Published online: 2019-12-13

320

Immature Platelets As a Predictor of Disease

Severity and Mortality in Sepsis and Septic
Shock: A Systematic Review
Christian Velling Thorup, MD1,2 Steffen Christensen, MD, PhD3 Anne-Mette Hvas, MD, PhD1

1 Thrombosis and Haemostasis Research Unit, Department of Clinical
Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2 Department of Emergency, Randers Regional Hospital, Randers, Denmark
3 Department of Anesthesia and Intensive Care Medicine, Aarhus
University Hospital, Aarhus, Denmark
Address for correspondence Anne-Mette Hvas, MD, PhD, Thrombosis
and Haemostasis Research Unit, Department of Clinical Biochemistry,
Aarhus University Hospital, Palle Juul-Jensens Boulevar 99, DK-8200
Aarhus N, Denmark (e-mail: am.hvas@dadlnet.dk).

Semin Thromb Hemost 2020;46:320–327.

Abstract Sepsis is associated with high morbidity and mortality, and short-term mortality
remains above 30% despite relevant supportive and antibiotic treatments. The aim of
this systematic review was to summarize and discuss the current evidence of the
association of an increased number of circulating immature platelets with disease

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severity and mortality in patients with sepsis or septic shock. The review was
conducted according to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) statement and was registered at the PROSPERO database
(registration number: CRD42018104326). A systematic literature search was per-
formed in PubMed, Web of Science, Scopus, and Embase on June 20, 2018, without
time restrictions. The included studies were quality-assessed by the National Institutes
of Health’s Quality Assessment Tools. In total, 14 studies were included. The param-
eters used for the determination of platelet maturity were mean platelet volume,
immature platelets fraction, reticulated platelet percentage, and absolute immature
platelets count. Nine studies reported significantly increased immature platelet
Keywords markers in nonsurvivors of septic shock compared with survivors, as well as in patients
► immature platelets with severe sepsis or septic shock compared with patients without severe sepsis and
► immature platelet septic shock. Six of these nine studies demonstrated that increased immature platelet
fraction markers were predictors of mortality and/or disease severity (area under the receiver
► mean platelet volume operating curve: 0.599–0.886). This review suggests that an increased number of
► mortality circulating immature platelets is associated with increased disease severity and
► biomarkers mortality in patients with sepsis and septic shock. Larger studies are needed to
► septic shock confirm whether immature platelets should be routinely monitored to support the
► sepsis prediction of disease severity and mortality in septic patients.

Sepsis is associated with increased morbidity and mortality,
and despite relevant supportive and antibiotic treatments,
the mortality is still above 30% in affected patients.1 Delay in
the diagnosis and initiation of antibiotic treatment plays a
significant contributory factor in the poor prognosis of
sepsis.2–4 Therefore, recent sepsis guidelines emphasize
early diagnosis,5,6 and current research focuses intensively
on potential biomarkers for early diagnosis.7,8
Following endothelial lesion, activated platelets interact
with other platelets, leucocytes, and the endothelial cells

published online Issue Theme Acquired Platelet
December 13, 2019 Dysfunction—Laboratory and Clinical
Implications; Guest Editors: Anne-Mette
Hvas, MD, PhD, Julie Brogaard Larsen, MD,
PhD, and Leonardo Pasalic, MBBS, PhD.
Copyright © 2020 by Thieme Medical DOI https://doi.org/
Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-3400256.
New York, NY 10001, USA. ISSN 0094-6176.
Tel: +1(212) 760-0888.

and are consumed in microvascular fibrin meshwork and
thrombi.9 In sepsis and septic shock, activation and consump-
tion of platelets and platelet–vessel wall interaction are un-
controlled, leading to the formation of microthrombi and
subsequent thrombocytopenia. Ultimately, this results in a
systemic thrombotic microangiopathy, in its most extreme
form as disseminated intravascular coagulation (DIC),10 which
contributes to organ failure and increases mortality.11–13
Immature platelets are characterized by higher RNA content
than mature platelets and are therefore also called reticulated
platelets.14 Biochemically, immature platelets are identified by
the measurement of increased mean platelet volume (MPV),
immature platelet fraction (IPF), and immature platelet count
(IPC).15–17 Automated measurements of immature platelets
are performed employing two different hematology analyzers:
XE- and XN-Series (Sysmex) or CELL-DYN Sapphire (Abbott).18
Only a few studies comparing the different markers of imma-
ture platelets are available and, overall, they showed weak-to-
moderate correlations.19–21 Thus, these parameters cannot be
used interchangeably,18 and the clinical utility may differ
according to different clinical settings.18
Previous studies indicate that immature platelets are more
hemostatically active than mature platelets and thereby poten-
tially contribute to an increased risk of thromboembolic dis-
ease.22–24 Immature platelets produce more thromboxane A2,
aggregate more rapidly, contain more dense granules, and show
increased expression of membrane receptors such as P-selectin
and glycoprotein IIIa.25,26 Recent studies indicate that the
assessment of circulating immature platelets might be useful
as a prognostic marker for disease severity and mortality in
patients with sepsis or septic shock.27,28 However, a substantial
drawback of previous investigations is the relatively small
sample size of the individual studies. This prevents firm con-
clusions on the potential role of immature platelets as predic-
tors of disease severity and mortality in patients with sepsis or
septic shock.
The aim of this systematic review was to summarize and
discuss the current evidence on the potential association of
an increased number of immature platelets with disease
severity and mortality in patients with sepsis or septic shock.
Material and Methods
The review was conducted according to the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement.29 The review protocol was registered in the PROS-
PERO database (registration number: CRD42018104326). A
systematic literature search was performed in PubMed, Web of
Science, Scopus, and Embase on June 20, 2018, without time
restrictions.
In PubMed, the search terms used were: Shock, Septic
[Mesh] OR Sepsis[Mesh]) AND (Platelet Count[Mesh] OR im-
mature platelet count OR immature platelet fraction OR mean
platelet volume. The filter Adult (19þ years) was activated. In
Web of Science, the search terms used were SepsisOR septic
shock AND mean platelet volume OR immature platelet frac-
tion OR immature platelet count OR platelet count. The search
was filtered by English language and articles, and the catego-
Immature Platelets in Sepsis Thorup et al. 321
ries pediatrics and veterinary science were excluded. In Sco-
pus, the search terms used were (Sepsis OR septic shock) AND
(mean platelet volume OR mean platelet count OR platelet
count OR immature platelet fraction). The search was limited
to adult studies. In Embase, the search terms used were:
(Sepsis OR septic shock) AND (mean platelet volume OR
mean platelet count OR platelet count OR immature platelet
fraction). The search was performed using Emtree and was
limited to adult studies and articles only. Beyond the system-
atic literature search, articles identified in reference lists were
included if they fulfilled the inclusion criteria.
The inclusion criteria were (1) biomarker reflecting plate-
let immaturity (e.g., MPV, IPF, and/or IPC), (2) sepsis and/or
septic shock investigated in human adults, (3) investigation
of an association between a biomarker reflecting platelet
immaturity and disease severity and/or mortality in sepsis
and/or septic shock, (4) laboratory tests performed in whole
blood (not platelet-rich plasma or bone marrow), and
(5) article written in English. The exclusion criteria were
reviews, meta-analyses, conference abstracts, case reports
with less than five cases, editorials, guidelines, comments,
and letters without original data.
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All records identified by the database search were initially
screened by title and abstract. A random sample of 50
abstracts was screened and discussed between two authors
(C. T. and A. M. H.), and the remaining abstracts were
screened by C. T. Studies considered relevant were then
evaluated in full text according to the prespecified inclusion
and exclusion criteria. Two authors (C. T. and A. M. H.) rated
all included articles according to the National Institutes of
Health’s Quality Assessment Tools for Observational Cohort
and Cross-Sectional Studies and Quality Assessment of Case-
Control Studies.30 Disagreement between the authors was
resolved by discussion until consensus. The studies were
rated as good, fair, or poor. Relevant data were extracted from
the articles for qualitative synthesis by one author (C. T.) and
validated by the two other authors. Since the studies were
heterogeneous with regard to measurements of immature
platelets, time of blood sampling, and disease severity scores,
we did not perform quantitative data synthesis.
Results
►Fig. 1 shows the inclusion and exclusion process of this
review. A total of 14 studies were included,27,28,31–42 among
which 13 were cohort studies27,28,31,33–42 and 1 was a case–
control study.32 ►Tables 1 and 2 show the results and charac-
teristics of the 14 included studies. The study by Guclu et al
reported both on mortality and severity of disease and
is therefore presented in both tables.33 Seven studies were
rated as good,27,28,33,34,36,38,41 three fair/good,35,39,40 three
fair,31,37,42 and one poor.32 Detailed information on
the rating of the 13 cohort studies is shown in
►Supplementary Table 1 (online only).
Immature Platelets and Mortality
Seven studies investigated the association between MPV and
mortality.27,31,33–37 Five studies were rated as good or
Seminars in Thrombosis & Hemostasis Vol. 46 No. 3/2020
322 Immature Platelets in Sepsis Thorup et al.
Fig. 1 Flowchart of study selection.
fair/good27,33–36 of which three studies found increased MPV to
be a predictor of mortality in septic patients,27,35,36 whereas
two studies found no difference in MPV between survivors and
nonsurvivors of sepsis/septic shock.33,34 The association be-
tween increased MPV and mortality was supported by two
studies rated as fair. They demonstrated higher MPV in non-
surviving than in surviving patients.31,37 In addition, Becchi
et al found increasing MPV with increasing Sequential Organ
Failure Assessment (SOFA) score in nonsurvivors.31
The study by Muronoi et al found increased IPF to be a
predictor of 28-day mortality in septic patients.28 On the
contrary, Koyama et al reported decreased absolute IPC as a
predictor of 28-day mortality in septic patients.41
Immature Platelets and Sepsis Severity
Three studies investigated the association between MPV and
sepsis severity.32,33,38 Among these, two studies were rated
as good and found increased MPV to be associated with
sepsis severity.33,38 Montero-Chacón et al found increased
MPV to be associated with an increased need for vasopres-
sors and assisted mechanical ventilation and longer length of
stay in ICU.38 In contrast, Acikgoz et al demonstrated no
difference in MPV between patients with or without DIC.32
Two studies, rated as fair/good, reported that increased
IPF discriminated between severe and nonsevere sepsis.39,40
In accordance with this, Liu et al demonstrated increased
reticulated platelets in patients with severe sepsis and/or
septic shock compared with all septic patients included in
the study.42 Koyama et al found decreased absolute IPC to be
associated with the development of severe thrombocytope-
nia in septic patients.41
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Discussion
This systematic review, including 14 observational studies
with 2,509 septic patients in total, suggests that an increased
number of circulating immature platelets is associated with
disease severity and mortality in patients with sepsis or
septic shock.
Nine studies supported that increasing IPC is associated with
increased mortality and disease severity in sepsis.27,28,35–40,42
Five of these studies reported increased immature platelets at
admission in nonsurvivors compared with survivors,27,28,35–37
and four studies reported increased immature platelets in
severe sepsis compared with nonsevere sepsis.38–40,42 Two
studies found no difference in immature platelets according
to sepsis severity or mortality.32,34 The results from the remain-
ing three studies were ambiguous; Guclu et al reported a higher
number of immature platelets in severe sepsis than in non-
severe sepsis but found no difference between survivors and
nonsurvivors.33 In contrast, Becchi et al reported low immature
platelets in nonsurvivors compared with survivors at diagnosis,
but immature platelets were increasing with change in SOFA
score in nonsurvivors and decreasing in survivors.31 Koyama
et al calculated absolute IPC, which is IPF multiplied with
platelet count, and found decreased absolute IPC to be a
predictor of mortality.41 However, since most of the patients
had thrombocytopenia with continuously decreasing platelet
counts, this decreasing absolute IPC might merely reflect the
decreasing platelet count.
The association of increased immature platelets with disease
severity and mortality in sepsis might indicate an increased
platelet turnover due to increased platelet consumption in
 Immature Platelets in Sepsis Thorup et al. 323

Table 1 Results and characteristics of the included studies that examined immature platelets and mortality in sepsis

Author Study Study population, n age Sepsis-related clinical characteristics Results, platelet indices
(year), design (mean  SD or (mean  SD or median [range])
rating median [range], years)
MPV
Becchi Cohort Sepsis, n ¼ 70 (71  1.6) Not reported MPV (fL), mean  SD: survivors vs. nonsurvivors Blood
et al31 study Survivors vs. nonsurvivors, sampling at enrollment and every  8% change in SOFA
(2006), n were not reported score:
fair Sample 1: 10.54  0.9 vs. 9.96  1.7
Sample 2: 10.45  0.8 vs. 10.15  1.6
Sample 3: 10.20  1.1 vs. 10.47  1.8
Sample 4: 10.02  0.9 vs. 10.8  1.5
Sample 5: 9.88  1.1 vs. 11.1  1.6
MPV differences in sample 5 and sample 1 (MPV5-MPV1)
was positively distributed in nonsurvivors while negatively
distributed in survivors
Logistic regression analysis of death probability: MPV cutoff
at enrollment < 9.7 fL, OR ¼ 3.04, p < 0.05
Guclu Cohort Sepsis, n ¼ 145 Nonsurvivors with thrombocytopenia, MPV (fl), median (range): survivors 8.0 (7.0–9.0) vs.
et al33 study Survivors, n ¼ 51 n ¼ 19 (37.3%), vs. survivors without nonsurvivors 7.0 (7.0–9.0), p ¼ 0.114
(2013), (66.5  18.5) vs. thrombocytopenia, n ¼ 30 (31.9%),
good nonsurvivors, n ¼ 94 p ¼ 0.51
(60.7  18.5), p ¼ 0.073
Sadaka Cohort Septic shock, n ¼ 484 APACHE II: survivors 23  7 vs. MPV (fL), mean  SD: survivors 10.5  0.9 vs.
et al34 study Survivors n ¼ 314 nonsurvivors: 27  9, p < 0.05 nonsurvivors 10.6  0.9
(2014), (66  15) vs. nonsurvivors, SOFA: survivors 9.8  2.8 vs. OR: 1.11 (0.77–1.62), p ¼ 0.5
n ¼ 170 (70  14), p < 0.05 nonsurvivors 11.3  2.9, p < 0.05

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good ROC analysis of MPV predicting mortality; AUC: 0.5
Gao et al35 Cohort Septic shock, n ¼ 124 APACHE II score, median (range): MPV (fL), median (range): survivors 10.3 (9.68–11) vs.
(2014), study Survivors, n ¼ 36 survivors 30 (28–33) vs. nonsurvivors 11.2 (10.5–12.5), p ¼ 0.01
fair/good (61.17  20.64) vs. nonsurvivors 35 (27–37.5), p ¼ 0.04 ROC analysis of MPV as a predictor of mortality
Nonsurvivors, n ¼ 88 MPV (admission) AUC: 0.81; cutoff: 10.5; sensitivity:
(61.70  17.88), p ¼ 0.82 81.81%; specificity: 65.71%
MPV (last day) AUC: 0.88; cutoff: 10.5; sensitivity:
81.82%; specificity: 85.71%
Kim et al36 Cohort Sepsis, n ¼ 345 APACHE II: survivors 16.5  6.6 vs. MPV (fL), mean  SD: survivors vs. nonsurvivors:
(2015), study Survivors, n ¼ 310 nonsurvivors 25.9  6.8, p < 0.001 MPV (admission): 8.54  1.10 vs. 9.54  1.66,
good (63.7  15.9) vs. SOFA: survivors 7.7  2.6 vs. p ¼ 0.001
Nonsurvivors, n ¼ 35 nonsurvivors 11.1  3.0, p < 0.001 MPV (72 h): 8.80  1.01 vs. 10.35  1.69, p < 0.001
(68.9  13.0), p ¼ 0.060 ΔMPV (72-h admission): 0.26  0.89 vs. 0.80  1.30,
p ¼ 0.021
Multivariate Cox proportional hazards of ΔMPV (72-h
admission) (per 1 fL) analysis for 28-d all-cause mortality
Unadjusted 1.90 (1.36–2.66), p < 0.001
Adjusted 1.44 (1.01–2.06), p ¼ 0.044
ROC analysis of MPV as a predictor of mortality.
MPV (admission) AUC: 0.653
ΔMPV (72-h admission) AUC: 0.698
Oh et al27 Cohort Sepsis, n ¼ 120 APACHE II: survivors 15 (11–19) vs. MPV (fL), median (range), survivors vs. nonsurvivors:
(2017), study Survivors, n ¼ 103 nonsurvivors 22 (18–24), p < 0.001 MPV (0 h): 8.3 (7.6–9) vs. 8.8 (8.1–9.6), p ¼ 0.060
good (69 [60–75]) vs. MPV (24 h): 8.4 (7.8–9.4) vs. 9.6 (8.7–10.1), p ¼ 0.009
nonsurvivors, n ¼ 17 MPV (48 h): 8.6 (8.1–9.5) vs. 9.4 (8.9–10.4), p ¼ 0.052
(69 [60–74]), p ¼ 0.928 MPV (72 h): 9 (8.2–9.9) vs. 10 (8.9–10.2), p ¼ 0.149
MPV/platelet ratio (0 h): 3.671 (2.799–6.953) vs. 5.063
(3.803–31.429), p ¼ 0.049
MPV/platelet ratio (24 h): 4.296 (3.274–7.018) vs. 6.897
(3.803–45.556), p ¼ 0.041
MPV/platelet ratio (48 h): 4.913 (3.617–9.513) vs. 5.954
(4.593–14.068), p ¼ 0.357
MPV/platelet ratio (72 h): 6.289 (3.867–10.933) vs. 8.148
(5.64–10.375), p ¼ 0.289
Cox regression analysis for 28-d mortality, HR (95% CI):
MPV (24 h): 1.36 (1.033–1.789), p ¼ 0.028
MPV/platelet ratio (0 h): 1.028 (1.007–1.049), p ¼ 0.008
MPV/platelet ratio (24 h): 1.043 (1.022–1.063), p < 0.001
Cox regression analysis for 28-d mortality after adjusting for
clinically significant variables, HR (95% CI)
MPV/platelet ratio (0 h): 1.04 (1.015–1.066), p ¼ 0.002
MPV/platelet ratio (24 h): 1.032 (1.012–1.054), p ¼ 0.002;
MPV cutoff: 8
Orak et al37 Cohort Sepsis, n ¼ 330 Not reported MPV (fL), mean  SD: survivors 8.19  1.66 vs.
(2018), study Survivors, n ¼ 111 nonsurvivors 8.75  1.82, p ¼ 0.006
good (52.94  20.05) vs.
nonsurvivors, n ¼ 219
(67.78  17.04), p < 0.001
(Continued)

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324 Immature Platelets in Sepsis Thorup et al.

Table 1 (Continued)

Author Study Study population, n age Sepsis-related clinical characteristics Results, platelet indices
(year), design (mean  SD or (mean  SD or median [range])
rating median [range], years)
Other markers of immature platelets (IPF, AIPC)
Muronoi Cohort Sepsis, n ¼ 101 APACHE II: 21.0 (16.0–27.0) Cox regression analysis of IPF (%) at admission as a
et al28 study Survivors, n ¼ 93 SOFA: 6 (4–8) predictor of 28- mortality, HR (95% CI):
(2016), Nonsurvivors, n ¼ 8 Univariate analysis: 1.38 (1.18–1.61), p ¼ 0.0002
good Multivariate analysis: 1.33 (1.11–1.58), p ¼ 0.0007
ROC analysis for predicting 28-d mortality, AUC (95% CI):
IPF: 0.886 (0.754–0.952); APACHE II: 0.857
(0.748–0.924)
Combined IPF and APACHE II: 0.912 (0.790–0.966);
p ¼ 0.0029 (IPF), p ¼ 0.032 (APACHE II)
Koyama Cohort Sepsis, n ¼ 205 Sepsis with severe thrombocytopenia: AIPC (IPF%  platelets) was independently associated with
et al41 study Survivors, n ¼ 183 APACHE II: 29.1  7.3 the development of severe thrombocytopenia, OR (95% CI)
(2018), Nonsurvivors, n ¼ 22 SOFA: 1v1 (7–13) AIPC (day 3): 0.49 (0.35–0.66), p < 0.0001
good Sepsis with severe AIPC (day 5): 0.59 (0.45–0.75), p < 0.0001
thrombocytopenia Multivariate cox regression analysis for predicting 28-d
(<40  103/μL), mortality, HR (95% CI)
n ¼ 61(68.6  4.4) AIPC (day 3): 0.70 (0.52–0.89), p ¼ 0.0029
AIPC (day 5): 0.68 (49  0.87), p ¼ 0.0012
Decrease in AIPC adjusted for SOFA and APACHE II score
was a significant predictor of 28-d mortality

Abbreviations: AIPC, absolute immature platelet count; APACHE II, Acute Physiology And Chronic Health Evaluation II; AUC, area under the curve; CI,
confidence interval; fL, femtoliter; HR, hazard ratio; IPF, immature platelet fraction; MPV, mean platelet Volume; OR, odds ratio; ROC, receiver

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operating characteristic; SD, standard deviation; SOFA, Sequential Organ Failure Assessment.
Note: admission refers to admission in intensive care unit. Studies that reported MPV are listed in the top of the table, and studies that reported IPF
and AIPC are listed in the bottom.

sepsis and septic shock. As immature platelets are more
hemostatically active than mature platelets, an increased num-
ber of immature platelets might contribute to the formation of
microthrombi and organ failure, increasing risk of severity and
mortality in sepsis.
Four studies investigated the predictive value of imma-
ture platelet markers in septic patients and found immature
platelet markers to be a predictor of mortality.27,28,35,36
Moreover, two studies found increasing immature platelet
markers as a predictor of severe sepsis or septic shock.39,40
However, these findings were not supported by Sadaka et al,
who reported MPV to have no predictive value of mortality in
septic shock.34
Overall mortality varied between studies; the majority of
studies found rather low mortality at 8 to 16%,27,28,34,36,38,41
whereas Sadaka et al reported mortality at 35%30 and three
studies reported mortality rates above 60%.33,35,37 The dif-
ferent results across studies could be because of different
disease severity at baseline indicated by diverse APACHE
(Acute Physiology and Chronic Health Evaluation) scores
across the study populations. This might also explain why
Sadaka et al did not demonstrate immature platelets as a
predictor of mortality in sepsis as they only included patients
with septic shock who all had a high MPV.34 Furthermore,
this suggests that monitoring immature platelet markers
should be initiated early in septic patients. This is supported
by a meta-analysis that investigated MPV as a predictor of
mortality in critically ill patients, which showed that the
prognostic potential of MPV tended to be better in patients
with less severe sepsis than in patients with more severe
sepsis.43 Seven studies measured immature platelets at
different time points and found gradually increasing imma-
ture platelets in septic patients from intensive care unit
admission until death.27,28,31,35,36,38,41 These findings sug-
gest that sequential monitoring of changes in immature
platelets may be informative.
The World Health Organization estimates that sepsis causes
around 6 million deaths each year,44 which is roughly 10% of all
global mortality.45 According to the Third International Con-
sensus Definitions for Sepsis and Septic Shock (Sepsis-3), the
SOFA score is currently the best score monitoring septic
patients, whereas the quick SOFA (qSOFA) score has a higher
prognostic accuracy for in-hospital mortality than the systemic
inflammatory response syndrome (SIRS) criteria.46 However,
the diagnostic values of the qSOFA and SOFA scores are not
perfect, and additional predictors of disease severity and
mortality are still needed in monitoring septic patients.
Markers of immature platelets remain interesting candidates
in this matter and may be used as additional and complemen-
tary markers to already established scores.
Overall, the study objectives and study populations of the
included studies were clearly specified, and the participation
rates in the studies were high. The inclusion criteria of the
studies were similar as 11 studies used the SIRS
criteria27,28,31–36,39,40,42 and two studies used the Sepsis-3
criteria,38,41 whereas Orak et al did not report any sepsis
inclusion criteria.37 The studies determined the exposure
(immature platelets) before outcomes (disease severity, mor-
tality), and the study timeframes were sufficient. Both expo-
sures and outcomes were clearly defined and reliable in the
included studies. However, neither of the studies provided a
sample size justification. Seven studies assessed immature
platelets more than once over time. 27,28,31,35,36,38,41 None of
the studies blinded the exposure to the outcome assessors.
Some potential confounders (e.g., age, gender, platelet count,
APACHE score, SOFA score, Charlson Comorbidity Index) were

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 Immature Platelets in Sepsis Thorup et al. 325

Table 2 Results and characteristics of the included studies that examined immature platelets and disease severity in sepsis

Author Study Study population, n age Sepsis-related clinical characteristics Results, platelet indices
(year), design (mean  SD or (mean  SD or median [range])
rating median [range], years)
MPV
Acikgoz Case– Sepsis, n ¼ 60 Not reported MPV (fL) mean  SD: non-DIC 9.196  1.428 vs. DIC
et al32 control DIC, n ¼ 18 (69  16), vs. 8.887  1.021, p ¼ 0.410
(2012), study non-DIC, n ¼ 42 (62  20)
poor
Guclu Cohort Sepsis n ¼ 145 Severe sepsis with thrombocytopenia, MPV (fl), median (range): nonsevere sepsis 7.0
et al33 study Nonsevere sepsis, n ¼ 57 n ¼ 36 (40.9%), vs. nonsevere sepsis (7.0–8.0) vs. severe sepsis 8.0 (95% CI: 7.0–9.0),
(2013), (62.2  20.1), vs. with thrombocytopenia, n ¼ 13 p ¼ 0.001
good Severe sepsis, n ¼ 88 (22.8%), p ¼ 0.01
(63.1  17.6), p ¼ 0.788
Montero- Cohort Sepsis, n ¼ 37 APACHE II: 19 (9–24) Multiple linear and logistic regression models:
Chacón study Survivors, ¼ 31 Length of stay: 10 d (6.5–17 d) Length of stay, coefficient ΔMPV
et al38 Nonsurvivors, n ¼ 6 Need for vasopressor: 20/37 patients (72-h admission): 0.59, p < 0.001
(2018), Need for assisted mechanical ventila- Need for vasopressor: MPV (0 h): OR: 0.85,
good tion: 20/37 patients p ¼ 0.08; MPV (72 h) OR: 1.35, p ¼ 0.02
Need for assisted mechanical ventilation: MPV
(0 h): OR: 2.50, p ¼ 0.04. MPV (72 h) OR: 2.62,
p ¼ 0.03
Other markers of immature platelets (IPF, reticulated platelets)
Enz Hubert Cohort Sepsis, n ¼ 33 SOFA (admission): sepsis 3 (2–9) vs. IPF (%), mean  SD: nonsevere sepsis 3.6  2.6 vs.
et al39 study Nonsevere sepsis, n ¼ 11 severe sepsis/septic shock 10 (2–17), severe sepsis/septic shock 6.2  3.0, p ¼ 0.03

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(2015), Severe sepsis/septic p ¼ 0.01 ROC analysis estimation of diagnostic accuracy for the
fair/good shock, n ¼ 12 APACHE II (admission): sepsis 12 presence of severe sepsis/septic shock: IPF (%) AUC:
(6–27) vs. severe sepsis/septic shock 0.76 (95% CI: 0.56–0.96), p ¼ 0.04
20 (12–37), p ¼ 0.001 APACHE-II AUC: 0.82 (95% CI: 0.64–1.00), p ¼ 0.01
Park et al40 Cohort Sepsis, n ¼ 215 Not reported IPF (%), median (range): uncomplicated sepsis 4.1
(2016), study Complicated (severe þ shock), (0.8–25.6) vs. Complicated sepsis 5.3 (0.8–37.4),
fair/good n ¼ 151 (66 [20.0–92.0]), vs. p ¼ 0.022
uncomplicated, n ¼ 64 ROC analysis for IPF in the discrimination of
(65 [20.0–90.0]), p ¼ 0.129 complicated septic patients from uncomplicated septic
patients: AUC: 0.599 (95% CI: 0.530–0.665)
Best IPF cutoff > 4.1%; sensitivity: 64.9%; specificity:
53.1%; accuracy: 61.4%
Liu et al42 Cohort Sepsis, n ¼ 89 Not reported Reticulated platelets (%), median (range):
(2017), fair study Severe sepsis, n ¼ 39 Sepsis: 6.7 (5.60–8.25)
(58.23  17.45) Severe sepsis: 10.2 (8.30–12.42)
Septic shock, n ¼ 18 Septic shock: 16.25 (13.93–17.50)
(57.88  17.10)

Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; AUC, area under the curve; CI, confidence interval; DIC, disseminated
intravascular coagulation; fL, femtoliter; HR, hazard ratio; IPF, immature platelet fraction; MPV, mean platelet Volume; OR, odds ratio; ROC, receiver
operating characteristic; SOFA, Sequential Organ Failure Assessment.
Note: admission refers to admission in intensive care unit. Studies that reported MPV are listed in the top of the table, and studies that reported IPF
and reticulated platelets are listed in the bottom.

measured and/or adjusted for in nine studies.27,28,33–36,38,39,41 Funding

However, some limitations must be considered; the study No funding was provided for this study.
populations were, in general, small, and due to considerable
heterogeneity in study design and measured biomarkers, it Conflicts of Interest
was not possible to perform a quantitative analysis. None of the authors has any conflicts of interest regarding
this manuscript.

Conclusion
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This systematic review suggests an association of increased
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septic patients. Markers of immature platelets might be used
together with SOFA and qSOFA in monitoring sepsis patients.
Larger clinical studies are needed to evaluate whether
markers of immature platelets could be used as predictive
markers of mortality and disease severity in patients with
sepsis and septic shock.
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