INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY

Spurious counts and spurious results on haematology

analysers: a review. Part I: platelets
M. ZANDECKI, F. GENEVIEVE, J. GERARD, A. GODON

Haematology Laboratory, SUMMARY

University Hospital of Angers,
Angers, France The widespread use of haematology analysers (HA) has led to a major
improvement of cellular haematology, because of quick and accurate
Correspondence:
M. Zandecki, Haematology Laborat-
results found in most instances. However, in several situations, spurious
ory, University Hospital of Angers, 4 results are observed. Inadequate blood samples, situations induced by the
rue Larrey, 49000 Angers, France. anticoagulant(s) used, peculiar changes related to the pathology in the
Tel.: +33 2 41 35 53 53; Fax: patient, and technical considerations about performances of the various
+33 2 41 35 55 99;
E-mail: [email protected] HA must be considered. Spurious thrombocytopenia occurs in several
circumstances related to the presence of ethylenediamine tetra-acetic
doi:10.1111/j.1365-2257.2006.00870.x acid (EDTA) used as the anticoagulant. Mechanism of EDTA-dependent
platelet (PLT) agglutination is related to circulating (auto)antibodies
Received 30 January 2006;
accepted for publication 30 July directed against normally hidden epitope(s) in the glycoprotein alpha
2006 IIb/beta IIIa complex from PLT membrane exposed only in the presence
of EDTA. Other spuriously low PLT counts may be related to EDTA,
Keywords including PLT rosetting around white blood cells (WBC; satellitism) and
haematology analysers, automated PLT-WBC aggregates, but mechanisms responsible for those latter
count, cell blood count, spurious
count, platelets phenomena are less well known. Spurious increase of PLT count may
be related to several situations, including fragmented red blood cells,
cytoplasmic fragments of nucleated cells, cryoglobulins, bacteria or fungi,
and lipids. Flags generated in several of these situations alert the operator
on possible abnormal findings and may identify the problem. Analysing
only PLT parameters is not sufficient: in many situations the WBC
differential scattergram is of crucial help for flagging. Flags generated
depend on the software version on the HA used, the performance in
detecting the same anomalies may differ according to which analyser is
used, even those from the same manufacturer. Operators must be aware
of the characteristics of their analyser and be able to recognize and
circumvent anomalous results.

ical parameters including size, impedance and light

INTRODUCTION
scattering. Quick and accurate results are the rule, in
For haematology analysers (HA), blood cells corres- both normal and abnormal samples. However, in sev-
pond to particles that differ according to various phys- eral instances related to abnormal characteristics of
 2007 The Authors
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 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 5

the sample, corresponding either to a peculiar pathol- components. The first part of this paper will focus on
ogy in the patient or to changes induced after samp- abnormal PLT counts, whereas abnormal counts and
ling, HA may generate erroneous results for one (or measurements related to the other parameters of the
more) parameter(s) of the cell blood count (CBC), cell blood count (CBC), including WBC, RBC, haemo-
because of performance limitations. Such failures to globin (Hb), RBC indices, and reticulocytes will be dis-
determine accurately one or more of the blood com- cussed in the second part of this paper.
ponents began to be reported as soon as HA began to
replace manual techniques (late 60s). In the early 80s,
GENERAL CONSIDERATIONS ABOUT
improvement of instrument hardware and software
PLATELET COUNTS
led to a higher degree of analysis of abnormal results.
Quality and control of data increased dramatically in On impedance-type instruments (including: Beckman-
many ways, including various internal flagging rou- Coulter, Miami, FL, USA; ABX, Kyoto, Japan; Abbott,
tines generated in order for analytic errors to be Abbott Park, IL, USA; Sysmex, Kobe, Japan; Bayer,
detected more accurately and graphic presentation of Tarrytown, NY, USA; and other instruments) particles
particle analysis for identification and enumeration of analysed are suspended in an electrolyte solution and
specific blood components. Development of new indi- the dilution is passed through an aperture that links
ces or parameters outside the classical red blood cell two chambers, one containing a positive and the
(RBC) indices, such as red cell distribution width other a negative electrode. As cells pass through the
(RDW), mean platelet volume (MPV), percentage of orifice they cause a momentary increase in electrical
hypochromic or macrocytic RBC, that will not be dis- resistance, which registers as a pulse. One pulse repre-
cussed extensively here, also led to many studies sents a cell and the size of the pulse is proportional to
regarding their possible use in haematological prac- the size of the cell. Using this principle PLT and RBC,
tice. which are both analysed in the same channel(s), are
Even on the most recent HA, most of the anomal- discriminated according to their volume, and volume
ies are related either to a specific condition of the histograms are generated next. For PLT, the histogram
patient, or to the sampling condition [aggregation of generates a log curve if the distribution of PLT vol-
blood platelets (PLT), white blood cells (WBC) and umes fits that of a (log) normal distribution: eventu-
red blood cells (RBC) in presence of EDTA for exam- ally all particles located under the fitted curve are
ple], or to the principle of the technology used for the considered as PLT. Mean PLT volume ranges from 6
analysis of blood samples. It is important to note that to 10 fl, but impedance-type counters analyse particles
every HA is affected with at least one part of spurious ranging from 2 to 20 fl and, according to the fitted
measurements, although the degree by which the curve, the upper threshold that discriminates PLT
count is affected varies. Over the years, manufacturers from RBC may either be at 36 fl or may vary auto-
have taken these problems into account and are con- matically depending on the characteristics of individ-
tinuously improving the performances of their instru- ual blood samples (Sysmex). Instrument flags are
ments, and providing educational programme using triggered for cases corresponding to inability to separ-
oral information for technical and biological staff and ate clearly PLT from RBC. On laser-type HA (Abbott,
printed or on-line information, corresponding to the Bayer, others) each particle passes through a laser
so-called « user’s guide for the automate ». However, beam and scatters light that is detected by a photodi-
in some smaller HA, the software, histograms and/or ode (or related). The amount of light scattered (at
graphs and/or flags are less complex or even absent, one, two, or even four angles for some HA) is propor-
leading to inability to detect at least part of spurious tional to the area and therefore to the volume of the
counts. So, as Bain and Bates (2001) stated « it is particle. PLT are identified on a scatter histogram
important for instrument operators to be familiar with based on their volume (1–30 fl) and refractive index
the types of factious results to which their instrument values (1.35–1.40). Some HA provide up to three
is prone ». Our aim was to give information on the counts on the same dilution if required, corresponding
most current situations leading to the inability of HA to optical, impedance, and immunological (CD61)
to perform accurate counts for individual blood cell counts (Abbott). Other HA may determine, if
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

required, an optical PLT count together with the reti- 1988; Cunningham & Brandt, 1992; Bizzaro, 1995). As
culocyte count, after the use of a RNA fluorescent thrombocytopenia discovered in a patient may induce
stain (Sysmex). An accurate PLT count is the rule in several procedures including unnecessary bone
most instances, but several situations lead to spurious marrow aspiration or/and PLT transfusion, recognition
results (Table 1). of this phenomenon is important (Payne & Pierre,
1984; Vicari, Banfi & Bonini, 1988; Foresti et al., 1990;
Berkman et al., 1991; Bizzaro & Brandalise, 1995;
SITUATIONS LEADING TO SPURIOUSLY
Cohen et al., 2000). The most important feature related
LOW PLT COUNTS
to this condition is that it is unaccompanied by any
signs or symptoms of haemorrhage. In some instances,
Pseudothrombocytopenia related to EDTA
pseudothrombocytopenia was reported to hide either
anticoagulant
true thrombocytopenia (Forscher et al., 1985) or
Ethylenediamine tetra-acetic acid (EDTA)-dependent thrombocytosis (Dahlqvist, Nilsson & Norberg, 1988).
pseudothrombocytopenia (EDP) is an in vitro phenom- In addition to generating spurious PLT count, PLT
enon caused by specific proteins from the samples that clumps may be as large as WBC and may be enumer-
react with PLT only in EDTA-anticoagulated blood and ated as such by HA (discussed in part II).
produce PLT clumps (Gowland et al., 1969; Watkins & The prevalence rate of EDP was reported as 0.07–
Shulman, 1970; Shreiner & Bell, 1973; Berkman et al., 0.20% according to the authors (Payne & Pierre,
1991; Bizzaro & Brandalise, 1995) (Figure 1a). HA do 1984; Savage, 1984; Vicari, Banfi & Bonini, 1988;
not enumerate PLT from the large clumps and the Garcia Suarez et al., 1991; Bartels, Schoorl & Lom-
number printed corresponds to that from a mixture of barts, 1997; Sakurai et al., 1997). Prevalence was
small clumps and unaggregated PLT, leading to PLT 0.2% in plateletpheresis donors (Sweeney et al.,
counts as low as 20 · 109/l, whereas the accurate 1995). For hospitalized patients, 0.1–2.0%, incidence
number is within normal ranges (Cohen et al., 2000). was reported (Manthorpe et al., 1981; Payne & Pierre,
Anticoagulants other than EDTA (citrate, oxalate and 1984; Savage, 1984; Bragnani et al., 2001). Up to 17%
heparin) are also concerned in several reports of patients referred to the outpatient clinic for isolated
(Watkins & Shulman, 1970; Shreiner & Bell, 1973; thrombocytopenia were in fact found to have EDP
Onder, Weinstein & Hoyer, 1980; Pegels et al., 1982; (Silvestri et al., 1995; Cohen et al., 2000). According to
Savage, 1984; Payne, 1985; Lombarts & de Kieviet, the various reports, EDP may or may not be either

Table 1. Situations leading to altered platelet counts on haematology analysers

Alteration of other parameters

Spurious decrease
PLT agglutination (EDTA, but other anticoagulants may be concerned) PLT aggregates enumerated as WBC
PLT satellitism (mainly related to EDTA)
Around polymorphs
Around other WBC (normal; pathological)
PLT-neutrophil agglutination (mainly related to EDTA) WBC count spuriously low
Large PLT (outside the normal range) Enumerated together with WBC
Coagulation within the sample Abnormal CBC
Overfilling the sample (inadequate mixing) Abnormal CBC
Spurious increase
Fragmented RBC (schistocytes, severe iron deficiency anaemia, burns) RBC count spuriously low (anecdotal)
Cytoplasmic fragments of nucleated cells (leukaemia, lymphoma cells)
Cryoglobulins, cryofibrinogen WBC count spuriously increased
Bacteria
Fungi (Candida)
Lipids (samples taken after a meal, lipid drips) WBC and haemoglobin spuriously high

 2007 The Authors

Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 7

(a) (b)

Figure 1. (a) EDTA-induced thrombocytopenia. Aggregates observed on peripheral blood smears may contain vari-
able number of PLT within each clump. Some PLT clumps are large enough to be enumerated as WBC by HA. (b)
Platelet satellitism around polymorphs (1). In some instances PLT satellitism is the first part of a peculiar phenom-
enon that develops within several hours into the sample: PLT migrate to one pole of the polymorph (2), clump
together (3), and eventually leave the polymorph (4) (peripheral blood smear; MGG staining).

slightly more frequent in males and/or in older instance, PLT aggregates may be generated in vivo and
patients (Berkman et al., 1991; Garcia Suarez et al., enumerated on HA if the relevant blood samples are
1991; Casonato et al., 1994; Bizzaro, 1995; Sakurai anticoagulated with sodium citrate (Shimizu et al.,
et al., 1997; Bragnani et al., 2001). Patients are either 2003).
healthy at the time of presentation or, when diseases The first important observation concerning the
are present, they are heterogeneous (Boehme, Mah- mechanism of aggregation in EDP was that serum or
mood & Phanuphak, 1980; Veenhoven, Van der Schans EDTA-plasma not only induced agglutination of PLT
& Nieweg, 1982; van der Lelie, van der Plas-Van from the patient but also induced agglutination of
Dalen & von dem Borne, 1984; Solanki & Blackburn, EDTA-PLT from nearly all normal individuals
1985; Garcia Suarez et al., 1991; Casonato et al., (Watkins & Shulman, 1970; Shreiner & Bell, 1973;
1994), although some reports hypothesized a possible Veenhoven et al., 1979; Onder, Weinstein & Hoyer,
relationship with either autoimmune or clinically evi- 1980; van der Lelie, van der Plas-Van Dalen & von
dent neoplastic pathology (Imai et al., 1983; Bragnani dem Borne, 1984), with the exception of PLT from
et al., 2001) but in fully healthy patients no clinical patients with Glanzmann’s disease, suggesting that the
manifestation of disease occurred, up to 10 years after fibrinogen receptor, Glycoprotein (GP) alpha IIb beta
follow-up (Bizzaro, 1995). EDP may appear during IIIa (GPIIb/IIIa), was involved in EDP (Pegels et al.,
the hospitalization period (Berkman et al., 1991; Gar- 1982; Casonato et al., 1994; Ryo et al., 1994; Bizzaro,
cia Suarez et al., 1991; Huss et al., 1995; Gschwandt- 1995; Schrezenmeier et al., 1995). Indirect evidence is
ner et al., 1997), or may be transient (Takeuchi et al., shown with artifactual pseudothrombocytopenia that
1993; Mori et al., 2000), or an increase in the amount develops frequently in patients following exposure to
of the related agglutinin may be observed under the PLT GPIIb/IIIa receptor antagonists (Christopoulos &
same circumstances (Edelman & Kickler, 1993). EDP Machin, 1994; Stiegler et al., 2000). Other authors
is not restricted to humans and has been reported in a implicated either a 78-kDa PLT GP related to GPIIb/
horse (Hinchcliff, Kociba & Mitten, 1993). EDP has no IIIa complex (De Caterina et al., 1993), or more pre-
relationship with the enhanced PLT activity consid- cisely GPIIb (Ginsberg et al., 1986; van Vliet, Kappers-
ered to play a role in the pathogenesis of arterial Klunne & Abels, 1986; Fiorin et al., 1998). A new
thrombosis, such as cerebral and myocardial infarction monoclonal antibody was recently developed that
(Konstantopoulos et al., 1995). But, in the latter recognized an epitope on the alpha IIb/beta IIIa
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

integrin, whose accessibility was increased upon EDTA 1995), or other mechanisms, as the interaction of cir-
treatment of PLT (Dabadie et al., 2001). So far, the culating immune complexes with PLT membrane Fc
most likely hypothesis is that the antigen-binding site, receptors causing agglutination in presence of EDTA
normally hidden (cryptic) in the GPIIb/IIIa complex is (Manthorpe et al., 1981).
modified by EDTA or exposed only in the presence of Agglutination usually occurs within a few minutes
EDTA. Some authors observed that PLT antibodies after sampling into EDTA and is more conspicuous in
were associated to antiphospholipid antibodies in most blood samples kept at room temperature. Aggregates,
patients tested, suggesting that antibody subpopula- as observed in a haematimetric chamber or on stained
tions (naturally occurring autoantibodies?) directed smears, are quite variable in size, consisting at times of
against negatively charged phospholipids could bind three to five PLT but not infrequently in up to 100 PLT
to antigens modified by EDTA on the platelet mem- or more (Figure 1a). The most pronounced decreases
brane, and might be responsible for pseudothrombo- in PLT counts were associated with the presence of
cytopenia genesis (Bizzaro & Brandalise, 1995). In large aggregates in one study (Casonato et al., 1994).
most instances, no abnormality of PLT function was PLT clumps are resistant to RBC lysis agents, and on
reported in association with EDP (Casonato et al., HA which show a WBC differential scattergram,
1994). Abnormal PLT from myeloproliferative diseases clumps are plotted as a cloud of particles of low to
have been shown to be much more sensitive than moderate size (Figure 2). If PLT clumps reach the size
normal ones to clumping in presence of EDTA of WBC, falsely elevated WBC counts may be observed
(Norberg & Nilsson, 1987). (see part II). HA do not identify these clumps as a def-
Agglutinins were shown to be IgG, IgM, or IgA in inite population of WBC, leading the instrument to
33–50%, 10–63%, and 4–40% of cases, respectively generate a flag (PLT clumps, large or giant PLT, or rela-
(Watkins & Shulman, 1970; Shreiner & Bell, 1973; ted). Of crucial importance is that alarms are mainly
Onder, Weisntein & Hoyer, 1980; Pegels et al., 1982; related to inaccuracy to determine WBC count or inab-
Imai et al., 1983; van Vliet, Kappers-Klunne & Abels, ility to determine WBC differential rather than related
1986; Casonato et al., 1994; Bizzaro & Brandalise, to the inaccuracy to analyse PLT on the PLT channel(s)
1995; van der Meer et al., 2002). Agglutinins react (Solanki & Blackburn, 1983; Payne & Pierre, 1984;
more strongly at room temperature or below (« cold » Vicari, Banfi & Bonini, 1988; Bartels, Schoorl & Lom-
agglutinins), but some are temperature independent barts, 1997). So, PLT clumps are usually detected on
or react even better at 37 C. The pathophysiology of HA which analyse WBC populations in order to per-
antibody production is unknown: it has been sugges- form a WBC differential, whereas HA, which do not
ted that they could correspond either to natural auto- perform WBC differential frequently overlook PLT
antibodies or to acquired ones, resulting from the PLT clumps. Bartels, Schoorl and Lombarts (1997)
destruction observed in diseases such as septicaemia, observed that, in situations corresponding to EDP,
toxaemia of pregnancy, thrombotic thrombocytopenic WBC histograms generated a specific flag for PLT
purpura, or myelodysplasia (van der Lelie, van der clumps in nearly all instances (90% sensitivity and
Plas-Van Dalen & von dem Borne, 1984; Denomme 100% specificity), whereas analysis of PLT into the
et al., 1992; Kunicki & Newmann, 1992; Bizzaro & PLT channel(s) generated less frequently abnormal
Brandalise, 1995). In several instances it was shown findings or specific alarms. In up to 10% of cases, nor-
that EDP appeared during hospitalization, and particu- mal PLT and WBC histograms are displayed and EDP is
larly after an infection, and that antibodies frequently overlooked (Cunningham & Brandt, 1992).
bind to PLT from the relevant patient but also to PLT Immediate dilution without any anticoagulant or
from all patients, with the exception of PLT from collecting blood using the Unopette system (Becton
Glanzmann type I patients (van der Lelie, van der Dickinson, Franklin Lakes, NJ, USA) (or related)
Plas-Van Dalen & von dem Borne, 1984; Berkman containing ammonium oxalate and a haematimetric
et al., 1991; Edelman & Kickler, 1993). However, it is chamber (phase contrast microscopy) obviate the
not possible to exclude non-Ig proteins as inducing phenomenon. Heparin is not suitable, but an easy
EDP in some instances (Mant et al., 1975; Onder, alternate is analysis of samples anticoagulated with
Weisntein & Hoyer, 1980; Bizzaro & Brandalise, 10% trisodium citrate (meaningful count is obtained
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 9

Figure 2. WBC scattergram form on normal patient (left) and another one showing EDTA-induced PLT aggregates
(right). PLT aggregates generate a rocket of particles of small and intermediate size (outing from the origin from
the X–Y display), leading to inability to perform accurate identification of WBC (Bayer Advia 120). Ly, lympho-
cytes; LUC, large unstained cells; Mo, monocytes; PMN, polymorphonuclear neutrophils; Eo, eosinophils.

after mathematical correction because of the dilution), mature polymorphonuclear neutrophils (PMN; Fig-
although clumping may also occur on such samples ure 1b), and occasionally to other cells (Figure 3), PLT
(Rabinovitch, 1984; Garcia Suarez et al., 1991; Bizzaro, surrounding WBC in EDTA-anticoagulated blood sam-
1995). In some instances, agglutination was noted as ples (Zeigler, 1974; Mende, Doring & Thomas, 1975).
abolished or less evident for samples both drawn and This phenomenon is rare (1 of 12 000 blood counts;
maintained at 37 C (Watkins & Shulman, 1970; Fiorin Bizzaro, Goldschmeding & von dem Borne, 1995),
et al., 1998), but agglutination occurring at room tem- sometimes related to an autoimmune process, but in
perature cannot be reverted by warming and leads in most instances unrelated to any specific disease (Lazo-
most instances to increase in PLT clumping (Watkins & Langner et al., 2002). Its clinical significance is not
Shulman, 1970; Cornbleet, 1983; Payne & Pierre, known. Cryofibrinogen has been associated to the phe-
1984; van Vliet, Kappers-Klunne & Abels, 1986). Var- nomenon in one report (McGregor et al., 1980), and
ious other anticoagulants have been proposed to cir- thrombospondin has been involved in the mechanism
cumvent aggregation, including ACD (Lombarts & de in another report (Christopoulos & Mattock, 1991). In
Kieviet, 1988), mixture of citrate, pyridoxal, and Tris other reports, after the use of either anti-IgG antibo-
(Lippi et al., 1990), theophillin (Ohnuma, Shirata & dies or specific absorption to remove IgG fraction, IgG
Miyazawa, 1988; De Caterina et al., 1993), MgSO4 were involved as mediators, implicating or not Fc-
(Nakamoto et al., 1986), or addition of aminoglycosides gamma receptors from PMN (Zeigler, 1974; Greipp &
that both dissociate the aggregates and prevent the Gralnick, 1976; Bodensteiner, Talley & Rosenfeld,
phenomenon (Sakurai et al., 1997). 1987; Yamanaka et al., 1993; Bizzaro, Goldschmeding
& von dem Borne, 1995; Lazo-Langner et al., 2002).
GPIIb/IIIa from PLT membrane was involved in the
Pseudothrombocytopenia related to satellitism
mechanism (Yamanaka et al., 1993; Bizzaro et al.,
around WBC
1995), but also an IgG autoantibody directed against a
PLT satellitism, or satellitosis or rosetting, is an in vitro cryptic antigen, sharing community with both GPIIb/
phenomenon related to the adherence of PLT to IIIa from the PLT and Fc-gamma receptor III (CD16)
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

(a) (b)

Figure 3. (a) Platelets surrounding lymphocytes in a patient known for chronic lymphocytic leukaemia. (b) Neutro-
phil–Platelet aggregates; that latter situation is related to PLT satellitism around polymorphs: PLT are ‘bridges’
between PLT-neutrophil rosettes, generating peculiar clumps, differing from neutrophil aggregates, as no PLT is
observed within the latter (peripheral blood smears; MGG staining).

from the PMN, possibly unmasked in presence of ling to analysis, satellitism or PLT aggregates may be
EDTA, has been suggested (Bizzaro, Goldschmeding & the abnormal finding observed as well.
von dem Borne, 1995). Phagocytosis of PLT by PMN Besides rosetting around PMN, satellitism around
has been reported, either after optical or electron both PMN and monocytes in EDTA samples was
microscopical study of the rosettes, but is not a consis- reported (Greipp & Gralnick, 1976). Heparin was also
tent finding (Mende, Doring & Thomas, 1975; White involved as generating rosetting around monocytes
et al., 1978; Payne, 1981; Bizzaro, 1991), and may be (Cohen et al., 1980). PLT satellitism was also reported
related to PLT dysfunction observed in some cases around basophils but not other cells in a chronic
(White et al., 1978; Yoo, Weems & Lessin, 1982). myelocytic leukaemia patient (Liso & Bonomo, 1982),
When PLT satellitism occurs the PLT count is mod- and around eosinophils (Fabryova, Burgi & Brugger,
erately reduced (from 50 to 100 · 109/l), leading to 1991; Lazo-Langner et al., 2002). PLT satellitism to
pseudothrombocytopenia in some but not in all cases. lymphocytes (Figure 3a) or to lymphoma cells was
Flagging is not consistent, and in most cases it is gen- also reported, the mechanism either involving or not
erated after analysis of the WBC differential scatter- involving Ig and CD16 as mediators in the latter
gram, mainly because PMN are abnormally located on instances (Fabryova et al., 1991; Muglia & Davis,
the graphs, being either difficult to separate from 1997; Espanol, Muniz-Diaz & Domingo-Claros, 2000;
lymphocytes (impedance-type HA) or looking larger Cesca, Ben-Ezra & Riley, 2001). Other situations
than usual (laser-beam HA). An alarm corresponding related to EDTA have been described under the term
to WBC with high peroxidase value may be generated « satellitism », but such situations corresponded either
on Bayer HA. In our experience with this anomaly, to lymphocytic clumps (Juneja, Wolf & McLennan,
changes may vary with time within the blood sample: 1992) or to RBC surrounding either lymphocytes or
satellitism is observed within a few minutes after col- mature PMN in the presence of EDTA (Feizi et al.,
lecting the blood sample, followed by a progressive 1973; Sherwood, Shulman & Pierre, 1998).
migration of PLT to one pole of the PMN after 1–3 h,
mimicking a clump of PLT stuck to the PMN and,
EDTA-dependent platelet-neutrophil
eventually, after 4–6 h, clumps of PLT unbind from
agglutination
the PMN, leaving PMN free of PLT on the one hand
and PLT clumps free in the blood on the other hand Large aggregates containing hundreds of PLT and
(Figure 1b). According to the time elapsed from samp- >100 PMN were observed, that seemed to be the end
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 11

point of an evolving process initiated by a typical HA may consider particles up to 30 or 36 fl in volume

satellitism of PLT around PMN (Ahmed, Minnich & (or up to 60 fl for some laser-beam analysers) as PLT.
Michael, 1978; Lombarts et al., 1992; Moraglio, Banfi According to the instrument and to the blood sample,
& Arnelli, 1994) (Figure 3b). As the number of cases some very large PLT (>30–40 fl) may be missed, or
reported is low, studies dealing with that artifact are not. In pathological situations, such as in myeloprolif-
scarce and do not allow any definite conclusion erative or in myelodysplastic syndromes, one must
about the mechanism of clumping to be drawn, take care of some PLT as large as WBC that are not
namely what differs with classical PLT satellitism identified as such, and at times enumerated as RBC or
around PMN (Ahmed, Minnich & Michael, 1978; WBC (Norberg & Nilsson, 1987; see part II). However,
Lombarts et al., 1992; Moraglio, Banfi & Arnelli, missing large PLT is a real challenge in thrombocytop-
1994). In one patient who demonstrated both PLT enic states, as true PLT count is of crucial importance
aggregation and PLT-PMN agglutination, PLT-PMN for the management of bleeding. In these instances,
clumping was not abolished by dithiothreitol, even if considerable improvement has been made on
occurred only at room or low temperature, and was discriminating large PLT from other particles (fitted
restricted to EDTA anticoagulant, three conditions curve, changing threshold between PLT and RBC,
that were not fulfilled for PLT aggregation, suggesting multi angle scatter, refractive index), some problems
that PLT clumps on the one hand and PLT-PMN owing to PLT counting persist. In some instances,
agglutination on the other hand corresponded to two namely if the number of large PLT is high, alternative
different phenomena (Moraglio, Banfi & Arnelli, approaches using immunologic markers have been
1994). If PLT-PMN clumps are large they are not proposed, that require the use of fluorescent flow
detected by HA. Depending on the severity of clump- cytometers, either optimized for that routine clinical
ing, the WBC differential is likely in most cases to be use, or dedicated and integrated to the HA (Ault et al.,
affected to certain degrees, and usually an accom- 1997; Harrison et al., 2000; Kunicka et al., 2000; Sand-
panying WBC flag will be generated to alert the haus et al., 2002).
operator. Spurious PLT counts are likely in most
cases. Examination of a peripheral blood film at low
Technical considerations regarding sampling
magnification is compulsory for each leukopenic
sample from an unknown patient or when WBC Preanalytical variables may contribute to anomalous
count falls dramatically: a step of examination at low results. The venepuncture site may lead to spuriously
magnification is often necessary to demonstrate the low counts, corresponding to samples diluted because
clumps. In one instance spurious WBC count was of proximity to a drip or taken from a line. Whatever
the consequence of both diminished number of PMN the anticoagulant used, an increase in its concentra-
(located within clumps) and artifact of PLT aggregates tion within the sample (less blood drawn because of
that falsely elevated the WBC count (Moraglio, Banfi difficult venepuncture, or difficult sampling in newb-
& Arnelli, 1994). orns; also discussed in part II) or a delay between
The phenomenon described above is related to sampling and analysis may change PLT volume, lead-
EDTA and appears in vitro: it is quite different from ing to an inability of the HA to generate a fitted
the PLT-WBC aggregates that may appear in vivo in curve or to ascertain the criteria used to define parti-
several inflammatory and thrombotic conditions, the cles as PLT (volume and refractive index; Wynn et al.,
latter related to enhanced expression of P-selectin 1995).
after PLT activation (Hu et al., 2003). A flow cytomet- Overfilling of blood collection vacuum tubes has
ric assay was proposed to enumerate these PLT-WBC been reported to generate a spuriously low PLT count,
aggregates (Li, Goodall & Hjemdahl, 1999). because of an inadequate sample mixing: after several
aspirates progressive return to nearly accurate results
occurred (Pewarchuk, VanderBoom & Blajchman,
Large platelets
1992). Delay in contact between whole blood and the
In normal and in many pathological situations a few anticoagulant, or difficult venepuncture, may initiate
PLT demonstrate a high volume and for that reason coagulation and generate PLT clumps.
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
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12 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

(Savage, Lucas & Hoffman, 1983; Savage & Hoffman,

1985), microangiopathic haemolysis with a large
number of schistocytes (Cornbleet & Kessinger, 1985),
or microspherocytosis because of acute burns (Akwari,
Ross & Stass, 1982), leading to spuriously elevated
PLT counts. In such situations altered RBC counts
have also been reported (see part II). In acute burns
RBC may be split into a large number of very small
fragments, which disturb PLT count, leading to a
peculiar PLT histogram (Figure 5) similar to that
Figure 4. Schistocytes are small RBC fragments which
size may reach that of large platelets (arrow). Most observed with the presence of other very small parti-
impedance-type haematology analysers analyse PLT cles, such as bacteria or cryoglobulins (see later). On
according to their volume and print next a ‘fitted’ Beckman-Coulter HA the threshold between PLT and
curve (arrowhead), the latter allowing discrimination RBC is fixed at 36 fl, whereas on Sysmex and some
with small RBC and accurate count (Coulter STKS Abbott HA that threshold may vary automatically to
II).
ascertain better the « valley » between the peak of
PLT and that of RBC, improving discrimination
between PLT and small RBC in some instances. On
SITUATIONS LEADING TO SPURIOUSLY
laser-beam HA (Abbott, Bayer) a two dimensional
ELEVATED PLT COUNTS
method determining both volume and refractive index
of PLT or fluorescent staining of platelets (Sysmex)
Fragmented RBC
allows an accurate partition between PLT, large PLT,
Accurate PLT and RBC counts are determined both on small RBC, and RBC fragments in most samples. Some
the same channel(s), but the size of particles (and HA enumerate PLT using impedance and optical
refractive index for laser beam HA) clearly differs in methods, and report both results on the same ticket
normal subjects. For impedance-type HA a fitted (Abbott, Sysmex), whereas one HA can perform opti-
curve of PLT histogram is generated to improve accu- cal, impedance, and immunological (CD61) counts on
racy and in most patients discrimination between the same sample, if required (Abbott). Confirmation
large PLT and small RBC is achieved (Figure 4). How- of PLT result, either by analysing the blood film, or
ever in presence of RBC with extremely low volume, manual count, or using another sample and another
wrong fitted curves may be generated in some cases, method of counting, such as flow cytometry
namely in severe microcytic iron deficiency anaemia (Dickerhoff & Von Ruecker, 1996), should be

Figure 5. After acute burns several changes may be observed on RBC, including spherocytes (arrowheads) and very
small RBC fragments (small schistocytes, arrows) (left; peripheral blood smear, MGG staining). Small schistocytes
are enumerated together with PLT, leading to a peculiar PLT histogram showing an excess of small particles (right;
Coulter counter STKS II).

 2007 The Authors

Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 13

performed at least in each following circumstances: PLT mias, spurious PLT counts could be related to buds
curve failing to return to baseline at 20 fl, population of that could develop on the surface of PMN, generating
microcytes appearing on the PLT histogram, exaggerat- pseudo-PLT, difficult to distinguish from PLT on
edly elevated mean PLT volume (MPV) or RBC distri- blood smears, but easier to demonstrate at electron
bution width (RDW; Savage & Hoffman, 1985). microscopic level because of their myeloperoxidase
positivity (Merz, 1983).
Routine stained smears show that these cytoplas-
Cytoplasmic fragments of nucleated cells
mic parts of nucleated cells are much more heteroge-
Beside RBC fragments or schistocytes, part of the neous in size and content than PLT (Figure 6). The
cytoplasm of abnormal cells was reported as leading incidence of this abnormality is far from being small,
to the elevation of PLT counts, including leukaemic as shown in a recent study, which found at least
blasts, monoblasts, or lymphoblasts (Armitage, Goe- some ‘pseudoplatelets’ on May Grünwald-Giemsa
ken & Feagler, 1978; Malcolm, Monks & Katz, 1978; stained smears in 43 of 169 (25.4%) patients with
Hammerstrom, 1992; Li & Salhany, 1999; Kakkar & acute leukaemia, corresponding in seven (4.1%)
Garg, 2005). Particles originating from leukaemic patients to a corrected PLT count <15 · 109/l,
cells were also reported during the leukaemic phase whereas the mean automated PLT count was
of poorly differentiated lymphocytic lymphoma, both 39 · 109/l (range: 21–75; Van der Meer et al., 2003).
at diagnosis and during chemotherapy (Stass et al., In some reports PLT transfusion was mentioned to
1979) (Figure 6), and in hairy cell leukaemia (Stass be delayed because of spuriously elevated counts,
et al., 1977; Ballard & Sidhu, 1981). In some of the and the authors proposed that, as high or normal
above-mentioned cases, cytochemistry (butyrate PLT counts are infrequent in acute leukaemias, they
esterase), immunocytochemistry (peroxidase, CD61), should be considered as spurious and verified using
or electron microscopy was performed that demon- another method of counting, namely if bleeding
strated the leukaemic origin of that particles, and symptoms are present (Hammerstrom, 1992; Li &
that only a few particles were true PLT. In some Salhany, 1999). In many but not in all instances a
situations, related mainly to acute myeloid leukae- flag is generated but, as the HA cannot identify these
cytoplasmic fragments as such, various kinds of flags
may be printed, including: thrombocytopenia, large
PLT, RBC ghosts, or other flags related to the inabil-
ity to produce a fitted curve.

Microorganisms
Bacteria may induce falsely elevated PLT counts,
because of their presence in vivo (Gloster et al., 1985;
Kakkar, 2004). Although it is a rare situation, even
in septic patients, some bacteria may be observed on
the peripheral blood smear and are associated with
positive blood cultures (Marshall, Theil & Brandt,
1990). Histogram of PLT volumes is abnormal and
shows a shift towards low sized particles, correspond-
ing to bacteria or to bacterial clumps (Figure 7). In
Figure 6. Parts of cytoplasm from lymphoma cells our experience with infected patients, abnormal PLT
(arrows) may be found within blood stream: such histograms related to bacteria were always associated
fragments are at times difficult to distinguish from with bacteria observed on the peripheral blood film
PLT, both by HA and after microscopic examination and to extreme clinical situations. An intermediate
(diffuse large B-cell lymphoma in relapse; MGG
situation is that related to bacterial overgrowth in
staining).
the blood sample from infected patients, because of
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
14 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

Iwatani & Kabutomori, 1999). If the increase was

reported as low and unimportant in patients with nor-
mal counts (rise in 2–40 · 109/l), it could not be neg-
lected in those patients with low PLT counts,
especially the leukaemic ones treated with L-asparagi-
nase, a drug known as inducing lipid abnormalities
(Cantero, Conejo & Jimenez, 1996; Kabutomori et al.,
1999). Lipids possess a high refractive index and can
Figure 7. Bacteria or bacterial aggregates may be enu- generate abnormal signals located near PLT or at the
merated together with PLT and appear as a peak of same place as the so-called debris (corresponding to
particles of small size (2 fl or less). In this patient small RBC or RBC ghosts in normal subjects). On
(septicaemia) the fitted curve was established and
some HA that analyse WBC on two channels, reagents
PLT count was not overestimated (Coulter counter
STKS II). used in each channel are not equally sensitive to
lipids and, according to the amount and composition
of lipids, discrepancy between WBC counts from both
channels may be observed (Bayer Advia 2120; Sys-
the delay between sampling and analysis (Kakkar, mex). Specific flagging and scattergram review are
2004). An unsterile tube used for blood sampling key items to appreciate the potential interference of
may cause bacterial overgrowth. In this situation, lipids on CBC. Methods were reported to discard spe-
the PLT count and PLT histogram are altered, cifically lipids from the sample, but some led them-
whereas clinical condition of the patient is unrelated selves to spurious PLT counts, either low or elevated
to infection. (Nicholls, 1983). Changes more or less superimposable
Fungi may show the same size as PLT and may be to those observed with lipid droplets were reported
observed on peripheral blood smears (Arnold, Jowzi & after the use of perfluorocarbon emulsions (Cuignet
Bain, 1999). They were reported recently as increas- et al., 2000).
ing PLT counts in thrombocytopenic patients infected
by Candida (Latif et al., 2003).
Cryoglobulins, cryofibrinogen and related
In one patient treated for malaria, small RBC infec-
ted by trophozoites of Plasmodium falciparum were mis- Cryoglobulins may lead to spuriously elevated PLT
interpreted as PLT by a HA, leading to a spuriously counts and in a few instances to altered RBC counts,
normal PLT count (Crabbe, Van Poucke & Canti- but were put forward first as generating erroneous
nieaux, 2002). WBC counts (Emori, Bluestone & Goldberg, 1973).
Cryoprecipitates disturb measurements according to
their size: if precipitates are small enough, they may
Lipids
lead to very high spurious PLT counts, and up to
In patients with hyperchylomicronemia, in samples eight times elevation may be observed (Fohlen-Wal-
taken after a meal, or after parenteral nutrition ther- ter et al., 2002). Anomalies are more obvious on HA
apy, lipids may form small droplets in vitro, that dis- that act at room temperature (Figure 8), but those
turb PLT counts (Nicholls, 1983; Savage, 1989; which use heated reagents are not fully devoid of
Cantero, Conejo & Jimenez, 1996), and/or haemoglo- changes (Bayer Advia 120). As the mechanism lead-
bin, RBC parameters, and WBC counts (discussed in ing to spurious elevation of PLT and WBC counts is
part II). Some authors compared the effects of similar, both changes will be discussed together in
hyperchylomicronemia on PLT counts performed by part II of this report. Spuriously elevated PLT counts
two types of HA: they observed a moderate increase may also be observed relating to the presence of cry-
of PLT count for the analyser using an optical method ofibrinogen but, as for cryoglobulins, WBC counts
for counting when compared with the one using an are frequently affected, and changes related to that
electrical impedance method that seemed unaffected peculiar condition will also be discussed in part II of
(Cantero, Conejo & Jimenez, 1996; Kabutomori, this report.
 2007 The Authors
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M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS 15

Figure 8. Cryoglobulins may precipitate during the dilution procedure into the HA, and the small particles are enu-
merated together with PLT. On impedance-type HA (Coulter STKS II) the small size of particles generates a shift to
the left of the PLT histogram (up left). On laser-beam HA (Bayer ADVIA 120) the PLT scattergram is overloaded
with particles of various sizes, the largest ones accumulating at the top of the scattergram (down left). After warm-
ing the sample at 37 C cryoglobulin dissolves, and prompt analysis leads to full disappearance of abnormalities (up
right and down right, for the relevant HA, respectively).

Miscellaneous ting PLT counts on the same HA (Malcolm, Monks &

Katz, 1978; Morton et al., 1980).
Air bubbles, which have resulted from mechanical
leaks, being introduced into flow cells and to imped-
ance apertures, can cause spurious counts. Also rea- Concluding remarks
gent contamination and debris build up into the
Preanalytical and analytical variables should be con-
analyser can cause erroneous counts. Cleaning and
sidered first within the laboratory, including human
background counting procedures as well as quality
errors in sample identification, site of venepuncture
control are stressed to prevent these events.
(adjacent to a drip or out of a line), or inadequate
mixing prior to analysis. Instrument malfunction,
Previous generation HA inability to recognize quality control failure, cleaning
and background counting procedures are also of con-
Some HA of previous generations, such as Hemalog 8
siderable importance before pointing out spurious
(Technicon-Bayer), measured PLT counts on whole
results from the HA.
blood after lysis of RBC, leaving abnormal intraerythr-
EDTA-dependent thrombocytopenia is certainly
ocytic particles free, which could be enumerated as
one of the most frequent anomalies associated with
PLT. So, nuclei of nucleated red blood cells, Howell
spurious counts on HA: an alarm or a flag is not con-
Jolly bodies, malarial parasites, and Pappenheimer
sistent and, in previously unknown patients with low
bodies were reported to disturb PLT count in such
PLT count by automated cell-counting, looking for at
instances (Morton et al., 1980). Other changes, such
least PLT clumps (blood smear, haematimetric cham-
as aggregated RBC stroma secondary to haemolytic
ber) is required. Samples should not be heated to
action of RBC antibodies were also reported as eleva-
 2007 The Authors
Journal compilation  2007 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2007, 29, 4–20
 1751553x, 2007, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2257.2006.00870.x by Algeria Hinari NPL, Wiley Online Library on [19/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
16 M. ZANDECKI ET AL. ABNORMAL PLATELET COUNTS ON HAEMATOLOGY ANALYSERS

dissociate aggregates and in many instances another alarms are generated because of abnormal finding on
blood sample will be helpful. Many other situations the WBC differential scattergram: HA which do not
may induce spurious PLT counts, either high or low analyse WBC subpopulations are unable to detect
(Table 1) but, even if we consider one given mechan- some spurious results.
ism for spurious count, the depth of the deviation
between the true and the spurious result will differ
ACKNOWLEDGEMENTS
from one patient to the other. As reported in Table 1,
if some changes are restricted to PLT, in several situa- We are indebted to Mathilde LINARD for kindly
tions spurious PLT counts are or may be associated reviewing English manuscript.
with other abnormalities of the CBC (see also part II).
Beside the anomalies described above, others are cer-
CONFLICT OF INTEREST
tainly unexplained (Savage, 1989) and unreported.
An important finding is that, in many cases, flags or No conflict of interest.

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