Received: 8 June 2017 | Revised: 19 August 2017 | Accepted: 22 August 2017

DOI: 10.1111/chd.12530

ORIGINAL ARTICLE

Determinants of platelet count in pediatric patients

with congenital cyanotic heart disease: Role of immature
platelet fraction

Randa M. Matter, MD1 | Iman A. Ragab, MD1 | Alaa M. Roushdy, MD2 |

Ahmed G. Ahmed, MB, BCh1 | Hanan H. Aly, MD1 | Eman A. Ismail, MD3

1
Pediatrics Department, Faculty of Medicine,
Ain Shams University, Cairo, Egypt
Abstract
2
Cardiology Department, Faculty of Objectives: Congenital heart defects are common noninfectious causes of mortality in children.
Medicine, Ain Shams University, Cairo,
Bleeding and thrombosis are both limiting factors in the management of such patients. We
Egypt
3
assessed the frequency of thrombocytopenia in pediatric patients with congenital cyanotic heart
Clinical Pathology Department, Faculty of
Medicine, Ain Shams University, Cairo, disease (CCHD) and evaluated determinants of platelet count including immature platelet fraction
Egypt (IPF) and their role in the pathogenesis of thrombocytopenia.

Correspondence Methods: Forty-six children and adolescents with CCHD during pre-catheter visits were studied;
Iman Ahmed Ragab, Ain Shams University. median age was 20.5 months. Complete blood count including IPF as a marker of platelet produc-
Pediatric Hospital, Hematology-Oncology tion and reticulated hemoglobin content (RET-He) as a marker of red cell production and iron
Unit, Abbasseya Square, Cairo, Egypt.
status were done on Sysmex XE 2100 (Sysmex, Japan). C-reactive protein, prothrombin time (PT),
Email: [email protected]
Activated partial thromboplastin time (APTT) were also assessed.

Results: Thrombocytopenia was found in 6 patients (13%). PT was prolonged (P 5 .016) and IPF
was significantly higher in patients with thrombocytopenia compared with patients with normal
platelet count (14.15 6 5.2% vs 6.68 6 3.39%; P 5 .003). Platelet count was negatively correlated
with IPF while significant positive correlations were found between IPF and hemoglobin, red blood
cells (RBCs) count, hematocrit (Hct), PT, reticulocytes count, and immature reticulocyte fraction.

Conclusions: We suggest that elevated IPF in CCHD patients with thrombocytopenia may denote
peripheral platelets destruction as an underlying mechanism. Hemoglobin level, RBCs count, Hct,
and RET-He were not significant determinants for platelet count in CCHD.

KEYWORDS
CCHD, immature platelet fraction, RET-H, thrombocytopenia

1 | INTRODUCTION subsequently identified and attributed to thrombocytopenia, shortened

platelet survival, and deficient von Willebrand multimers.2
Congenital heart defects are the most common developmental anom- In patients with CCHD, platelets are shown to have both qualita-
aly and are the commonest noninfectious causes of mortality in new- tive and quantitative abnormalities.3 However, there are conflicting
borns; they affect up to 6–8/1000 infants and in most cases the cause data as regards the etiology of thrombocytopenia in CCHD.4 A signifi-
1
is unknown. Erythrocytosis, thrombocytopenia, platelets function cant association has been reported between thrombocytopenia and a
defects, coagulation factors deficiencies are the main hematologic dis- high hematocrit in cyanotic patients and multiple etiologies has been
orders in patients with cyanotic congenital heart disease (CCHD). The suggested including chronic compensated disseminated intravascular
hemorrhagic tendency in CCHD was initially attributed to an increase coagulation (DIC), reduced synthesis of clotting factors and/or
in tissue vascularity, but co-existing hemostatic defects were deranged platelet aggregation.5

Congenital Heart Disease. 2017;1–6. wileyonlinelibrary.com/journal/chd V

C 2017 Wiley Periodicals, Inc. | 1
2 | MATTER ET AL.

Immature reticulated platelets represent the youngest platelets 2.1 | Sample collection and laboratory investigations
6
released into the circulation by regenerated marrow megakaryocytes
Peripheral blood samples were collected on potassium-ethylene dia-
and are the analogue of the red cell reticulocyte. The rate of platelet
mine tetraacetic acid (K2-EDTA) (1.2 mg/mL) for complete blood count
turnover can be evaluated by the relationship between the percent of
(CBC) and in vacutainer tubes containing 0.2 ml 3.8% trisodium citrate
reticulated platelets and the platelet count.7 Measurement of immature
in a ratio of 9 volumes of blood to 1 volume of citrate for coagulation
platelet fraction (IPF) could reflect platelet production rate. It could be
studies. Samples collected in both tubes were properly mixed with the
used as a rapid and inexpensive automated marker for the etiology of
used anticoagulant. For chemical analysis, clotted samples were
thrombocytopenia and can be integrated as a standard parameter to
obtained and serum was separated by centrifugation for 15 minutes at
evaluate the thrombopoietic state of the bone marrow.8 IPF is also
1000 3 g.
helpful in predicting the course of thrombocytopenia and identifying
CBC was performed using Sysmex XE-2100 (Sysmex, Kobe, Japan)
patients with a risk for rapid severe drop in platelet count.9,10
with assessment of IPF%, mean platelet volume (MPV), RET-He and
The measurement of reticulocyte hemoglobin content is a direct
immature reticulocyte fraction (IRF). To exclude infections, C-reactive
assessment of the incorporation of iron into erythrocyte hemoglobin
protein was determined by latex agglutination test (Omega, UK). Deter-
and thus a direct estimate of the recent functional availability of iron
mination of coagulation profile; prothrombin time and activated partial
into the erythron. The reticulocyte hemoglobin equivalent (RET-He)
thromboplastin time (APTT) was done using Stago STA compact (Diag-
has been available for use on the Sysmex XE 2100 (Sysmex Corpora-
nostica Stago, Parsippany, NJ, USA).
tion, Kobe, Japan), broadening the availability of a tool for assessing
reticulocyte hemoglobin content.11
2.2 | Echocardiography
This study aimed to assess the frequency of thrombocytopenia in
pediatric patients with CCHD as well as evaluating determinants of pla- All patients underwent echocardiographic studies using a Philips iE33
telet count including IPF as a marker of platelet production, RET-He as machine (Philips Medical Systems, Andover, MA, USA). Standard 2D
a marker of red cell production, and iron status and their role in the echocardiogram was done for all patients enrolled in the study using
pathogenesis of thrombocytopenia among those patients. phased array transducers of different frequencies tailored according to
each patient’s age, body built and weight. Philips S8–3 Sector Array
Transducer with a frequency range from 8 to 3 megahertz was gener-
2 | MATERIALS AND METHODS
ally used for children below 3 years of age and Philips S5–1 Sector

This cross-sectional study included 46 children and adolescents with Array Transducer with a frequency range from 5 to 1 megahertz was

CCHD 18 years of age) who attended the Pediatric Cardiology Clinic, used for older children with few exceptions. The study included 2D, M

Ain Shams University during pre-catheter visits. An informed consent mode and color flow Doppler from all standard echocardiographic win-

was obtained from the guardian of each patient before participation. dows (ie, subcostal, apical, parasternal, and suprasternal) applying the

The procedures applied in this study were approved by the Ethical sequential analysis to establish the situs, AV and VA connections, great
vessel relation and abnormalities, ventricular dimensions and functions,
Committee of Human Experimentation of Ain Shams University, and
state of cardiac valves, venous connections, and any intracardiac
are in accordance with the Helsinki Declaration of 1975.
shunts.13,14
Exclusion criteria were evident sepsis, septic shock, high fever,
localizing infections, radical operation for a heart defect due to hypo-
plastic pulmonary arteries, or high pulmonary vascular resistance for 2.3 | Statistical analysis
the Fontan circulation or due to Eisenmenger syndrome and intake of Analysis of data was done using Statistical Program for Social Science
anti-platelet or anti-inflammatory agents. Patients with congenital non- version 21 (SPSS Inc., Chicago, IL, USA). Quantitative variables were
cyanotic heart disease, dysmorphic features/DiGeorge syndrome, described in the form of mean and standard deviation or median and
down and Noonan syndromes were also excluded. No platelet transfu- interquartile range (IQR: difference between 25th and 75th percen-
sion was given prior to hematological analysis. Patients were divided tiles). Qualitative variables were described as number and percent. In
into two groups according to the platelet count; CCHD with thrombo- order to compare parametric quantitative variables between two
cytopenia (platelet count <100 3 109/L) and CCHD with normal plate- groups, Student t test was performed. For comparison of non-
let count (platelet count 100 3 109/L). parametric quantitative variables between two groups, Mann-Whitney
Data collection from hospital records included age, sex, presence test was applied. Qualitative variables were compared using chi-square
of parental consanguinity, age at onset of cyanosis, cyanotic episodes (X2) test or Fisher’s exact test when frequencies were below five. Pear-
and their frequencies, bleeding manifestations, family history of throm- son correlation coefficients were used to assess the association
bocytopenia, drug history with assessment of liver, spleen and lymph between two normally distributed variables. When a variable was not
nodes. Data on height, sitting height and weight were transformed into normally distributed, a Spearman correlation test was performed. Mul-
12
SD scores (SDS) according to the standards of Tanner et al. Oxygen tivariable linear regression analysis was employed to determine the
saturation was measured by pulse-oximetry. Vital data as temperature, relation between platelet count and clinical and laboratory variables.
heart rate, respiratory rate and blood pressure were recorded. A P value <.05 was considered significant in all analyses.
MATTER ET AL. | 3

TA BL E 1 Clinical data among CCHD patients with and without thrombocytopenia

Patients with CCHD

Variables Thrombocytopenia (n 5 6) Normal platelet count (n 5 40) P value

Age (months), median (IQR) 34 (58.3) 18.5 (57) .62

Weight SDS, median (IQR) 20.81 (5.3) 21.7 (2.4) .25

Height SDS, median (IQR) 23.1 (4.4) 22.5 (3.0) .46

Sex, n (%)
Male 4 (66.7) 26 (65) .93
Female 2 (33.3) 14 (35)

Consanguinity, n (%) 1 (16.7) 14 (35) .37

Order of birth, n (%)

First 3 (50) 23 (57.5) .12
Second 2 (33.3) 14 (35)
Third 0 (0) 2 (5)
Fourth 1 (16.7) 0 (0)
Fifth 0 (0) 1 (2.5)

Type of CHD, n (%)

TGV 2 (33.3) 7 (17.5) .63
TOF 4 (66.7) 6 (65)
DRV 0 (0) 6 (15)
Single ventricle 0 (0) 1 (2.5)

Cyanosis, n (%) 2 (33.3) 5 (12.5) .18

Age of start of cyanosis (days), median (IQR) 8.5 (3.0) 10 (1.2) .13

Cyanotic spells/month, median (IQR) 4.5 (1.25) 4 (1.1) .18

Duration of cyanotic spells (minutes), mean 6 SD 5 6 0.5 4.7 6 0.6 .31

Clubbing, n (%) 2 (33.3) 5 (12.5) .18

Systolic BP (mm Hg), mean 6 SD 95 6 13.7 94.5 6 8.4 .93

Diastolic BP (mm Hg), mean 6 SD 60 6 10 58.5 6 8.3 .69

Respiratory rate, mean 6 SD 28 6 5.8 29.4 6 5.9 .58

Heart rate (beat/min), mean 6 SD 107.5 6 11.7 107.3 6 13.1 .98

Oxygen saturation (%), mean 6 SD 81.2 6 3.18 79.6 6 10.1 .78

Abbreviations: CCHD, congenital cyanotic heart disease; SDS, standard deviation score; CHD, congenital heart defect; TGV, transposition of great vessels;
TOF, tetralogy of Fallot; DORV, double outlet right ventricle; BP, blood pressure; IQR, interquartile range (difference between 75th and 25th percentile).
Data were expressed as mean 6 SD where Student t test was used or as median (IQR) using Mann-Whitney test for comparison unless specified as
number (percentages) using chi-square (X2) test for comparisons.

3 | RESULTS 3.2 | Thrombocytopenia among patients with CCHD

Thrombocytopenia was present in 6 (13%) of the screened patients.
3.1 | Clinical and laboratory characteristics of the
The mean platelet count was 244.7 6 88.6 3 109/L in patients
studied patients with CCHD
without thrombocytopenia and 63.2 6 21.9 3 109/L in the thrombo-
The 46 studied patients with CCHD included 30 males and 16 females cytopenic group. No significant difference was found between
with a male to female ratio of 1.9:1. Their ages ranged from 1–192 patients with thrombocytopenia and those with normal platelet
months, with a median of 18.5 months (IQR, 55 months). Nine (19.6%) count as regards age, sex, weight SDS and height SDS, presence of
patients had transposition of great vessels (TGV), 30 (65.2%) had tetral- consanguinity, patients’ order of birth, types of congenital heart
ogy of Fallot (TOF), 6 (13%) had double outlet right ventricle (DORV) defects, cyanosis, cyanotic spells, vital signs or oxygen saturation
and one (2.2%) patient had single ventricle. Positive parental consan- (P > .05) (Table 1).
guinity was observed in 31 (67.4%) patients. None had abnormal liver As shown in Table 2, IPF and PT were significantly higher in
function tests or hepatosplenomegaly. None of the patients com- patients with thrombocytopenia compared with the non-
plained of overt bleeding manifestations. thrombocytopenic group while other variables including white blood
4 | MATTER ET AL.

TA BL E 2 Hematological and coagulation profile of CCHD patients with thrombocytopenia compared with normal platelet count

Patients with CCHD

Variables Thrombocytopenia (n 5 6) Normal platelet count (n 5 40) P value
9
WBC count (3 10 /L), median (IQR) 13.1 (13.5) 8.8 (5.2) .289

Hemoglobin (g/dL), median (IQR) 13.2 (12.3) 12.1 (4.6) .757

MCV (FL), mean 6 SD 80.9 6 11.7 75.8 6 8.9 .275

MCH (pg), mean 6 SD 24 6 4.3 23.8 6 3.9 .971

Hct (%), median (IQR) 48.5 (38.7) 47.2 (16.7) .694

Reticulocyte count (%), median (IQR) 0.95 (5.6) 1.2 (0.76) .909

RET-He (pg), mean 6 SD 25.1 6 6.9 25.8 6 6.3 .803

LFR, mean 6 SD 76.9 6 11.9 83.3 6 10.7 .196

MFR, mean 6 SD 14.53 6 5.5 11.94 6 6.4 .260

HFR, mean 6 SD 8.5 6 9.4 4.8 6 5.1 .282

IPF (%), median (IQR) 16.3 (9.5) 6.6 (4.5) .003

MPV (FL), median (IQR) 11.2 (2.4) 11.5 (1.7) .989

PT (s), mean 6 SD 17.08 6 3.37 13.99 6 1.41 .016

APTT (s), mean 6 SD 34.3 6 3.61 32.12 6 3.5 .272

Abbreviations: WBC, white blood cell count; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; Hct, Hematocrit; RET-He, reticulo-
cyte hemoglobin equivalent; LFR, low fluorescence reticulocytes; MFR, medium fluorescence reticulocytes; HFR, high fluorescence reticulocytes IPF,
immature platelet fraction; MPV, mean platelet volume; PT, prothrombin time; APTT, activated partial thromboplastin time.
Data were expressed as mean 6 SD where Student t test was used or as median (IQR) using Mann-Whitney test for comparison unless specified as
number (percentages) using chi-square (X2) test for comparisons.

cells (WBCs) count, hemoglobin, hematocrit (Hct) and RET-He were Moreover, IPF was positively correlated with hemoglobin (r 5 0.430,
nonsignificant among both groups (Table 2). P 5 .003), red blood cells (RBCs) count (r 5 0.483, P 5 .001), Hct
(r 5 0.501, P 5 .002), PT (r 5 0.293, P 5 .048), reticulocytes count
3.3 | Relation between platelet count and the studied (r 5 0.352, P 5 .016) and IRF (r 5 0.302, P 5 .041). Multivariable linear
laboratory variables among CCHD patients regression analysis (Table 3) revealed that IPF is the only significant
We found significant negative correlations between platelet count with independent determinant of platelet counts among CCHD patients
IPF (r 5 20.659, P < .001) (Figure 1) and PT (r 5 20.427, P 5 .003). (r2 5 0.712).

F I G U R E 1 Correlations between immature platelet fraction and platelet count (A) and hematocrit level (B) among patients with congenital
cyanotic heart disease
MATTER ET AL. | 5

TA BL E 3 Multivariable linear regression analysis of the relation platelet microparticles in patients with CCHD and the patients were
between platelet count and laboratory variables in CCHD not thrombocytopenic. The authors attributed platelet activation to
Unstandardized Coefficients polycythemia.21
Independent Standard On the other hand, Lill et al.15 found low absolute reticulated pla-
variables B Error P value telet count denoting decreased platelet production, together with nor-
(Constant) 494.381 95.963 <.001 mal thrombopoeitin level, PT, APTT, and D-dimer excluding the
possibility of DIC. Nevertheless, all their thrombocytopenic patients
IPF (%) 214.340 2.964 <.001
had Eisenmenger Syndrome; therefore, they hypothesized that right-
PT (seconds) 213.523 11.743 .295
to-left shunts deliver whole megakaryocytes into the system arterial
Abbreviations: IPF, immature platelet fraction; PT, prothrombin time. circulation, bypassing the lungs where megakaryocytic cytoplasm is
Dependent variable: Platelet count.
fragmented into platelets, thus reducing platelet production.15 It has
also been suggested that polycythemia increases blood viscosity and
4 | DISCUSSION reduces tissue perfusion. The resultant hypoxia of marrow tissues
causes inhibition of platelet production, causing thrombocytopenia.3
Platelet count in CCHD appears to represent a continuum beginning
In our study, PT was prolonged among patients with thrombocyto-
with low normal counts and ending with thrombocytopenia. 15 The fre-
penia and whether subclinical DIC could be a contributing factor for
quency of thrombocytopenia was 13% among our patients with
thrombocytopenia in CCHD is another possibility. Increased D-dimer in
CCHD. In a previous study for prevalence of thrombocytopenia in
CCHD has been reported.16 However, in a review of hematologic
CCHD, Lill et al. (2006) found that out of 105 patients with CCHD, 26
abnormalities among patients with CCHD, it has been suggested that
(25%) had thrombocytopenia; however, all these patients with throm-
hyperviscosity of the blood and sluggishness of the microcirculation
bocytopenia had Eisenmenger syndrome and their mean platelet count
causes hypoxic damage to the liver decreasing the synthesis of vitamin
was 155 6 12 3 109/L (range, 125–332 3 109/L).15 Another more
K-dependent clotting factors.3,21
recent study found that the mean platelet count of patients with
Although some studies reported a significant negative correlation
CCHD was 159 6 60 3 109/L.16
between platelet count and the Hct values,16,18 we found no significant
To determine the pathogenesis of thrombocytopenia, platelet pro-
difference in hemoglobin, Hct or RET-He values between patients with
duction was determined by assessment of IPF as previously reported.17
CCHD with and without thrombocytopenia. Moreover, platelet count
We found higher IPF levels in CCHD patients with thrombocytopenia
was not correlated with Hct; however, a significant positive correlation
compared with the nonthrombocytopenic group suggesting increased
was found between Hct and IPF.
platelet production among those patients. Elevated IPF levels among
One limitation of the present study is that we included a relatively
our CCHD patients with thrombocytopenia mean the absence of cen-
tral marrow pathology and the significant negative correlations small number of patients. However, our findings were clear and indica-

between the platelet count and each of IPF and PT make the likelihood tive, allowing us to assume that IPF could have a potential clinical value

of peripheral platelet destruction and/or platelet activation a higher among patients with CCHD. It is possible that the inclusion of more

possibility. These results were supported by multiple regression analy- patients would have revealed further correlations, in addition to those

sis which showed that IPF was the only significant independent factor derived from the present analysis.
related to platelet count in CCHD. However, the cause of increased In conclusion, we suggest that CCHD can be complicated with

destruction whether subclinical DIC or increased platelet activation is thrombocytopenia which occurred in 13% of the studied patients. IPF
not yet settled. as a marker for platelets production was elevated in CCHD patients
Four pathogenic mechanisms were suggested in CCHD (1) with thrombocytopenia suggesting peripheral platelets destruction as
decreased megakaryocyte production, (2) decreased platelet produc- underlying mechanism. Hemoglobin level, RBCs count, Hct and RET-
tion, (3) increased platelet destruction, and (4) increased platelet activa- He as a marker for red cell production and iron status were not signifi-
tion.15 Some studies suggested that thrombocytopenia does not cant determinants for platelet count in CCHD.
originate from the process of platelet production (fragmentation of
megakaryocytes)18 and patients with CCHD had abnormalities of plate-
let turnover secondary to an increase in their peripheral destruction.19 CONFLIC T OF I NTE RE ST
While others showed that the thrombocytopenia of CCHD is primarily
The authors report no declarations of interest.
related to a decrease in platelet production and/or an increase in plate-
let activation.15,20,21
Platelet activation in patients with CCHD has been shown in a
recent study18 where platelet microparticles and p-selectin were AUTHOR CONTRIBUTI ONS

increased. Although platelet count was lower in CCHD group com- All the authors equally contributed in this article.
pared with acyanotic heart disease, their patients with CCHD did not All authors were involved in concept, design, data collection, analysis
have thrombocytopenia18; Horigome et al.21 also reported elevated and drafting of the manuscript.
6 | MATTER ET AL.

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