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To cite this article: Andrea Aguglia, Andrea Amerio, Pietro Asaro, Matilde Caprino, Claudia
Conigliaro, Gabriele Giacomini, Valentina Maria Parisi, Alice Trabucco, Mario Amore & Gianluca
Serafini (2020): High-lethality of suicide attempts associated with platelet to lymphocyte ratio and
mean platelet volume in psychiatric inpatient setting, The World Journal of Biological Psychiatry,
DOI: 10.1080/15622975.2020.1761033
Article views: 10
Authors: Andrea Aguglia1,2*, Andrea Amerio1,2, Pietro Asaro1,2, Matilde Caprino1,2, Claudia
Conigliaro1,2, Gabriele Giacomini1,2, Valentina Maria Parisi1,2, Alice Trabucco1,2, Mario Amore1,2,
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Gianluca Serafini1,2
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Affiliation:
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Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics Maternal and Child Health,
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University of Genoa, Section of Psychiatry, Genoa, Italy.
2
IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
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*
Corresponding author:
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Address: Section of Psychiatry, IRCCS Ospedale Policlinico San Martino - Largo Rosanna Benzi
Email: andrea.aguglia@unito.it
Telephone number: 0039 010 555 7232; Fax number: 0039 010 555 6716
Abstract
Objectives: A wide range of potential psychosocial, biological, genetic and environmental factors
interact with each other in determining suicidal behaviors. The aim of this study was to evaluate
several biological parameters referred to the complete blood count values in 259 suicide attempters
(SA) and 164 non-suicide attempters (control group), according to the lethality of suicidal behavior.
Methods: After attempting suicide, subjects were admitted to the emergency ward of the IRCCS
Ospedale Policlinico San Martino and later to the section of Psychiatry from 1st August 2013 to
31st July 2018. Socio-demographic and clinical characteristics as well as blood cell were collected.
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Results: Individuals with high-lethality suicide attempts had a higher number of neutrophil, mean
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platelet volume, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lower number of
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lymphocyte relative to both those with low-lethality suicide attempts and control group. Afer
regression analysis, only the mean platelet volume and platelet to lymphocyte ratio resulted
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associated with high-lethality suicide attempt (HLSA).
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Conclusions: Our findings provide a potential and useful peripheral biological marker able to help
clinicians in understanding the complex phenomenon of suicide. However, further studies are
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Suicide is the act of taking one's own life voluntarily and intentionally. As reported by the
World Health Organization (WHO), suicide is the second leading cause of death among 15-29 year-
old and every year around 800.000 people die by suicide. Suicide rates vary within and between
countries, with as much as a ten-times difference between regions; this variation is partly correlated
with economic status and cultural differences (WHO, 2019). Despite an increased understanding of
risk factors and mechanisms, the burden of suicide keeps weighing on multiple sectors of society,
including health, education, labor, business, justice, politics, and the media.
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A wide range of potential psychosocial, biological, genetic and environmental factors interact
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with each other in determining suicidal behaviors (Christodoulou et al., 2012; Rumble et al., 2018).
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Social isolation and low social support, unemployment, mental disorders (in particular bipolar
altered neurotransmission, are only few of the main factors that could promote the transition from
suicide ideation to suicide attempts (Pompili et al., 2012, 2013; Aguglia et al., 2016; Turecki and
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Brent, 2016; Lutz et al., 2017; Aguglia et al., 2019a; Solano et al., 2019).
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Evidence from the current literature suggested that there are biological differences – such as
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dyslipidemia, neuroendocrine, and blood changes - between those who commit high-lethality
suicide attempts and those who commit low-lethality suicide attempts (Pompili et al., 2017; Daray
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et al., 2018; Ludwig and Dwivedi, 2018; Aguglia et al., 2019a,b). Furthermore, indices of low
serotonin turnover have been associated with different nosological entities such as poor impulse
suicidal behaviors (Asberg et al., 2016; Sokolowski et al., 2016; Lutz et al., 2017). On one hand,
this correlation may be explained by fewer noradrenergic neurons and glutamate transporters in the
locus coeruleus with a reduction of serotonin transporters, on the other hand by an increase of
tryptophan hydroxylase 2 with more serotonin neurons and negative consequences on serotonin
function and neurotransmission (Turecki and Brent, 2016; Lutz et al., 2017). Plasma platelets
contain serotonin and they may synthesize, release and reuptake serotonin, similarly to neurons of
the central nervous system (Antypa et al., 2013; Williams, 2013). Stressful life events may increase
blood catecholamines leading to an increase of either mean platelet volume (MPV) and platelet
activity through a cascade event (Thompson et al., 1982). There are evidence showing alterations in
platelet serotonin levels in patients who have attempted suicide compared to controls (Alvarez et al.,
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1999; Askenazy et al., 2000). Moreover, platelet 5-HT content has been shown to be sensitive to
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different pharmacological treatments acting on the 5-HT system (e.g. selective and non-selective
serotonin reuptake inhibitors) (Galan et al., 2009). The neutrophil-lymphocyte ratio (NLR) might be
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considered an interesting biological parameter that can be combined with neuroinflammation
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markers . It was found that NLR changes in major depressive disorder (MDD) are associated with
several factors including suicidal behavior, chronic stress, and impulsiveness (Ekinci and Ekinci,
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2017). A recent study published by Orum and colleagues examined the complete blood count
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(CBC) values in three groups of 38 subjects divided into violent suicide attempts (VSAs), non-
violent suicide attempts (NVSAs), and controls. The VSA group showed a decrease of platelet
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levels (PLT) and an increase of MPV and NLR (Orum et al., 2018a).
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The aim of the present study is to evaluate several biological parameters referred to the
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complete blood count (CBC) values in 259 suicide attempters (SA) and 164 non-suicide attempters
(NSA), according to the lethality of suicidal behavior. Our hypothesis is based on the existence of a
Sample
The present study was conducted in a sample of inpatients who were recruited from 1 st
January 2014 to 31st June 2019 at the Section of Psychiatry, Department of Neuroscience,
Silverman's operative definition of “suicide attempt” was used in this study, i.e. a kind of
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suicide-related behavior, classified as a suicidal act and characterized by self-inflicted, potentially
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injurious behavior with non-fatal outcome for which there is evidence - either explicit or implicit -
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of intent to die (Silverman et al., 2007). Moreover, our definition involved the presence of a lethal
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intent that may be of varying intensity but needs to be present in the decision to carry out the
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suicidal act (Pompili et al., 2015). The following inclusion criteria for the present study were
considered: (a) hospitalization in our emergency psychiatric unit for a suicide attempt; (b) aged
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more than 18 years old; (c) acceptance to participate in the study by signing a written informed
consent. The exclusion criteria consisted of: (a) pregnancy or having just given birth; (b) severe
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medical comorbidities or any other conditions that could affect the measured parameters, including
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current substances use disorder; (c) having a positive history of acute neurological injury, such as
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severe neurological conditions; d) the refusal or inability to provide a valid consent prior the
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A control group was included and represented by admitting patients without a history of
current and/or lifetime suicide attempt (inclusion and exclusion criteria were applied similarly to
suicide-attempter group.
All participants received a detailed explanation of the study design and a written informed
consent was obtained from all respondents, according to the guidelines provided in the current
version of the Declaration of Helsinki. The study design was approved by the local Ethical Review
Board.
Clinical evaluations were carried out by expert clinicians and carefully reviewed by a senior
psychiatrist (with more than ten years of clinical experience in inpatient clinical setting). If patients
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had more than one psychiatric diagnosis, the principal diagnosis was recorded. Socio-demographic
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(e.g., age, gender, marital and occupational status, education level) and clinical (psychiatric
diagnosis, suicide method) characteristics were investigated through the standardized clinical chart
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and lifetime computerized medical record used in our Psychiatric Unit. All available information
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were cross-referred.
Patients with suicide attempts were immediately brought to the emergency hospital where a
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consultation psychiatrist was constantly present to evaluate either the individual clinical and
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psychopathological conditions. Patient data were written to the hospital registration system and the
first evaluation is usually sufficient to determine the patient’s suicide lethality (high or low).
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Furthermore, blood test was the first procedure in individuals presenting with suicide attempts as
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they included count of neutrophil, lymphocyte, platelets, MPV, red blood cell (RBC), hemoglobin,
hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean
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corpuscular hemoglobin concentration (MCHC), red blood cell distribution width - coefficient of
variation (RDW). Blood samples were drawn during the access in the Emergency department and
examined in the laboratory section of IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Data
Furthermore, the term “suicidal lethality” has not yet been defined outside health literature. In
our study, we adopted the concept of lethality as defined by Shneidman's (1996) and Joiner's (2007)
criteria also used in recently published reports (Aguglia et al., 2019a,b), as the term “suicidal
lethality” has not yet been defined outside health literature. Within suicide lethality, the only
individual intent is to perish as a result of the lethality of self-inflicted actions. Methods of suicide
attempt were dichotomized in terms of lethality. Therefore, a high-lethality suicide attempt was
defined as a suicide attempt that warranted hospitalization for at least 24 h and either treatment in a
specialized unit (including intensive care unit, hyperbaric unit, or burn unit), surgery under general
anesthesia, or extensive medical treatment (beyond gastric lavage, activated charcoal, or routine
neurological observations), including antidotes for drug overdoses, telemetry, or repeated tests or
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investigations. Conversely, a low-lethality suicide attempt was defined as a suicide attempt that did
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not meet these criteria (Aguglia et al., 2019a,b).
Statistical Analysis
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We carried out all the statistical analyses using the Statistical Package for Social Sciences
(IBM Corp., Armonk, NY, USA) for Windows 23.0 and the significance was set at p<.05 (two-
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tailed).
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frequency and percentage for categorical variables while mean and standard deviation (SD) were
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used for continuous variables. Normal distribution was assessed using Kolmogorov-Smirnov test.
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Firstly, the sample was divided into two subgroups based on the presence/absence of current
Subsequently, the subgroup of patients admitted for a current suicide attempt was divided
according to the lethality of the suicide attempt: therefore, we identified HLSA and LLSA in the
second part of our analysis and we used the psychiatric population with no current and/or lifetime
suicide attempt as control group. In order to analyze differences between these three subgroups, we
value of our significant differences to bivariate analyses (we reported only the main findings).
Lastly, a multinomial regression model was performed to assess the variables associated with
the lethality of suicide attempt (dependent variable) and each of the other independent variables
previously found associated in the statistical analyses, correcting for socio-demographic and clinical
RESULTS
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We excluded fifty-eight patients because of severe medical comorbidities that could affect
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blood cell and thirty-five patients for missing data. Four hundred twenty-three inpatients were
enrolled in the present study, of which 259 (61.2%) committed a suicide attempt prior to the
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hospitalization. The control group was composed of 164 psychiatric inpatients with no current
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and/or lifetime suicide attempts.
The mean (±SD) age of the sample was 49.93 (±18.63) and three hundred and seventeen
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(74.9%) were females; 49.4% (N=209) of the sample was represented by single and 25.8% (N=109)
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was in active working status. More than thirty percent (31.9%) of the sample had bipolar disorder,
10.9% schizophrenia, and 29.8% major depressive disorder. There were no statistically significant
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According to the definition of lethality of suicide attempt, we identified 86 (33.2%) and 173
(66.8%) individuals admitted to our psychiatric unit for high- and low-lethality suicide attempts,
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respectively. Drug intoxication (N=164, 63.3%) was the most prevalent suicide method which was
Laboratory analyses associated with high-lethality suicide attempts are displayed in Table 4.
both with LLSA and psychiatric control group. Furthermore, a higher mean platelet volume
110.94±50.63, p<.001) were significantly associated with HLSA compared to the other two
subgroups. Other clinical variables were not significantly associated with high-lethality suicide
ROC curve, performed to assess the diagnostic value of significant findings at bivariate
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analyses, is shown in Figure 1. The area under ROC curve of platelet-lymphocyte ratio was 0.725,
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of neutrophil-lymphocyte ratio was 0.746 and of mean platelet volume was 0.718.
When the multinomial regression was performed, only the mean platelet volume and the
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platelet-lymphocyte ratio resulted associated with predicted HLSA (Table 5).
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DISCUSSION
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causes. In the last decades, several studies focused on neuroanatomic, genetics, and molecular
correlates of suicidal behavior, as summarized in recent reports upon this topic (Lutz et al., 2017).
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The present study tested the association between cell blood count in a relatively large sample
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of psychiatric inpatients, comparing high- vs. low-lethality suicide attempts. A control group of
psychiatric inpatients who never attempted suicide was included in our analyses.
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Many biological factors have been proposed as possible contributors to suicide risk. In
particular, evidence from the current literature underlined the importance of serotonin and
noradrenergic system dysfunction (such as low serotonin level in the brain stem and plasma,
reduced 5-HT2A receptor activity of platelets, decreased binding to the serotonin transporter in the
prefrontal cortex, reduced levels of norepinephrine and metabolites at the level urinary, plasma and
liquor, and reduced ability to bind β-adrenergic receptors in the frontal cortex), hyper-activation of
the hypothalamic-pituitary-adrenal axis (e.g. early-life adversity causing behavioral abnormalities
with increased anxiety and impulsivity and modifications of cognitive abilities and social
integration), reduced expression of neurotrophic factors (e.g. brain derived neurotrophic factor).
Nowadays, the most blamed mechanism is the reduction of brain serotonergic activity which
is associated with the increased risk of attempting suicide, accompanied by the up-regulation of
some serotonergic post-synaptic receptors such as 5-HT1A and 5-HT2A (Arango et al., 1990).
Studies that tried to differentiate changes associated with depression or suicide, identified small
changes regarding serotonin transporter and receptor expression (5-HT1A) and serotonin genotypes
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and expression patterns specifically linked to suicidality (Brezo et al., 2010; Miller et al., 2013;
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Sullivan et al., 2015), respectively.
Changes in lipid profile (e.g. total cholesterol decrease) have been widely investigated as
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possible peripheral biological markers for suicidal behavior. Available evidence suggested that
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alterations of membrane lipid raft structure and a consequently increased of n-6:n-3 polyunsatured
fatty acid ratio might promote a reduction of serotonin transmission and neuro-inflammation
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(Pompili et al., 2017; Daray et al., 2018; Mathew et al., 2018; Aguglia et al., 2019a).
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Other potential peripheral biological markers for suicidal behavior are blood cells containing
serotonin, particularly plasma platelets (Mathew et al., 2018). They may synthesize, release and
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reuptake serotonin similarly to neurons in the central nervous system. Sharing a similar receptor and
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serotonin second-messenger system, platelet serotonin could be considered a reliable index for
presynaptic serotonin activity (Plein and Berk, 2001), although its relation to central serotonergic
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function remains not completely clarified (Antypa et al., 2013; Williams, 2013). Pandey and
colleagues confirmed this hypothesis reporting more 5-HT2A binding and more mRNA in the pre-
frontal cortex according to post-mortem brain studies of subjects dies by suicide (Pandey et al.,
2002).
To the best of our knowledge, no studies investigated directly the association between blood
cell count and lethality of suicide attempts. At bivariate statistical analysis, individuals with HLSA
were significantly associated with higher number of neutrophils, mean platelet volume, neutrophil-
lymphocyte ratio, plateletlymphocyte ratio, and lower number of lymphocyte compared both
patients with LLSA and controls. Only mean platelet volume and platelet to lymphocyte ratio
leading mechanisms evoked as potential biological pathways underlying suicidal behavior. With
regard to the neuro-inflammation pathway, white blood cells, particularly neutrophils, are
considered active inflammatory mediators for their phagocytic and apoptotic activities, while
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lymphocytes represent the regulatory component of the immune system. Data from the existing
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literature suggested NLR as a new useful and cheap biological marker of chronic inflammation and
precursor to measure clinical outcomes being less influenced by confounding factors compared to
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cytokines (IL-6, TNF-α and c-reactive protein) (Cakir et al., 2015; Ekinci and Ekinci, 2017). Recent
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studies also showed an association between NLR changes and bipolar disorder, chronic distress,
depression, impulsivity traits, all factors that may enhance suicide risk (Han-Almis and Aksoy,
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Our results are in line with recent clinical trials that demonstrated a relation between NLR and
suicidal tendency in depressed patients (Ekinci and Ekinci, 2017). More recently, Orum and
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colleagues (2018a) showed in a small sample a significant association between violent suicide
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Mean platelet volume has been considered as a marker of platelet activity since long time. We
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found a significant association between high-lethality suicide attempts and increased mean platelet
volume compared to low-lethality suicide attempts and psychiatric controls with no lifetime suicide
attempts. Increased mean platelet volume in HLSA may be related to increased platelet activation
due to sympathetic system activation. Furthermore, in LLSA lower platelet levels were found,
presumably due to the inverse relation between MPV and platelet count. Considering platelets and
lymphocytes, PLR may predict the inflammatory response. In this study, we found an increased
PLR in HLSA compared to LLSA and controls: platelet activation is mediated by inflammatory
factors such as serotonin, dopamine, glutamate, cytokines and P-selectin (Mazza et al, 2019). These
pathways play a very important role on the pathophysiology of severe psychiatric disorders, such as
mood-disorders (BD and MDD) and schizophrenia (Mazza et al., 2018), psychiatric conditions
which are more likely to be linked to high lethality suicide attempts, also according to the socio-
demographic characteristics of our sample. Thus, we can assume that increased neuroinflammation
is the common pathway in HLSA, while a lower neuroinflammatory activation is common to LLSA
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This finding is in accordance with a previous study conducted on a small sample of patients
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admitted to a psychiatric unit for a violent suicide attempt (Orum et al., 2018a).
Aggressiveness and impulsiveness of suicidal behavior were associated with serotonin content
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and the total number of 5-HT2A receptor on platelets surface (Spreux-Varoquaux et al., 2001).
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Therefore, a higher MPV could cause an increase of platelet activation 5-HT2A receptor mediated -
partly influenced by stressing factors - with the release of aggregation mediators through
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sympathetic system activation (Mann and Arango, 1992). Therefore, greater platelet 5-HT2A
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indirect measure of signal transduction could explain the correlation between platelets and suicide
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attempts, including high lethality or violent suicide method which was used (Malone et al., 2007). A
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recent study showed significantly lower levels of platelet serotonin in suicide attempters compared
respectively. Low platelet monoamine oxidase B activity, a proxy of low central serotonergic
function, was associated with interpersonal violence in male suicide attempters but not in females
(Jokinen et al., 2018). Lastly, no significant decreased platelet count was observed in patients with
suicidal behavior, even with a reduction in platelet 5-HT content compatible with platelet up-
One of the most relevant strengths of this study was the recruitment of a large sample
including a control group on the main outcome. The psychiatric controls were well-matched in
terms of socio-demographic characteristics but alsoand psychiatric diagnoses. However, this study
needs to be interpreted in light of the following limitations/caveats. First, the cross-sectional design
of the study does not allow the correct distinction between cause/effect, limiting the generalization
of our findings. The recruited sample is also derived by a single psychiatric inpatient center and
treated in a specialized university clinic setting; any information about lifetime suicide attempts of
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participants has been not available according to our data. Moreover, since no evaluation scale is
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validated in Italian language, we preferred to rely upon Shneidman's and Joiner's definitions of
lethality, although the use of a specific instrument may provide with adjunctive relevant data. The
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use of clinical diagnostic technique rather than a structured one, such as M.I.N.I. or SCID-5, is
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another potential limitation of this study. Lastly, all blood analyzes were performed following
CONCLUSION
According to the existing literature, after multivariate analysis mean platelet volume and
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platelet to lymphocyte ratio were the only variables that remained significantly associated with
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high-lethality suicide attempts. Despite the mentioned shortcomings, our study extends prior
knowledge providing novel information in the assessment of patients who are engaging in suicidal
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behavior. Our findings provide further potential and useful peripheral biological markers to help
clinicians in understanding the complex phenomenon of suicide. Therefore, we suggest that cell
blood count might be considered a useful and feasible method to assess of suicidal behavior in the
clinical practice. Further studies are needed to replicate our findings in order to provide clinical
Conflict of Interest Statement: The authors declare that the research was conducted in the absence
interest.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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Suicide No Suicide
Total sample
Attempt Attempt t/χ2 p
(N=423) (N=259) (N=164)
Gender (female), N (%) 317 (74.9) 192 (74.1) 125 (76.2) .233 .629
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Age (years), mean±SD 49.93±18.63 48.88±19.89 51.59±16.36 1.457 .146
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Education level, mean±SD 11.07±3.34 11.15±3.29 10.93±3.43 -.653 .514
Diagnosis, N (%)
Bipolar and related disorders 135 (31.9) 87 (33.6) 48 (29.3) 1.679 .642
Schizophrenia and related disorders 46 (10.9) 25 (9.7) 21 (12.7)
Depressive disorders 126 (29.8) 78 (30.1) 48 (29.3)
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Total sample
(N=259)
Suicide Attempt, N (%) 259 (61.2)
High Lethality 86 (33.2)
Low Lethality 173 (66.8)
Type of Suicide Attempt (N=259), N (%)
Drug Intoxication 164 (63.3)
Defenestration 25 (9.7)
Weapon 1 (0.4)
Stabbing 4 (1.5)
Burn/Gas/Caustic 16 (6.2)
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Strangling 9 (3.5)
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Cuts 40 (15.4)
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Tabella 3: Socio-demographic and clinical characteristics according to the lethality of suicide
attempt.
High-lethality Low-lethality No
suicide suicide suicide
t/χ2 p
attempt attempt Attempt
(N=86) (N=173) (N=164)
Gender (female), N (%) 53 (61.6) 139 (80.3) 125 (76.2) 10.951 .004
t
Married
8 (20.9) 37 (21.4) 37 (22.6)
ip
Divorced
Widowed 8 (9.3) 17 (9.8) 11 (6.7)
cr
Working status, N (%) 23 (26.7) 44 (25.4) 42 (25.6) .055 .973
Diagnosis, N (%)
Bipolar and related disorders
Schizophrenia and related disorders
Depressive disorders
36 (41.9)
14 (16.3)
23 (26.7) us
51 (29.4)
11 (6.4)
55 (31.8)
48 (29.3)
21 (12.7)
48 (29.3)
16.364 .012
an
Others 13 (15.1) 56 (32.4) 47 (28.7)
M
ed
pt
ce
Ac
Table 4: comparison of cell blood count values among three subgroups
Low- Psychiatric
mean±SD High-Lethality Post-hoc
Lethality Controls F P
(N=86) (Bonferroni)
(N=173) (N=164)
Neutrophil 6.35±3.07 5.23±2.47 4.87±2.16 10.231 <.001 A>B=C
Lymphocyte 1.81±0.69 2.16±0.81 2.37±0.86 13.378 <.001 A<B=C
Platelet 249.45±81.94 238.32±67.40 233.11±62.71 1.590 .205 A=B=C
Mean platelet volume 8.99±1.22 7.92±1.25 8.00±1.14 14.432 <.001 A>B=C
Neutrophil-lymphocyte
4.00±2.72 2.62±1.31 35.442 <.001
ratio 2.21±1.02 A>B=C
Platelet-lymphocyte ratio 157.83±76.71 126.16±59.86 110.94±50.63 16.989 <.001 A>B=C
t
Red blood cell 4.43±0.62 4.46±0.50 4.55±0.56 1.868 .156 A=B=C
ip
Hemoglobin 127.40±19.47 129.00±19.31 142.05±103.60 2.124 .121 A=B=C
cr
Hematocrit 38.89±4.29 39.34±4.17 40.21±4.92 2.880 .057 A=B=C
Mean corpuscolar volume 88.57±7.55 88.53±6.85 88.70±7.13 .024 .976 A=B=C
Mean corpuscolar
hemoglobin
29.33±2.75 29.32±2.57
us
30.01±4.37
1.996 .137
A=B=C
an
Mean corpuscolar A=B=C
327.53±33.22 329.43±24.94 329.62±27.40 .437 .646
hemoglobin concentration
Red blood cell
M
distribution
14.18±1.30 13.86±2.08 14.02±1.74 1.221 .296 A=B=C
width_coefficient of
variation
ed
t
ip
Platelet to lymphocyte ratio .001 .004 .109 .741 1.001 .994-1.009
Mean platelet volume -.009 .116 .006 .936 .991 .790-1.243
Gender .461 .358 1.655 .198 1.585 .786-3.197
cr
Age -.012 .007 2.475 .116 .988 .974-1.003
Diagnosis of Bipolar Disorder .124 .291 .180 .671 1.132 .640-2.002
us
Category of reference: controls
an
M
ed
pt
ce
Ac
Ac
ce
pt
ed
M
an
us
cr
ip
t