0.60 _NSNS _−0.7−0.7(_(−2.6−6.5to_to5.0)_1.1) BC-6800 RT 98.3(97.5to99.1) 0.20 0.30 NS 0.1(−0.5to0.6) 4◦C 91.7(87.1to95.0) 0.60 0.80 NS 0.7(0.2to1.2) MFR (%) XN-9000 RT 6.1(4.0to6.9) 0.15 0.60 NS 6.8(−22.5to36.2) 4◦C 12.0(10.6to13.8) −0.55 −0.40 NS −5.6(−10.7to−0.5) BC-6800 RT 1.7(0.9to2.5) −0.20 −0.30 NS −8.9(−28.9to11.1) 4◦C 8.0(5.0to11.6) −0.30 −0.60 NS −18.9(−42.5to4.8) HFR (%) XN-9000 RT 0.5(0.1to1.0) 0.00 0.00 NS 6.9(−56.2to70.0) 4◦C 2.8(1.4to7.9) 0.40 0.30 NS 19.0(−2.1to40.1) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 NS 2.6(−1.7to6.9) 4◦C 0.0(0.0to1.2) 0.00 0.00 NS −38.8(−70.2to−7.4)

WBC:whitebloodcells;RBC:redbloodcell;RT:Roomtemperature;Hb:hemoglobin;HT:hematocrit;MCV:meancorpuscularvolume;MCH: meancorpuscularhemoglobin;MCHC:meancorpuscularhemoglobinconcentration;RDW-CV:distribution-coefficientofvariation;RDW-SD: RBCdistributionwidth-standarddeviation;NRBC:nucleatedredbloodcell;RET:reticulocyte;IRF:immaturereticulocytefraction;LFR: low-fluorescencereticulocyte;MFR:medium-fluorescencereticulocyte;HFR:high-fluorescencereticulocyte;NS:Xnotsignificantthroughoutthe studyperiod;NE:notevaluated;Temp:Temperature.

a _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_CD%. b _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_OP-Bias%. c _Bias%_(between_baseline_T0_and_the_time_point_X)_is_always_higher_than_OP-Bias%.

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233

Table4–Samplesstabilityofgroupofnormalsamplesfor:DIFFandPLTproﬁlesparameters.MedianHodges–Lehmannlocationshift(X);Bias%(B%)betweenbaseline (T0)andthetimepoint(2hupto48h)at4◦Candroomtemperature(RT)comparisonofOP-Bias%toCriticalDifference%(CD).

Temp T0medianvalue (95%CI)

X(TX−T0)Hodges–Lehmannlocationshift Xwithp<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 2h 4h 6h 8h 24h 36h 48h NE (109_/L) XN-9000 RT 4.4(3.5to4.7) 0.01 0.08 −0.02 0.00 0.21 0.06 0.00 NS 0.5(−3.1to4.1); p=0.0273;48h NE 4◦C 0.07 0.07 0.09 0.06 0.04 0.14 0.13 NS 2.5(−3.4to8.3); p=0.4509;48h NE BC-6800 RT 4.0(3.0to4.6) 0.17 0.12 0.09 0.21 0.40 0.27 0.42 NS 3.5(0.9to6.1); p=0.3950;48h NE 4◦_C _0.02 _0.10 _0.00 _0.05 _0.23 _0.34 _0.51 _NS _11.0_(7.1_to_14.8); p=0.1137;24h NE LY (109_/L) XN-9000 RT 2.3(1.7to2.5) −0.02 −0.02 −0.07 −0.05 0.00 0.03 0.05 NS 1.1(−1.7to3.9); p=0.0626;48h NE 4◦_C _−0.03 _0.01 _−0.02 _0.00 _−0.09 _−0.06 _−0.11 _NS _7.6_(3.1_to_12.1); p=0.0885;48h NE BC-6800 RT 2.0(1.6to2.3) 0.01 0.00 0.02 0.02 0.02 0.00 −0.01 NS 1.0(−2.7to4.7); p=0.1480;48h NE 4◦C −0.01 −0.02 −0.03 0.00 −0.13 0.12 0.24 NS 0.3(−2.9to−3.47); p=0.0372;8h 16.4(11.1to21.7); p<0.0001;48hb MOa (109_/L) XN-9000 RT 0.6(0.6to0.9) 0.00 0.00 −0.01 −0.01 −0.12 −0.15 −0.03 NS 16.0(5.0to27.0); p=0.0884;48h NE 4◦_C _0.02 _0.00 _0.02 _0.02 _−0.01 _−0.06 _−0.17 _NS _8.8_(1.94_to_−15.7); p=0.5053;24h 28.1(19.1to37.1); p<0.0001;48hb BC-6800 RT 0.5(0.4to0.7) 0.00 0.00 0.01 0.00 −0.04 −0.04 −0.12 48h 12.3(5.1to19.4); p=0.1128;36h 33.2(24.7to41.6); p<0.0001;48hb 4◦C 0.02 0.03 0.02 0.01 −0.01 −0.07 −0.13 48h 3.4(−1.5to8.2); p=0.1816;24h 36.7(28.6to44.8); p<0.0001;48hb EO (109_/L) XN-9000 RT 0.2(0.1to0.3) 0.00 0.01 0.02 0.03 −0.02 −0.05 −0.01 NS 14.5(2.0to−26.9); p=0.4507;48h NE 4◦_C _0.00 _0.00 _0.01 _0.00 _0.01 _0.00 _0.00 _NS _0.4_(−11.7_to_12.5); p=0.1175;48h NE BC-6800 RT 0.1(0.1to0.3) 0.01 0.00 0.01 0.01 0.00 0.01 0.00 NS 6.1(−1.2to13.4); p=0.2908;48h NE 4◦C 0.01 0.01 0.00 0.01 0.01 0.01 0.01 NS 10.01(0.9to19.3); p=0.966;48h NE BA (109_/L) XN-9000 RT 0.1(0.0to0.1) 0.00 0.00 0.00 0.00 0.01 0.01 0.01 NS 20.2(−4.5to44.9); p=0.3032;48h NE 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.01 NS 26.1(1.3to50.9); p=0.1362;48h NE

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234

rev bras hema tol hemoter. 2 0 1 6; 3 8(3) :225–239 Table4–(Continued)

Temp T0medianvalue (95%CI)

X(TX−T0)Hodges–Lehmannlocationshift Xwithp<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 2h 4h 6h 8h 24h 36h 48h BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 3.8(−9.9to17.4); p=0.5552;48h NE 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS 10.5(−10.8to30.9); p=0.7777;48h NE HFC (109_/L) XN-9000 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 −0.01 −0.01 −0.01 NS −88.3(−134.8to−41.9) CD%datanot available 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS −26.7(−73.9to20.6) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS −28.7(−84.4to27.1) 4◦C 0.00 0.00 0.00 0.00 0.00 0.00 0.00 NS −58.0(−112.1to−3.9) PLT (109_/L) XN-9000 RT 262.0(231.0to 299.0) −1.0 3.0 −3.0 −1.0 −19.0 −15.0 −10.0 NS 5.2(1.9to8.5); p=0.1847;48h NE 4◦_C _−14.5 _−16.5 _−20.5 _−19.0 _−21.0 _−19.5 _−23.0 _NS _6.0_(4.0_to_8.0); p<0.0001c 9.5(6.1to12.8); p<0.0001;48hb BC-6800 RT 250.0(227.0to 279.0) 9.0 7.0 12.0 6.5 3.0 7.0 5.0 NS 4.0(1.2to6.8); p=0.0045;48h NE 4◦C 4.0 3.0 4.0 −1.0 −3.0 −2.0 −5.0 NS −0.6(−2.9to1.7); p=0.4497;48h NE MPVa_(fL) XN-9000 RT 10.8(10.2to11.3) 0.40 0.50 0.60 0.60 1.30 1.50 0.90 24h 3.7(2.9to4.5);p<0.0001 c _9.2_(6.9_to_1.0); p<0.0001;48hb 4◦C 0.00 −0.10 0.20 0.10 0.50 0.60 0.90 48h 0.8(−0.4to1.5); p=0.1719.8h 5.7(4.3to7.0); p<0.0001;48hb BC-6800 RT 9.5(9.1to9.9) 0.60 0.80 1.00 0.80 0.80 0.80 1.10 4h 6.1(4.9to7.2);p<0.0001 c _8.8_(5.7_to_11.9); p<0.05;24hb 4◦C 0.60 0.50 0.70 0.60 0.90 1.00 1.20 24h 1.3(1.1to1.4); p=0.5307;48h 1.3(1.1to1.4); p<0.0001;48hb PDWa (fL) XN-9000 RT 12.5(11.8to14.0) 0.70 0.90 1.00 0.90 1.30 3.40 2.05 24h 19.7(14.7to24.3) CD%datanot available 4◦C 0.20 −0.20 0.40 0.00 1.00 1.30 2.00 48h 13.7(10.9to16.4) BC-6800 RT 10.95(10.40to 11.30) 0.80 1.10 1.20 1.10 1.30 1.20 1.50 24h 1.3(0.5to2.0) 4◦C 1.00 0.60 1.25 1.30 1.60 1.60 2.10 24h 1.7(1.1to2.3) PCTa_(%) XN-9000 RT 0.28(0.25to0.33) 0.01 0.01 0.01 0.01 0.02 0.03 0.02 NS 7.2(3.9to10.5) 4◦_C _−0.02 _−0.02 _0.02 _−0.02 _−0.01 _−0.01 _0.00 _NS _−2.3₍_−4.8_to_0.3) BC-6800 RT 0.2(0.2to0.3) 0.02 0.02 0.03 0.03 0.02 0.02 0.03 NS 15.4(10.5to20.4) 4◦C 0.02 0.01 0.02 0.01 0.02 0.03 0.30 NS 11.6(8.5to14.7) P-LCRa (%) XN-9000 RT 32.3(27.4to36.0) 3.65 4.20 5.00 4.45 10.70 12.00 7.40 24h 30.3(23.2to37.3) 4◦C 0.05 −0.70 1.25 0.40 3.55 5.00 6.95 48h 20.1(18.1to22.2) BC-6800 RT 23.4(19.8to25.5) 3.80 5.00 6.00 5.30 5.05 5.00 6.80 6h 30.1(19.1to41.0) 4◦_C _3.95 _3.00 _4.65 _4.20 _6.40 _6.90 _8.25 ₂₄_h _33.0_(28.0_to_38.0)

NE:neutrophil;LY:lymphocyte;MO:monocyte;RT:Roomtemperature;EO:eosinophil;BA:basophil;HFC:HIGHﬂuorescencecells;PLT:platelet;MPV:meanvolumeplatelet;PDW:PLTdistributionwidth; PCT:plateletcrit;P-LCR:PLTlargercellratio;NS:Xnotsigniﬁcantthroughoutthestudyperiod;NE:notevaluated;Temp:Temperature.

a _Parameters_with_median_value_a_T0_signiﬁcant_difference_between_two_analyzer_in_the_same_samples_with_p_<_0.0001. b _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_CD%.

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Table5–SamplesstabilityofgroupofpathologicalsamplesforDIFFandPLTproﬁlesparameters.Median

Hodges–Lehmannlocationshift(X);Bias%(B%)betweenbaseline(T0)andthetimepoint(4hupto8h)at4◦Candroom temperature(RT)comparisonofOP-Bias%toCriticalDifference%(CD).

Temp T0medianvalue (95%CI) X(TX−T0) Hodges–Lehmann locationshift Xwith p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 4h 8h NE (109_/L) XN-9000 RT 2.9(2.3to4.5) −0.03 −0.09 NS 0.2(−8.9to9.3); p=0.3146;8h NE 4◦C 5.8(4.2to7.6) 0.07 0.03 NS 1.0(−1.2to3.1); p=0.015;8h NE BC-6800 RT 3.0(2.3to4.6) 0.01 −0.03 NS 1.2(−1.8to4.3); p=0.0324;8h NE 4◦C 5.9(4.3to7.7) 0.12 −0.87 NS 2.2(0.8to3.6); p=0.0017;4h 18.7(6.9to30.6); p<0.0001;8ha LY (109_/L) XN-9000 RT 1.6(0.9to2.2) 0.02 −0.02 NS −2.8(−33.2to27.5); p=0.6514;8h NE 4◦C 1.2(1.0to1.8) −0.01 0.00 NS −1.7(−15.1to11.8); p=0.4237;8h NE BC-6800 RT 1.6(0.9to2.2) −0.02 −0.04 NS 4.4(0.2to8.5); p=0.7316;8h NE 4◦C 1.2(0.9to1.7) −0.01 −0.17 NS 0.9(−1.9to−3.7); p=0.0559;4h 13.3(4.7to21.4); p<0.0001;8ha MO (109_/L) XN-9000 RT 0.5(0.4to0.7) 0.01 −0.02 NS −4.9(−17.0to7.2); p=0.0618;8h NE 4◦C 0.8(0.6to0.9) 0.01 −0.02 NS 2.3(−4.2to8.7); p=0.1814;8h NE BC-6800 RT 0.4(0.3to0.5) 0.01 −0.01 NS 5.5(−0.6to11.7); p=0.7159;8h NE 4◦C 0.6(0.5to0.7) 0.02 −0.13 NS 3.0(−0.2to6.2); p=0.0279;4h 25.1(7.9to42.3); p<0.0001;8ha EO (109_/L) XN-9000 RT 0.1(0.0to0.4) 0.01 0.01 NS 43.4(−16.0to102.7); p=0.2463;8h NE 4◦C 0.1(0.1to0.1) 0.01 0.02 NS 8.9(1.7to16.0); p=0.7689;4h 31.5(16.2to46.7); p<0.0001;8ha BC-6800 RT 0.1(0.0to0.4) 0.01 0.01 NS 29.0(−6.0to65.2); p=0.0716;4h 29.6(−6.2to 65.3); p<0.05;8ha 4◦C 0.1(0.1to0.2) 0.01 0.00 NS 7.3(−19.7to34.4); p=0.8439;8h NE BA (109_/L) XN-9000 RT 0.0(0.0to0.0) 0.00 0.01 NS 32.7(−8.2to73.6); p=0.2113;8h NE 4◦C 0.0(0.0to0.0) 0.00 0.01 NS 15.5(−2.0to33.0); p=0.3737;4h 30.3(17.8to42.8); p<0.0001;8ha BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 NS 0.7(−15.9to17.3); p=0.3829;8h NE 4◦C 0.0(0.0to0.0) 0.00 0.00 NS 7.1(−16.1to30.4); p=0.9604;8h NE HFC (109_/L) XN-9000 RT 0.0(0.0to0.0) 0.00 0.00 NS −40.0(−125.8to45.8) CD%datanot available 4◦C 0.0(0.0to0.0) 0.00 0.00 NS −21.3(−54.8to12.3) BC-6800 RT 0.0(0.0to0.0) 0.00 0.00 NS 33.3(−26.1to92.8) 4◦C 0.0(0.0to0.0) 0.00 0.00 NS 4.3(−59.0to67.5) PLT (109_/L) XN-9000 RT 264(211to309) 0.8 16.4 NS _p4.0₌_0.8577;(−7.6to₈15.5);_h NE 4◦C 237(188to270) 1.1 −1.7 NS −0.6(−5.7to4.4); p=0.1548;8h NE BC-6800 RT 249(209to286) 0.5 −8.0 NS −3.7(−7.5to0.1); p=0.7113;8h NE 4◦C 235(178to276) −2.0 −9.0 NS −8.2(−17.7to1.3); p=0.2672;8h NE

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Table5–(Continued)

Temp T0medianvalue (95%CI) X(TX−T0) Hodges–Lehmann locationshift Xwith p-value<0.0001 atthetime[h] B%(95%CI)a timeofstability; p-value B%vs.OP-Bias%; Stableuntil[h] B%(95%CI); p-value B%vs.CD%; Stableuntil[h] 4h 8h MPV (fL) XN-9000 RT 10.7(10.2to11.3) 0.10 0.05 NS 0.3(−4.0to4.6); p=0.6606;8h NE 4◦C 11.2(10.6to12.0) 0.11 0.30 NS 1.0(0.3to1.6); p=0.4789;4h 2.6%(1.4to3.8); p<0.0001;8ha BC-6800 RT 9.7(8.7to10.2) 0.30 0.40 NS 2.6_p_<_0.0001(1.5tob3.7); 3.7%(2.7to4.7); p<0.0001;8ha 4◦_C _9.9_(9.4_to_10.5) _0.20 _0.50 _NS _2.7_(2.1_to_3.3); p<0.0001b 4.7%(3.7to5.9); p<0.0001;8ha PDW (fL) XN-9000 RT 13.0(11.3to15.1) 0.29 0.10 NS 0.3(−7.4to8.1) CD%datanot available 4◦C 13.2(12.2to15.1) 0.20 0.60 NS 4.6(2.1to7.2) BC-6800 RT 15.9(15.4to16.1) −0.05 0.00 NS 0.0(−0.6to0.5) 4◦C 15.8(15.7to16.1) 0.00 0.00 NS 0.1(−0.5to0.7) PCT (%) XN-9000 RT₄_◦_C 0.3_0.3(0.3_(0.2to_to_0.3)0.3) 0.00_0.00 _0.010.01 _NSNS 4.4_2.1₍(−6.1to14.9) −3.4to7.5) BC-6800 RT₄◦_C 0.2_0.2_(0.2(0.2to_to0.2)_0.3) _0.000.00 0.00_0.00 _NSNS _−4.2−0.1(−4.0_(−13.8to_to3.8)_5.4) P-LCR (%) XN-9000 RT 31.3(25.9to36.5) 1.36 0.72 NS 1.7(−9.7to13.1) 4◦C 34.3(29.4to40.3) 0.74 2.24 NS 6.5(3.7to9.4) BC-6800 RT 23.8(15.5to29.7) −0.20 −0.30 NS 9.2(6.7to11.7) 4◦C 24.5(21.0to29.4) 1.40 3.95 NS 12.8(8.8to16.7)

NE:neutrophil;RT:Roomtemperature;LY:lymphocyte;MO:monocyte;EO:eosinophil;BA:basophil;HFC:highﬂuorescencecells;PLT:platelet; MPV:meanvolumeplatelet;PDW:PLTdistributionwidth;PCT:plateletcrit;P-LCR:PLTlargercellratio;NS:Xnotsigniﬁcantthroughoutthe studyperiod;NE:notevaluated;Temp:Temperature.

a _Bias%_(between_baseline_T0_and_the_time_point_X)_is_lower_than_CD%.

b _Bias%_(between_baseline_T0_and_the_time_point_X)_is_always_higher_than_OP-Bias%.

collectioninsamplesstoredatRT(butnotinthosestoredat 4◦C)whenmeasuredwithbothanalyzers.Thecomparison oftheBias%atdifferenttimepoints(TX)withtheOP-Bias% showedthatHTisstableatroomtemperatureforupto8h usingboththeXN-9000(Bias%:0.9)andBC-6800(Bias%:1.9), whereastheBias%forHTinsamplesstoredatRTremained lower than the CD% for up to 24h. The same analysis in samplesstoredat4◦C showedgood stabilityforupto24h aftercollectionwhencomparedwiththeOP-Bias%,whereas theBias%alwaysremainedlowerthantheCD%throughout thestudyperiod(i.e.,upto48h)usingbothanalyzers.

ThevaluesofMCVandRDW-SDdisplayedsignificant differ-encesafter24hofstorageatRT,whereastheresultsremained substantiallyunchangedforupto48haftercollectionin sam-plesstoreda4◦C.Interestingly,theBias%ofMCVexceeded theOP-Bias%after2hofstorageatRTwiththeXN-9000and after8hofstorageatRTwiththeBC-6800,respectively.The Bias%ofMCVwaslowerthantherelativeCD%forupto8h ofstorageusingbothanalyzersatRT.Atvariance,theBias% alwaysremainedlowerthanCD%throughoutthestudyperiod insamplesstoredat4◦C.TheRDW-CVexhibitedsignificant variationsafter24hfromcollectionusingbothanalyzersat RT,whereassignificantdifferenceswereobservedafter24h ofstorageinsamplesstoredat4◦Cusing theXN-9000 but notwiththeBC-6800(Table2).Whencomparedwiththe OP-Bias%,RDW-CVvalueswerefoundtobestableforupto8h atbothRTand4◦CusingtheXN-9000,andforupto2hat

RTwiththeBC-6800.TheBias%ofRDW-CVwasalwayslower than the OP-Bias%for up to48h ofstorageusing the BC-6800.

Atvariancewithpreviousparameters,thevaluesofMCHC displayed a specific and instrument-dependent variation. Morespecifically,significantdifferenceswereobservedafter 4hofstorageatRTand2hofstorageat4◦CwiththeXN-9000. Accordingly,theBias%exceededtheOP-Bias%at2hofstorage atbothtemperatures,whereastheBias%didnotexceedthe CD%forupto8hofstorageatRTandforupto48hofstorage at4◦C.AsregardsMCHCvaluesobtainedwiththeBC-6800, significantdifferenceswerefoundafter24hofstorageatRT andatthe48htimepointafterstorageat4◦C.TheOP-Bias% wasexceededafter8hofstorageatRTand24hofstorage at4◦C,whereastheBias%remainedlowerthantheCD%for upto8hofstorageatRTandforupto48hofstorageat4◦C (Table2).

Alltheseparametersappearedtobesubstantiallystablefor upto8hatbothRTand4◦Cintheabnormalsamplesgroup usingbothanalyzers.Themostrelevantexceptionsare sum-marizedinTable3.Specifically,theNRBCmeasuredwiththe XN-9000showedsignificantvariations8haftercollectionin samplesstoredatRTand4haftercollectioninthosestored at4◦C,whereassignificantvariationsofNRBCmeasuredwith theBC-6800couldonlybeobservedafter8hofstorageat4◦C. ThecomparisonbetweentheBias%andOP-Bias%fortheMCH andRDW-CVmeasuredwiththeBC-6800showedasignificant

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variationafter4hofstorageat4◦C.AsregardstheXN-9000, onlytheBias%forMCHCincreasedovertheOP-Bias%after4h ofstorageatRT.Interestingly,theBias%wasfoundtobealways lowerthantheCD%forallparameterswithbothanalyzersfor upto8hofstorageatbothtemperatures.

Reticulocytes

The baselinevalues of the different RET parameters were foundtobealwaysdifferentoncomparingthemeasurements ofthetwohematologicalanalyzers(Table2).Inthegroupof normalbloodsamples,RETandpercentageofHFRwerefound tobestableforupto48husingbothanalyzersandatboth tem-peratures.TheBias%ofRETwasfoundtobehigherthanthe OP-Bias%after36hofstorageatbothtemperatures.The per-centagesofIRF,LFRandMFRwerefoundtobehigherthanthe T0valuesafter24hofstorageatRTwiththeXN-9000andafter 36hofstorageatRTwiththeBC-6800(Table4).Inthegroupof abnormalbloodsamplesalltheRETparameterswerefound tobestableforup to8h usingbothanalyzersand atboth temperatures(Table3).

Leukocytecountanddifferential

The baseline values of Leukocytes and DIFF counts did notexhibitstatisticallysigniﬁcantvariationsthroughoutthe studyperiodinthesubgroupofnormalsamples,usingboth analyzersandatbothtemperatures,withtheonlyexception oftheMOmeasuredwiththeBC-6800atthe48-htimepoint (Table4).Accordingly,theBias%ofMOincreasedoverthe OP-Bias%after36–48hofstorageatRTandafter24hofstorageat 4◦C.Importantly,theBias%wasfoundtobealwayslowerthan theCD%throughoutthestudyperiod,usingbothanalyzers andatbothtemperatures.

Inthe abnormalsamplesgroup the various parameters werealsofoundtobestableupto8hofstorageusingboth ana-lyzersandatbothtemperatures(Table5).TheOP-Bias%was exceededafter4hforNE,LYandMOat4◦C,andEOatRTusing theBC-6800.TheBias%ofEOalsoexceededtheOP-Bias%after 8hofstorageat4◦CusingtheXN-9000(Table5).

Platelets

Withthe exception ofPLT and PCT, the baselinevalues of allthePLTparameterswerefoundtobesigniﬁcantly differ-entbetweenthetwoanalyzersinthegroupofnormalblood samples(Table4).Inthisgroupofspecimens,PLTandPCT parameters were foundto bestable forup to48hat both RT and 4◦C using bothanalyzers (Table 4).The remaining parameters(MPV,PDW,PCTandP-LCR)showed instrument-dependentvariations.

TheBias%ofthePLTcountmeasuredwiththeXN-9000was foundtobehigherthantheOP-Bias%after2hofstorageat 4◦C,butremainedalwayslowerthantheCD%forupto48hof storageatthistemperature.ThevaluesofMPVmeasuredwith theXN-9000signiﬁcantlyincreasedafter24hofstorageatRT andat48hofstorageat4◦C.However,thevariationoftheMPV wasfoundtobehigherthantheOP-Bias%startingfrom2hof storageatRTand8hofstorageat4◦C(Table4).Importantly, theBias%oftheMPVneverexceededtheCD%throughoutthe

48hofstorage.AsregardstheBC-6800,theMPVvalueswere significantlyincreasedafter4hofstorageatRTand24hof storageat4◦C.ABias%largerthantheOP-Bias%wasobserved after2hofstorageatRT,althoughitremainedlowerthanthe CD%throughoutthe24hofstorageatRT(Table4).Thevalues ofthePDWmeasuredwithbothanalyzerswerefoundtobe significantlydifferentafter24hofstorageatRT,whereas sig-nificantdifferencesinsamplesstoredat4◦Cwereobserved after24hofstoragewiththeBC-6800andafter48hofstorage withtheXN-9000(Table4).

Inthegroupofabnormalsamples,thePLTparameterswere foundtobestableforupto8husingbothanalyzersatboth temperatures (Table5).Nevertheless, theBias%oftheMPV measuredwiththeBC-6800wasfoundtobehigherthanthe OP-Bias%after2hofstorageatbothtemperatures,whereas theBias%oftheMPVmeasuredwiththeXN-9000exceeded theOP-Bias%after4hofstorageat4◦C.Innocase,however, theBias%wasfoundtobehigherthantheCD%inupto8hof storageatbothtemperatures(Table5).

Discussion

Theongoingreorganizationoflaboratoryservicesaroundthe globefrequentlyentailstheconsolidationofsmalllabsinto larger facilities.20 _This_process _poses _serious _challenges _to sample quality, assometimes blood specimensneed tobe transportedoverlongdistancesandforlongperiodsoftime.21 Therefore, the aimofour study wastoobtain information about sample stability for many hematological parameters measured withboththe XN-9000andBC-6800 analyzers.It ishencenotsurprisingthatthestabilitydataobtainedinthis studywerequitesimilar.Analyzer-speciﬁctrendswereonly observedforafewparameterssuchasMCHC,MPVandMO. Morespeciﬁcally,MCHCwasfoundtobestableforlongerat bothRT and4◦C usingtheBC-6800, whereas theMPVwas foundtobestableforlongerat4◦CwiththeXN-9000.Asthe analyzers use rather similar analytical techniques,the dif-ferencesseemtobeattributabletoadifferenttechnological approachusedtoassessMCHCandMPV.

Overall,thestabilityappearedgreaterfornormalsamples whentheywerestoredat4◦CcomparedtoRT.Asimilartrend was observed for abnormalsamples, except forthe NRBC countasthisparametermeasuredwiththeXN-9000showed asigniﬁcantvariationafter4hofstorageat4◦Candafter8h ofstorageatRT.WhenmeasuredwiththeBC-6800,theNRBC countwasfoundtobestablethroughoutthestudyperiodat RT,whereasasigniﬁcantchangewasfoundafter8hofstorage at4◦C(Table3).

For the SysmexXN-series, inaccordwithprevious data publishedbyBriggsetal.,7_the_values_of_WBC,_NRBC_and leuko-cyte DIFFwere foundtobestable upto48hwhennormal sampleswerestoredat4◦C.Tanakaetal.publisheddataon thestabilityofthePLTcount,22_which_are_overall_similar_to theresultsobservedinthisstudy(PLTseemtobestablefor upto48hinbloodsamplesstoredatbothRTandat4◦C). Dis-crepantdatawereinsteadfoundcomparingourresultswith thoseobtainedbyDavesetal.23_and_by_Imeri_et_al.2_using_the SysmexXN-series.Speciﬁcally,largerdifferenceswerefound forsomeRBCparametersinnormalbloodsamples(i.e.,MCH,

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MCV,RDW-SD,PLTcountandMPV).Inthesepublished inves-tigations,thestabilitywasfoundtobelessthaninthecurrent studyinbloodsamplesstoredatbothRTand4◦C.

Conversely,thestabilityofMCHCvalueswasfoundtobe lessinourinvestigationthaninthestudypublishedbyDaves etal.23_The_differences_are_probably_attributable_to_the_use_of differentpre-analytical proceduresbetweenstudies.Infact, ourinvestigationwasdesignedusingstrictcriteriaforthe pre-analyticalphase(especiallyforcollectionandtransportation ofnormalsamples), accordingto whichthe collection and transportation ofhealthy sampleswas directly handled by laboratorypersonnel.Similarevidenceisunavailable inthe studiesofDaveset al.23 andImeri etal.,2 whopreferred to followadifferentapproach(i.e.,bloodcollectionandhandling bynurses),whichisprobablyclosertotherealityofroutine healthcarepractices.Notably,nopreviousinformationis avail-ableforbloodsamplestabilityassessedwiththeBC-6800,so thatadirectcomparisonisunfeasible.

Interestingresultsemergefromthecomparisonbetween theBias%ofthedifferentanalytesatdifferenttimesand tem-peratureconditions,whichmaybeusefulfordeﬁningthebest practiceforthepre-analyticalphaseofroutinehematological testing.Inthe analysisofnormalsamples,theMCV exhib-itedaBias%of−1.5%withtheXN-9000andaBias%of−0.15% withtheBC-6800inasamplestoredfor8hatRT.However, theBias%ofMCHCandRDW-CVmeasuredwiththeBC-6800 were−0.7%and2.7%after8hofstorageatRTandtheBias% ofMCHCmeasuredwiththeXN-9000was−2.4%after8hof storageatRT.TheHTexhibitedaBias%of4.9%withboththe analyzersafter24hatRT.Aftertheseperiodsofstorage,the variationoftheparameterswasfoundtobehigherthanthe CD%.

Themajorlimitationofthisstudywastheabsenceof stabil-ityevaluationofpathologicalsamplesupto72h(i.e.,12h,24h, 36hand72h)assuggestedintheICSHguidelines.3,4_This_was notpossiblebecausetheamountofeachpathological sam-pleincludedinthisstudywaslimited(onlyonetubeforeach samplecomparedtothreetubesfornormalsamples).

Theresults of this study show that the time and tem-perature of storage can have an impact on the quality of hematologicaltesting,withresultsthatmaysigniﬁcantly devi-atefromtheclinicallyallowablebias.Overall,wecanhence suggest thatthe blood samplesshouldalways beanalyzed within2hfromcollectionregardlessofstoragetemperature. WhentheBias%iscomparedtotheCD%,themaximumtime forsampleanalysiscanhowever beextendedtoupto 8h. Over8hitisnotadvisabletoreportthetimeor temperature-sensitiveparameters.

Conﬂicts

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interest

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1. LippiG,GuidiGC,MatiuzziC,PlebaniM.Preanalytical variability:thedarksideofthemooninlaboratorytesting. ClinChemLabMed.2006;44(4):358–65.

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