Platelets

ISSN: 0953-7104 (Print) 1369-1635 (Online) Journal homepage: https://www.tandfonline.com/loi/iplt20

Platelet functions and activities as potential

hematologic parameters related to Coronavirus
Disease 2019 (Covid-19)

Francesca Salamanna, Melania Maglio, Maria Paola Landini & Milena Fini

To cite this article: Francesca Salamanna, Melania Maglio, Maria Paola Landini & Milena Fini
(2020): Platelet functions and activities as potential hematologic parameters related to Coronavirus
Disease 2019 (Covid-19), Platelets, DOI: 10.1080/09537104.2020.1762852

To link to this article: https://doi.org/10.1080/09537104.2020.1762852

Published online: 13 May 2020.

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ISSN: 0953-7104 (print), 1369-1635 (electronic)

Platelets, Early Online: 1–6

© 2020 Taylor & Francis Group, LLC. DOI: https://doi.org/10.1080/09537104.2020.1762852

Platelet functions and activities as potential hematologic parameters

related to Coronavirus Disease 2019 (Covid-19)
Francesca Salamanna1, Melania Maglio1, Maria Paola Landini2, & Milena Fini1
1
Laboratory of Preclinical and Surgical Studies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy and 2Scientific Direction, IRCCS Istituto Ortopedico
Rizzoli, Bologna, Italy

Abstract Keywords
Coronavirus disease 2019 (COVID-19) is a new infectious disease that currently lacks standar- COVID-19, hematological parameters,
dized and established laboratory markers to evaluate its severity. In COVID-19 patients, the platelets
number of platelets (PLTs) and dynamic changes of PLT-related parameters are currently
a concern. The present paper discusses the potential link between PLT parameters and History
COVID-19. Several studies have identified a link between severe COVID-19 patients and specific
Received 13 April 2020
coagulation index, in particular, high D-dimer level, prolonged prothrombin time, and low PLT
Revised 26 April 2020
count. These alterations reflect the hypercoagulable state present in severe COVID-19 patients,
Accepted 26 April 2020
which could promote microthrombosis in the lungs, as well as in other organs. Further
information and more advanced hematological parameters related to PLTs are needed to
better estimate this link, also considering COVID-19 patients at different disease stages and
stratified in different cohorts based on preexisting co-morbidity, age, and gender. Increasing
the understanding of PLT functions in COVID-19 will undoubtedly improve our knowledge on
disease pathogenesis, clinical management, and therapeutic options, but could also lead to the
development of more precise therapeutic strategies for COVID-19 patients.

Introduction sometimes contradictory laboratory results are being reported,

In December 2019, a novel coronavirus, identified as a novel
enveloped RNA betacoronavirus2, SARS-CoV-2 (severe acute
respiratory syndrome coronavirus 2) induced pneumonia,
emerged in the Hubei region of China and led to an exponential
outbreak in the city of Wuhan. Since February 2020, the disease,
named coronavirus disease 2019 (COVID-19), was also identified
in Italy and Europe, with increasing incidence in all European
countries, and in all continents, with the exception of Antarctica.
On March 11, 2020, the WHO formally declared the COVID-19
outbreak a pandemic [1] and to date, the cumulative number of
confirmed cases worldwide reached 1,864,629 2,811,891 with
more than 115,286 197,162 COVID-19-related deaths (04/1325/
2020; COVID-19 Dashboard by the CSSE at JHU). Morbidity
and mortality of COVID-19 have been prevalently linked to
elderly age, gender (male), and preexisting co-morbidities (i.e.
hypertension, diabetes, obesity, cancer, chronic obstructive pul-
monary disease), leading to a poorer outcome to the viral infec-
tion for frail patients and more often resulting in hospitalization,
intensive care unit admittance, and need for invasive tracheal
intubation [2–7]. The mechanisms for high morbidity and mor-
tality in these patients are currently unknown. Despite the fact
that clinical characteristics of patients with COVID-19 are well
described and range from a mild upper respiratory tract infection,
generally associated by fever (82%) and cough (81%), to severe
acute respiratory distress syndrome and sepsis, few and
Correspondence: Melania Maglio, Laboratory of Preclinical and Surgical
Studies, IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano, 1/10,
Bologna 40136, Italy. E-mail: melania.maglio@ior.it
thus impacting the setup of patient prognosis, therapy, and follow-
up [8,9]. On April 13, 2020, 3814 articles related to COVID-19
were published on PubMed/Medline and most of them reported
specific hematologic parameters strongly related to severe
COVID-19 patients. The main reported parameters were low
platelets (PLTs) count, low lymphocyte count and percentage,
low total protein level, high D-dimer level, high leukocyte
count, high C-reactive protein, high creatinine level, high neutro-
phil count and percentage, high creatine kinase activity, and
prolonged prothrombin time [10–21]. In some cases, these para-
meters, though normal at the admission of mild cases, worsened
with the course of the disease and are found to be in about three-
fourths of patients in severe conditions [8,18]. The worsening of
these indices has been related to intensive care unit access and
poor prognosis [22,23].
PLT number and dynamic changes related parameters in
COVID-19 patients are currently a concern. Thus, here, we dis-
cussed the potential link between PLT parameters and COVID-19
(Figure 1).
Discussion
From studies where hematologic parameters related to severe
COVID-19 patients were examined, alterations of specific coagu-
lation index emerged, i.e. high D-dimer level, prolonged pro-
thrombin time and low PLTs count [10–23]. These alterations
reflect the hypercoagulable state present in severe COVID-19
patients, which could promote microthrombosis in the lungs and
in other organs [10–23]. Regarding pulmonary mircothrombosis,
the damage to endothelial cells leads to overactivation,
2 F. Salamanna et al.
Figure 1. Platelet and COVID-19.
aggregation, and retention of PLTs, and the formation of throm-
bus at the injured site, which may cause PLTs and megakaryo-
cytes to deplete, resulting in decreased PLTs production and
increased consumption. This is also in line with several evidences
that identify PLTs as dynamic cells that participate in inflamma-
tion and prothrombotic responses in many viral infections [24]. In
fact, hypercoagulability is also an important hallmark of inflam-
mation and several pro-inflammatory cytokines and chemokines,
such as interleukin (IL)-1β, IL-6, and IL-8, can affect all coagula-
tion pathways [24]. Thus, the blockade of PLTs overactivation
and aggregation could reduce the inflammation and the severity
of acute respiratory syndrome [24]. In this regard, an intriguing
aspect is the possible multiple role played by angiotensin-
converting enzyme 2 (ACE2), which has been recognized to be
the receptor for the SARS-CoV syndrome, but which is also
involved in the thrombotic process and mainly expressed in the
endothelial cells of lungs [25,26]. Despite the genomic sequence
of COVID-19 showing a distinct genome composition than SARS
and MERS, the pattern of alteration of the coagulation parameters
and hematological changes related to the increased consumption
of PLTs and/or the decreased production of PLTs are in common,
as well as the formation of thrombus in lungs [27]. In fact,
similarly to COVID-19 patients, several retrospective analyses
of SARS infected patients showed the occurrence of thrombocy-
topenia with the lowest PLTs count in about 40-50% of infected
patients [28,29]. As for COVID-19 patients, the presence of
thrombi has been recognized in pulmonary, bronchial, and small
lung veins of SARS lung autopsies, suggesting a prothrombotic
effect also of this virus [30,31]. Similarly, thrombocytopenia with
the lowest PLTs count was also associated with MERS disease in
about 37% of patients [32,33] as well as the presence of micro-
thrombi in the pulmonary vasculature [34]. However, differently
from SARS and MERS, preliminary autopsy studies on COVID-
19 patients showed the presence of thrombosis not only in the
lungs but also in the portal vein and in other vessels (https://www.
sforl.org/wp-content/uploads/2020/03/WUHAN-Experience.pdf).
It is known that endothelial dysfunction may be associated with
Platelets, Early Online: 1–6
expression of endothelial surface adhesion molecules, i.e. the
intercellular adhesion molecule, the vascular cell adhesion mole-
cule, E-selectin, and the von Willebrand factor, that play an
essential role in the binding of leukocytes, that lead to a local
inflammatory response, endothelial cell damage, and subsequent
plasma leakage and shock [35]. Thus, PLTs, together with
endothelial cells and circulating coagulation proteins could also
have a role in the development of thrombosis and microthrombo-
sis in organs and tissues other than lungs through their synergistic
interaction. However, to date, the effect of COVID-19 infection
on PLT-endothelial interactions is almost completely unknown.
In order to thoroughly evaluate these aspects in COVID-19
patients, most advanced hematological parameters related to
PLTs should be analyzed because of their importance in the
evaluation of the hypercoagulable state present in severe
COVID-19 patients. The following parameters linked to PLTs
function and activity are, to date, not available in the current
literature: PLT fraction, mean volume, distribution width, aggre-
gation, reticulated PLTs, PLT-derived microparticles (PMPs)
combined with D-dimer, and a combination of PMPs, PLTs
distribution width, PLTs count, and D-dimer. The assessment
of these parameters could lead to a great deal of information
on the hyper-activation of coagulation and on the development
of thrombosis and microthrombosis in COVID-19 patients.
Several studies have shown that MPV and immature platelet
fraction can be effectively used as markers of PLTs activation
and increased risk of thrombosis [36–38] Larger PLTs contain
more dense granules, produce more thromboxane A2, platelet
factor A and beta-thromboglobulin, and are consequently more
reactive with greater prothrombotic potential than smaller PLTs
[39]. Moreover, increased immature PLT fraction can predict
a decrease in PLT count during coagulopathy [40]. A key mar-
ker of PLTs activation for COVID-19 patients could also be the
PLTs distribution width that has been reported to be increased in
venous thrombosis as well as in several hypercoagulative state,
such as in cardiovascular diseases [41]. An additional PLTs
parameter particularly active in thrombus formation is the
DOI: https://doi.org/10.1080/09537104.2020.1762852
reticulated PLTs that reflect increased PLTs consumption during
the thrombosis progression and/or prelude to the development of
thrombosis [42]. In fact, reticulated PLTs may reflect an
increased PLT turnover in the setting of a normal PLTs count
and this aspect could be of critical importance in the early
diagnosis of COVID-19 [42]. Another efficient parameter that
can be also combined with PLT distribution width, PLTs count,
and D-dimer is the PLT-derived microparticles (PMPs) that play
a critical role in thromboembolism through direct cell-to-cell
contact interactions or release of active components [43]. Once
the blood vessels are injured, the PMPs release causes the
exposure of collagen and von Willebrand factor thus entailing
the adhesion, aggregation, and activation of PLTs [44].
Subsequently, factors produced by PLTs, i.e. thromboxane A2
and endothelin, lead to blood vessels contraction, thus support-
ing thrombogenesis [45]. In the meantime, the PMPs membrane
proteins accumulated on an anion phospholipid surface can
increase the gathering and catalytic activity of tissue factors,
thus worsen the blood clotting responses [46]. Since this strong
procoagulant activity PMPs in combination with PLTs distribu-
tion width, PLTs count and D-dimer may be used to increase the
sensitivity and specificity in the analysis of the hypercoagulable
state in COVID-19 patients. In addition, the alteration of these
PLTs parameters in association with the prolonged prothrombin
time, increase of D-dimer, and decrease of fibrinogen in
COVID-19 patients are of key importance to diagnose and/or
monitoring the worsening of coagulation. In the most serious
form, this worsening of coagulation leads to an inadequate blood
supply to different organs and contributing to multiple organ
failure/dysfunction, thus giving rise to disseminated intravascular
coagulation (DIC) disease [47]. This phenomenon, DIC, is in
line with what seems to occur in severe COVID-19 patients and
was recently described in several studies also using the
International Society on Thrombosis and Hemostasis diagnostic
criteria [48–50]. DIC is an intricate and multifactorial disease,
but several virus-activated events as endothelium exposure,
PLTs, and leukocytes damage-associated molecular patterns
seem to be the primary actors of DIC pathophysiology [51].
Despite, to date, the mechanisms by which PLTs might directly
contribute to DIC in COVID-19 patients are unclear, we
hypothesize that the strong endothelial cells and PLTs activation
induced by COVID-19 stimulate the initiation and propagation
of procoagulant pathways and inactivate the natural anticoagu-
lant systems and the endogenous fibrinolysis. These phenomena
lead to DIC, thus contributing to multi-organ failure. The ther-
apeutic approaches for these coagulation disorders in COVID-19
patients currently start from the classical guidelines related to
thromboembolic events and are constantly evolving in light of
the evidence emerging on the disease. The daily administration
of unfractionated heparin (UFH) or low molecular weight
heparin (LMWH) is recommended, especially in some Asiatic
countries in which the use of thrombomodulin or antithrombin is
not common [50,52]. Such antithrombotic prophylaxis seems to be
quite effective in severe COVID-19 patients, and many authors have
underlined that the inflammatory properties of LMWH can have
a role in the success of the therapy, in the light of the evidence related
to the cytokines storm which characterizes the pathology [53].
However, other data suggest caution in the choice of the type of
anticoagulant and especially in the administration of increasing
doses [54]. In addition, in many cases, these therapies require appro-
priate adjustments to avoid interactions not only with drugs already
taken in patients with previous diseases but also with therapies
aimed at treating the COVID-19 itself. Just to name a few of the
drugs currently being evaluated, bevacizumab can increase adverse
thromboembolic events, as opposed to hydroxychloroquine, which
can act as an antithrombotic agent [55]. These critical aspects
Link between COVID-19 and coagulation alteration 3
highlight the need to detect a safe therapeutic strategy or to adjust
it on the basis of patient clinical history and diagnosis. In addition,
the absence of an efficacy-proven antiviral treatment led to treat
severe COVID-19 patients with convalescent plasma containing
SARS-CoV-2 specific antibodies from recovery patients, showing
a decrease in the major inflammation symptoms and an increase in
lymphocytes counts and blood oxygen saturation [56–60]. The
transfusion of platelets or plasma (components) or fresh frozen
plasma is also an effective therapeutic strategy for the coagulopathy
treatment, including for DIC [61]. However, to date, to evaluate if
plasma treatment acts directly on the hypercoagulability state present
in severe COVID-19 patients additional results and rigorous clinical
trials also evaluating the efficacy of plasma not containing SARS-
CoV-2 specific antibodies (plasma from healthy subject) are needed
before we may draw definitive effectiveness conclusions on this
therapy.
In addition, it is important to underline that, as above
reported, severe COVID-19 patients are prevalently those
with preexisting comorbidities, as well as elderly and male
subjects. All these patients already present impaired PLTs
function and activity. It is known that PLTs of elderly and
young populations significantly differ in terms of number,
activity, and structure: PLTs count in old age is reduced by
35% in men and by 25% in women with respect to early
infancy [62]. Thus, PLTs count decreases with age, and
women have more PLTs than men [63]. Furthermore, PLTs
from older men and women have a greater sensitivity to aggre-
gation and this characteristic is, however, more pronounced in
a pathological state [62]. In addition to age and gender, many
other environmental and genetic factors, i.e. obesity, diabetes,
hypertension, cancer, metastases and chronic obstructive pul-
monary disease, influence PLTs aggregation, count, volume,
reticulation, and other parameter linked to PLTs activity and
structure [64–69]. Thus, in fragile patients, especially men,
where there is an already preexisting alteration of PLTs number
and platelet related-parameters, the positivity to COVID-19
could further compromise the PLT functions and activities
and this aspect could account the more severe course of the
disease. Another aspect that deserves further study is related to
full-term pregnant women affected by the disease. Although
the vertical transmission is still being evaluated, in some cases
of perinatal infection, changes in hematological values have
been found, including thrombocytopenia [70]. Finally, although
the current state of emergency makes these types of follow-ups
difficult, it would be interesting to evaluate how long these
values return to normal.
Conclusion
The knowledge presented in this communication should
increase the sensitivity of clinicians caring for COVID-19
patients with altered PLTs parameters as well as the need to
develop an aggressive treatment for these patients. More infor-
mation is mandatory in order to evaluate and confirm the hold
association between PLTs parameters and COVID-19 patients
at different stages of disease development and in a different
cohort of patients, considering and stratifying patients for their
co-morbidity, age, and gender. Despite the emergency in pro-
gress and limited time availability, only the production of
strong scientific evidences can avoid the risk of interpretative
errors, leading to potential delays in identifying the best care
and therapeutic strategies for COVID-19 patients. Increasing
our understanding of PLTs functions in COVID-19 will
undoubtedly improve our knowledge on diseases pathogenesis,
clinical management, therapeutic options, and innovative
4 F. Salamanna et al.
strategies, but could also lead to the identification of patients at
risk of infection and severe disease.
Acknowledgements
This work was supported by grants from IRCCS Istituto Ortopedico
Rizzoli (Ricerca Corrente). The authors gratefully acknowledge Silvia
Bassini for the support in the realization of the Figure related to
COVID-19 and platelet parameters.
Disclosure Statement
The authors report no conflict of interest.
Authors contribution
Conception of the work: FS; acquisition, analysis, and interpretation of
data: FS, MM; drafting of the work: FS, MM; critical revise: MPL, MF;
final approval: FS, MM, MPL, MF.
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