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The behavior of Mean Platelet Volume in Sepsis in critical patients with and without sepsis

Pablo Andrés Vélez 1. Lucy Baldeón R 2,3 Jorge Luis Vélez-Paez1,2.
Available from: http://dx.doi.org/10.21931/RB/2021.06.02.22 (registering DOI)
ABSTRACT
The
mean platelet volume is an anatomical biomarker that has shown its usefulness
in various cardiovascular and metabolic pathologies; in sepsis, it has been
positioning itself as an indicator of mortality, easily accessible and
immediately applicable when reported in the routine blood count. This study demonstrates
the mean platelet volume's biological behavior in critical patients with sepsis
compared with non-septic patients. An observational, longitudinal, prospective,
monocentric cohort study was conducted in 250 patients treated at the intensive
care unit of the Pablo Arturo Suárez Hospital, Quito- Ecuador, from January 2019
January 2020. A group of patients with sepsis (n = 125) and without infectious
pathologies (n = 125) were studied. The inclusion criteria were patients over
18 years of age of both genders, diagnosed with sepsis or septic shock using
SEPSIS 3 criteria, and patients without septic pathology. The mean platelet
volume (MPV) of days 1, 2, and 3 were studied. Septic patients had a mean
APACHE (18.74 SD 9.52) higher than the non-septic ones (11.93 SD 7.01) (p = <
0.000). The MPV was consistently higher in patients with sepsis than non-septic
patients, but it reached statistical significance on day 3 (9.13 SD 1.55 vs.
8.66 SD 1.34, p=0.042). The MPV on day 3 presented a significant area under the
curve (AUC =0.580) (CI. 0.500-0.661), where the cut-off point according to
Youden's index was positive for sepsis if MPV≥ 9.85 femtoliter (fL) with OR=3.30
and p-value= 0.005. Likewise, lactate on admission showed an AUC of 0.625 (CI. 0.555-0.694),
with a cut-off point ≥of 1.15 mmol / L, OR=2.51, and p=0.007. Age and
hypertension did not show a multivariate relationship with the presence of
sepsis. It was shown that MPV is higher in patients with sepsis compared to
non-septic ones. This observation reaches significance on day 3. Additionally,
elevated lactate at admission was also associated with a septic state. On the
other hand, platelet count did not show the expected behavior.
Keywords.
Mean Platelet Volume, sepsis, mortality.
INTRODUCTION
Sepsis is defined as the unregulated response of the body to an
infectious disease. Nowadays, this pathology is one of the main reasons for
admission to the intensive care unit. There are still few strategies described
to face it; however, it is known that an early antibiotic therapy, together
with the adequate support of organ failure, are measures that reduce its
pathophysiological impact and, therefore, its mortality 1.
Various biochemical markers (procalcitonin, C-reactive protein, and
interleukin 6) and prognostic scales such as APACHE II and SOFA can determine
this entity's severity. However, they are not always available in the daily
clinical requirement, or their high economic value does not allow their routine
use in low-income countries. Therefore, a new biomarker, such as the mean platelet
volume (MPV), could become a practical and easily accessible tool to predict
septic states.
Platelets are cell fragments from megakaryocytes, which are essential
for blood clotting. The MPV is the measurement of platelet size and has an
inverse relationship with the number of these; it is also an indicator of
platelet activation 2, 3.
There is no fixed cut-off point for MPV because the values change and
vary from population to population. They also vary according to the technique
used to measure it (impedance or laser scattering), the type of anticoagulant
used (EDTA or citrate), and the test time. However, it is established that
values greater than 9.5 femtoliters (fL) are correlated with
diseases related to inflammation, endothelial dysfunction, and pro-thrombotic
states 1. Additionally, increased MPV has been reported to be associated
with poor prognosis in patients with metabolic syndrome, diabetes mellitus,
cardiovascular diseases, pulmonary embolism, smoking, and immuno-inflammatory
diseases 2, 4, 5.
Van der Lelie et al. in 1983 reported that MPV increases in invasive
infectious septic disease, but not in local infection and that this biomarker
normalizes when controlling the disease 1. There are no studies that
demonstrate that platelet size is higher in sepsis compared to other critical
pathologies. Therefore, this study's objective is to demonstrate that mean
platelet volume (MPV) is higher in critical patients with sepsis than
non-septic patients.
MATERIALS AND METHODS
An observational, longitudinal, prospective, monocentric cohort study
was conducted. The sample consisted of 250 patients treated in the intensive
care unit of the Pablo Arturo Suárez Hospital in Quito, Ecuador, in the period
January 2019 - January 2020. The sample consisted of two groups, patients with
sepsis (n = 125) and patients with other non-infectious pathologies (n = 125).
The inclusion criteria were patients of both genders, older than 18 years with
a diagnosis of sepsis or septic shock who met the criteria of SEPSIS 3 [6] and
patients with non-septic pathology such as preeclampsia, eclampsia, HELLP
syndrome, acute pancreatitis, or cardiovascular diseases. Patients with
neoplasms or acute bleeding states that can alter MPV were excluded. Patient
data were coded, and the results of the routine tests requested were documented
in the clinical history for the required variables (lactate, MPV, leukocyte
count, platelet count, and procalcitonin) on days 1, 2, 3. The difference in
MPV between patients with and without sepsis and the value that determined the
progression to septic states was evaluated. The MPV was measured in a femtoliter
by impedance in a Siemens machine, in venous blood collected in EDTA tubes. The data was coded and entered into a database, to
which only the researcher has access. Analyzes
were carried out with R and SPSS version 22 software. Qualitative variables
were reported using tables and graphs representing absolute and relative
values. Quantitative variables were represented as measures of central tendency
and variability.
Inferential statistics were performed to compare the clinical
characteristics and laboratory parameters between the sepsis and non-sepsis
groups (bivariate analyzes). For categorical variables, the chi-square test was
applied to compare proportions. For the analysis of quantitative variables, the
assumption of normality was first verified. Thus, for variables that presented
normality, a t-test was used. For the variables that do not meet the normality
criteria, Mann Whitney test was used. Using the ROC Curve, the cut-off points
for MPV and lactate significant in the bivariate analysis were determined,
which were expressed as area under the curve (AUC). Besides, sensitivity, specificity,
positive predictive value (PPV), negative predictive value (NPV), and Odds
Ratio (OR) were determined for each cut-off point. A multivariate logistic
regression analysis was performed to determine the relationship of sepsis using
the OR. Statistical significance was established for the value of p <0.05;
the OR was considered significant, observing the limits of the 95% confidence
interval. It was considered a risk factor if the lower limit was more
significant than one.
ETHICAL CONSIDERATIONS
Researchers have followed the bioethical principles of human research.
The data were obtained from medical records (secondary data), the
identification of patients will not be disclosed, and they have been recorded
to avoid their recognition. The authors obtained the authorization for
publication.
RESULTS
The average age of patients with
sepsis was 60.73 years, and 45.21 years of patients without sepsis. Differences
in age between groups showed significance (p=0.000). In gender, no significant
differences were observed; the predominant ethnic group was mestizo in sepsis and
the non-infectious group (93.60% and 95.20%, respectively), without significant
differences. Significant differences were observed for APACHE (p= 0.000), in
patients with sepsis (18.74 points) and without sepsis (11.93 points). High blood pressure (HBP) presented
significant differences between the groups (p= 0.011). The percentage of non-survivors was 26.40% in the
sepsis group and 5.60% in the non-sepsis group, showing significance between
groups (p= 0.000). The patients who required mechanical ventilation were 76.80%
in the group of patients with sepsis and 52.80% in the patients without sepsis,
showing significant differences (p=0.000).
Patients who required sedation were 64.23% in the group sepsis and
35.54% in the group without sepsis, showing significant differences (p=0.000).
The average days of hospitalization were 6.96 days in the sepsis group compared
with 4.12 days without the sepsis group (p= 0.000) (see table 1).

Table 1. Distribution of demographic and clinical characteristics by
sepsis and non-sepsis group.
When comparing laboratory parameters
such as MPV in the sepsis (3 9.13 fL) and non-sepsis (8.66 fL) groups,
significant differences were observed on day 3 (p= 0.042) and at discharge (p=0.035).
Differences were also observed in leukocyte values on day 1 (p=0.007) and on
day 3 (p= 0.001). Mean lactate in the sepsis group was 2.85 mmol/L and 2.05
mmol/L in the non-sepsis group, showing significant differences (p=0.005). The
mean of procalcitonin in the sepsis group was 26.21 ng/ml and 3.37 ng/ml in the
non-sepsis group showing significant differences (p-value 0.000) (see table 2)

Table 2. Comparison of laboratory parameters by sepsis and non-sepsis
group.
Also, a graph was made to compare MPV values in survivors and
non-survivors patients with and without sepsis, in whom platelet size
superiority is evidenced in all measurements. (Figure 1)

Figure 1. MPV kinetics from day 1 to day 3 in septic patients that
survive and no-survive.
For the variables MPV on day 3, at
discharge, and lactate at admission, which were significant in comparing the
sepsis and non-sepsis groups, the cut-off point was determined using the ROC
curve.
The MPV at day 3 presented a
significant area under the curve (AUC) of 0.580 (CI 0.500-0.661), where the
cut-off point according to Youden's index was positive for sepsis if MPV ≥9.85
fL. Similarly, lactate on admission was significant with AUC 0.625 (CI
0.555-0.694), with cut-off points 1.15 and 1.25 to predict sepsis. Of these
points, the one that showed relevance in the statistical tests and was positive
for sepsis was lactate ≥1.15 mmol / L. (see Figure 2.)

Figure 2. ROC curve for MPV at day 3 and
lactate on admission to estimate sepsis.
The following values of sensitivity
and specificity for sepsis were observed for the cut-off points determined by
the ROC curve. MPV on day 3 presented a sensitivity of 30.48%, a specificity of
88.76%, PPV of 76.20%, NPV of 52.00%, the OR was significant for the cut-off
point. Patients with MPV at day 3 ≥9.85 fL are 3.46 times more likely to
present sepsis than those with values lower than this cut-off point.
Lactate on day 3 presented a sensitivity
of 80, 80%, a specificity of 42, 40%, PPV of 58, 40%, NPV of 68, 80%, the OR
was significant for the cut-off point. Patients with lactate on admission ≥1,
15 mmol/L are 3.10 times more likely to present sepsis than those with values
lower than this cut-off point.

Table 3. Sepsis predictor parameters
by cut-off points for MPV at day 3 and lactate on admission.
Logistic regression was used to
determine the multivariate relationship of sepsis with the cut-off points of
the MPV on day 3 and lactate at admission and the clinical characteristics of
age (median 55 years) and comorbidity due to HBP, which were significant in the
bivariate analysis.
The results showed that
the MPV (≥9.85 fL) on day 3 (p = 0.005) and lactate at admission ≥1.15 mmol /L
presented a multivariate relationship with sepsis. Patients with MPV on day 3
≥9.85 fL are 3.30 times more likely to present sepsis, while patients with
lactate on admission ≥1.15 mmol / L are 2.51 times more likely to present
sepsis. Age and HBP did not show a relationship with the presence of sepsis.

Table 4. A multivariate relationship
for sepsis.
DISCUSSION
This study shows that platelet MPV is higher
in critically ill patients with sepsis than non-septic patients. Similarly, it
was observed that a higher lactate value on admission to intensive care was
related to progression to septic states, establishing significant cut-off
points and ORs for both variables.
In
systemic processes with a high probability of organic impact, the coagulation
system is frequently activated 6,7. It has been shown that
coagulation and platelet activation occur in early stages in pathologies with a
different pathophysiological context, such as sepsis, ischemic heart disease,
brain infarction, preeclampsia, and eclampsia 1, 4, 8.
The
increase in platelet size and decrease in its count is due to pro-inflammatory
cytokines, thrombopoietin, and other substances that stimulate the massive
production of spherical and poorly functional young platelets due to the action
of spherical and poorly functional young platelets to the severity of the
septic shock. All this process leads to the formation of thrombi, almost always
culminating in unfavorable outcomes 9, 10
Several
studies have demonstrated the predictive utility of MPV in sepsis 9, 11-24
however;, there is little reported bibliography that compares platelet kinetics
in critically ill patients with and without sepsis, a critical situation to be
demonstrated since several non-infectious diseases can also potentially
increase platelet size.
Our findings indicate that the platelet is more significant in patients
with sepsis than those without sepsis, but this difference is significant at
day 3, marking a significant cut-off point of ≥9.85 fL. Simultaneously, we observed statistical
significance in the ROC curve with relevant AUC for lactate at admission with a
cut-off point of ≥1.15 mmol / L, which significantly marked septic states'
progression. Although no bibliography
contrasts these results in patients without sepsis, in patients with sepsis,
some studies, for example, two large meta-analyses 25,26 show that
the MPV increases at 72 hours, with cut-off points that differ in these studies
and is associated with septic states and even higher mortality. When the host's
inflammatory response has not been controlled, it has a strong impact, inducing
greater clinical severity and unfavorable outcomes.
Although
age and HBP were significant variables in the bivariate analysis, they did not
present a multivariate relationship, meaning that they do not intervene in the
outcome of presenting or not presenting septic states. Something
striking was that the platelet count, which is a point to be evaluated in
sepsis-induced multi-organ dysfunction, which is more severe than the lower number
of platelets, was not significantly different from non-septic pathologies. This
observation was unexpected and can be explained by the enrollment of patients
with hypertensive pathology of pregnancy (preeclampsia, eclampsia, and HELLP)
in the non-septic group; these pathologies also decrease the platelet count due
to a different pathophysiological mechanism 27, 28.
Our findings' relevance lies in the fact that we were
able to show significant differences in MPV between patients with and without
sepsis. This study is the basis for the execution of future studies
investigating this biomarker in specific populations; Furthermore, taking into
account that this biomarker is routinely reported in the common blood count, it
makes it desirable for its immediate applicability.
Among the study's limitations, we
can name the potential increase in MPV when using EDTA, which generates an
increase in size not attributable to the underlying pathology since it is a
post-analytical phenomenon and enhanced by the delay in the processing of the
sample. Taking into account that this phenomenon could affect both groups
(septic and non-septic); and that K3 tubes were also used, which preserve
platelet morphology, and that the processing time was less than 30 minutes (samples
from intensive care unit), we consider that this bias plays a minor role in our
results. Agustino et al. described similar findings and gave little relevance
to this bias in their studies that compared EDTA with citrate 29.
Another essential point to take into
account is that, in our work, a high MPV was associated with septic states, but
there is no generalized cut-off point reported. Perhaps ethnicity is an
important variable to consider since the values reported in eastern countries
show MPV cut-off points higher than 11 fL 30,31,32 compared to
western countries like ours, where we obtained a cut-off point somewhat lower
but no less significant. Besides, our study was carried out in the city of
Quito at 2800 meters above sea level. Evidence shows that at high altitudes,
hypoxia in non-acclimatized people could generate hyperreactivity and more
significant platelet aggregation in response to adenosine diphosphate (ADP),
which could also increase other cytometric indicators such as MPV, which
indicates the need for more studies to clarify this theory 33,34.
CONCLUSION
This study demonstrated that the
mean platelet volume is higher in patients with sepsis than in non-septic
patients, findings that are accentuated and become significant on day 3.
Likewise, lactate measured at the admission time is a biomarker whose elevation
is associated with septic states. On the contrary, the platelet count did not
show the expected behavior.
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Received: 10 November 2020
Accepted: 15 February 2021
Pablo Andrés Vélez 1. Lucy Baldeón R 2,3 Jorge Luis
Vélez-Paez1,2.
1. Servicio
de Medicina Crítica-Hospital Pablo Arturo Suárez.
2. Facultad
de Ciencias Médicas-Universidad Central del Ecuador.
3.
Instituto de Investigación en
Biomedicina Universidad Central del Ecuador.
ORCID
Pablo Andrés Vélez Páez 0000-0002-6392-3895 Correo: pavelez@uce.edu.ec
Jorge Luis Vélez Páez https://orcid.org/0000-0002-6956-4475 Correo: jlvelez@uce.edu.ec
Lucy
Baldeón R. https://orcid.org/0000-0002-0447-0136 Correo:
lybaldeon@uce.edu.ec
Correspondece: Dr.
Pablo Andrés Vélez Páez Facultad de Ciencias Médicas – Universidad Central del
Ecuador Iquique N14-121 y Sodiro – Itchimbía, El Dorado. Teléfonos: (593-02)
2528 690 Correo electrónico: pavelez@uce.edu.ec