Respiratory Medicine 171 (2020) 106098

Contents lists available at ScienceDirect

Respiratory Medicine
journal homepage: http://www.elsevier.com/locate/rmed

Review article

Platelets in chronic obstructive pulmonary disease: An update on

pathophysiology and implications for antiplatelet therapy
Haneen Mallah a, 1, Somedeb Ball a, *, 1, Jasmine Sekhon a, Kanak Parmar a, Kenneth Nugent b
a
Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
b
Division of Pulmonary and Critical Care Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Platelets are essential mediators of inflammation and thrombosis. Chronic obstructive pulmonary disease (COPD)
Aspirin is a heterogeneous multisystem disease, causing significant morbidity and mortality worldwide. Recent evidence
COPD suggests that the lung is an important organ for platelet biogenesis. Cigarette smoking has been shown to induce
Emphysema
platelet aggregation and decrease the capacity of mitochondrial electron transport system in platelets. Preclinical
Megakaryocytes
and clinical studies have suggested that platelets may contribute to the development of COPD through the
Hypoxia
Platelet aggregates breakdown of lung elastin by platelet factor 4, platelet activation and formation of platelet aggregates, and
modulation of hypoxia signaling pathways. Recent large population studies have produced encouraging results
indicating a potential role for aspirin in preventing exacerbations and delaying disease progression in patients
with COPD. This review summarizes the information about the lung as an organ for platelet production, path­
ophysiological functions of platelets and platelet mediators in the development of COPD, and the most updated
evidence on the utility of aspirin in patients with COPD.

1. Introduction biogenesis in lungs, to investigate the functions of platelets in the

Platelets are the primary cellular mediators of hemostasis and
thrombosis [1]. However, recent studies have identified emerging roles
of platelets in the initiation and maintenance of inflammation and im­
munity [2]. Chronic obstructive pulmonary disease (COPD) is a het­
erogeneous multisystem disease, causing progressive morbidity and
mortality in patients. The pathophysiology of COPD is characterized by
airway inflammation, mucus hypersecretion, tissue destruction with
impaired repair, and remodeling of pulmonary vasculature [3]. Recent
evidence suggests that the lung could be an essential organ for platelet
biogenesis with the bone marrow as the primary sites, thus implicating
the potential role of platelet mediators in the development and pro­
gression of COPD [4]. Platelets seem to contribute to the pathogenesis of
COPD through several mechanisms, including enhancement of elastase
activity, formation of platelet aggregates, and modulation of hypoxia
signaling pathways [5–7]. Moreover, the use of aspirin has been shown
to decrease the rate of acute exacerbations and delay the overall pro­
gression of COPD in recently published clinical studies [8,9]. Hence, the
objectives of this review are to summarize the information on platelet
pathophysiology of COPD, and to summarize the most updated evidence
for the use of antiplatelet drugs in patients with COPD.
2. Physiology of platelets
Platelets have a lifespan of 8–10 days, requiring a daily turnover of
100 billion platelets to maintain a physiological platelet concentration
of 150,000–450,000 per microliter of blood.[10] Megakaryocytes (size
50–100 μm) differentiate from hematopoietic stem cells (HSC) of
myeloid lineage primarily in the bone marrow, under the influence of
thrombopoietin (TPO) binding to its receptor Mpl [11]. Upon reaching
their perivascular microenvironment, megakaryocytes develop exten­
sions, structures described as proplatelets (2–4 μm) from which platelets
fragment into bone marrow sinusoids [12]. Other megakaryocytes and
some proplatelets enter within the bloodstream and travel to the lungs.
In the lungs, platelet shedding has been noted primarily in the areas of
high turbulence, such as pulmonary capillary branch points, which
provide shear stress for cytoskeletal reorganizations [13]. Some mega­
karyocytes are also found to reside in the pulmonary interstitium. These

* Corresponding author. Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA.
E-mail address: somedeb.ball@ttuhsc.edu (S. Ball).
1
Contributed equally in the manuscript and to be considered as co-first authors.

https://doi.org/10.1016/j.rmed.2020.106098
Received 12 April 2020; Received in revised form 14 June 2020; Accepted 26 July 2020
Available online 30 July 2020
0954-6111/© 2020 Elsevier Ltd. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).
H. Mallah et al.
are phenotypically different and primarily express genes involved in
immunity and inflammation [4].
Hemostasis is the primary physiological function of platelets in cir­
culation. Upon injury to the vessel, the exposed subendothelial collagen
and immobilized von Willebrand factor (vWF) interacts with the pro­
teins on the platelet surface, such as integrins and glycoproteins Ib-IIa
(GPIb-IIa) to mediate adhesion [14]. These platelets release adenosine
diphosphate (ADP) to recruit surrounding platelets through paracrine
signaling and form platelet aggregates. Concurrently, the coagulation
cascade is also started with the tissue factor mediated activation of
factor VII. Platelets also have a major role as immune cells. Many of the
non-hemostatic functions of platelets result from their ability to store
several biologically active molecules in intracellular granules (α-gran­
ules, dense granules, and lysosomes) and to generate their own proteins
through translation [2]. Various chemicals (chondroitin sulfate, P
selectin) released from the platelet α-granules act as potent trigger for
the classical and alternative complement pathway and provide a scaffold
for complement activation [15]. Also, platelet microparticles (size
100–1000 nm) released from the platelets contain membrane constitu­
ents which are required for communication between leukocytes and
vascular endothelial cells to mediate inflammation [2,16]. Platelets
have a key role in sepsis by the expression on their surfaces of Toll-like
receptors, the pattern recognition receptors, to bind bacteria and present
them to neutrophils and cells of the reticuloendothelial system. The
interaction between platelet bound bacteria and neutrophil leads to
activation and subsequent degranulation and formation of neutrophil
extracellular traps (neutrophil extensions filled with antibacterial en­
zymes). This occurs primarily in the lungs and liver, leading to the
development of multiorgan failure [17]. Activated platelets have
recently been shown to express CD154 that interacts with CD40 on
endothelial cells to recruit leukocytes and participate in adaptive im­
munity. By expressing the CD40 ligand, platelets enhance antigen pre­
sentation, stimulate B cell differentiation and immunoglobulin
class-switching, produce virus specific immunoglobulin G, and
augment the response of CD8 cells [18].
3. Megakaryocytes in the lung- an organ for platelet biogenesis
The bone marrow is known as the primary site for the production of
platelets from megakaryocytes. However, recent evidence suggests that
lungs may also contribute to platelet biogenesis, accounting for
approximately 50% of total platelet production from megakaryocytes
residing in the pulmonary capillary bed.4Megakaryocytes are migratory
and, therefore, can exit intact through the marrow sinusoids, ending up
in the capillary bed in the lung. A study by Zucker-Franklin et al. showed
that 10 times as many intact megakaryocytes are in pulmonary artery
blood compared to blood from the aorta; additionally, 98% of mega­
karyocytes leaving the lung were devoid of cytoplasm, indicating that
platelet formation from lung megakaryocyte had taken place. In a mouse
model, physiological stimuli in forms of phlebotomy and administration
of thrombopoietin resulted in an increase in platelet production on day
5. Samples from lung tissue of these mice showed many megakaryocyte
fragments with demarcated platelet fields in the pulmonary capillaries,
indicating platelet production by fragmentation of cytoplasm of mega­
karyocytes. These findings were more evident with increases in blood
platelet counts [19]. In another study, LeFrancais et al. directly imaged
the lung microcirculation in mice and showed that megakaryocytes
migrate from extrapulmonary sites such as the bone marrow. They used
fluorescent reporter mouse strains with megakaryocytes that were green
fluorescence protein positive (GFP+) to directly visualize platelet pro­
duction in the lung circulation. Results showed that for every large GFP
+ megakaryocyte, there were 500–1500 small GFP + cells (likely
platelets). Furthermore, staining for additional markers such as CD41,
CD42, GPVI, and c-Mpl confirmed that the smaller GFP + cells were
platelets [4]. All these findings provide strong evidence suggesting that
the lung is a major site of platelet biogenesis. Fig. 1 depicts the process of
2
Respiratory Medicine 171 (2020) 106098
platelet formation, activation, and consequent release of mediators in
the lung interstitium.
4. Effect of smoking on platelets
Smoking increases the platelet response to aggregation. Levine et al.
noted that smoking a single cigarette resulted in a change in platelets
that makes them more responsive to exposure to low doses of ADP. This
enhancement in aggregation can be due to direct or indirect effects of
nicotine on platelets, which can cause release of endogenous epineph­
rine or as a result of a smoking-induced increase in plasma catechol­
amines, mostly epinephrine, which is a well-studied stimulus of platelet
aggregation[20]. In a study on estimation of the acute effect of cigarette
smoking on platelet thrombus formation, investigators found that
smoking two standard cigarettes while being on full dose aspirin showed
an increase in platelet thrombus formation due to augmented response
to thrombin [21]. Chronic smoking reduces platelet lifespan signifi­
cantly and induces changes in the mitochondria of platelets. In a pilot
study investigating this hypothesis, a “COPD-like disease” was induced
in guinea pigs with cigarette smoke exposure defined as 4 h of smoke 5
days a week until symptoms of dyspnea were observed. The study of
mitochondrial respiratory parameters in platelets of these
smoke-exposed animals revealed an increase in protons and electron
leaks and relative reduction in the capacity of the electron transport
system [22]. These changes potentially lead to increased generation of
reactive oxygen species (ROS), which influence platelet production
through proliferation and differentiation of megakaryocytes from HSC
and platelet activation through glycoprotein-VI dependent pathway.
Glycoprotein- VI is a transmembrane receptor expressed on platelets and
megakaryocytes. After a ligand binds to this receptor, there is a rapid
increase in intracellular ROS in platelets [23]. Increases in ROS are
associated with HSC expansion, specifically the differentiation phase of
HSCs to megakaryocytes, whereas low levels of ROS are associated with
HSC quiescence for self-renewal. Reactive oxygen species are vital reg­
ulators that act on multiple different signaling pathways during devel­
opment of megakaryocytes [24].
5. Platelet indices in COPD
The number and function of platelets are routinely assessed using the
platelet count, mean platelet volume (MPV), and platelet distribution
width (PDW). Studies evaluating the association between these indices
in patients with COPD have produced variable results.
In a study including 964 smokers without any comorbidities, patients
with COPD had higher platelet counts compared to those without it [25].
Several studies have shown that thrombocytosis is associated with
increased morbidity and mortality in COPD patients. The results
remained significant after adjustment for confounding factors, thus
increasing the likelihood that the pathophysiologic mechanism under­
lying the association may be independent of an increase in cardiovas­
cular risk [26,27]. Studies have noted a variable relationship between
MPV and stable COPD in patients [28,29]. A recently published large
population study with data from the National Health and Nutrition
Examination Survey showed that individuals with a self-reported diag­
nosis of emphysema had a significantly higher likelihood of having MPV
lower than 10th percentile, compared to those who did not report the
diagnosis.[30]Other studies showed a significant increase in MPV and
thrombocyte aggregation with worsening hypoxemia, suggesting that
the lack of oxygen might stimulate platelet activity, volume, and ag­
gregation in these patients [31,32]. Investigators have studied the po­
tential utility of MPV in the prediction of exacerbations and
development of pulmonary hypertension in patients with COPD [27,33].
An elevated PDW has also been associated with significantly lower
forced expiratory flows in patients with stable COPD and was an inde­
pendent risk factor for mortality in these patients, even after adjustment
for potential confounding factors [34]. Characteristics of studies on the
H. Mallah et al. Respiratory Medicine 171 (2020) 106098

Fig. 1. Biogenesis and Activation of Platelets in Lung

[PF4- Platelet Factor 4, TG- Thromboglobulin, TXA2- Thromboxane A2, TXB2- Thromboxane B2, PAI-1- Plasminogen Activator Inhibitor-1, ROS- Reactive Oxygen
Species, MP- Microparticles]
* Sizes of Megakaryocyte- 50–100 μm, Proplatelet- 2–4 μm, Platelet- 1–3 μm, Microparticle- 100–1000 nm.

association of several platelet indices with COPD are summarized in
Table 1.
6. Role of platelets in pathogenesis of COPD
Studies have suggested that platelets contribute to the development
of COPD through different mechanisms, leading to studies on possible
therapeutic utility of antiplatelet medications in COPD. Potential roles of
platelets in the pathogenesis of COPD are summarized in Table 2.
6.1. Loss of elasticity and alveolar integrity
Lung elastin was purified from hamster lungs to determine if human
platelet factor 4 (PF4) stimulates the activity of human leukocyte elas­
tase (HLE) against lung elastin. Low-dose HLE and PF4 individually
failed to show any effect on lung elastin, whereas HLE stimulated by PF4
lowered lung elastin by 20%. Platelet factor 4 concentrations as low as
1.6 μg/ml increased HLE activity against lung elastin, with a linear
increment with additional PF4. Moreover, pressure-volume curves
showed a significant loss of lung elasticity in the lungs treated with HLE
and PF4. Morphologic studies demonstrated that low dose HLE resulted
in minimal emphysema like lesion, whereas HLE plus PF4 caused a
significantly more severe lesion. These findings suggest that PF4 may
have a role in the pathogenesis of emphysema [5]. In a mouse model,
deficiency of platelet-derived growth factor- A (PDGF-A) led to the
development of emphysema of the lung secondary to abnormal alveolar
septation. This finding in a preclinical study indicates the potentially
critical role of PDGF-A signaling pathways in the development and
maintenance of alveoli [35].

Table 1
Studies on Association between Platelet Indices and Chronic Obstructive Pulmonary Disease
[COPD- Chronic Obstructive Pulmonary Disease, AECOPD- Acute Exacerbation of COPD, MPV- mean platelet volume, PDW- Platelet distribution width, FEF 25-75-
Forced expiratory flow between 25% and 75% of vital capacity, OR- Odds ratio, HR- Hazard ratio, CI- Confidence interval].
Author & Year Study Type Number of Patient characteristics Platelet Results
Participants Indices
Studied

Cakmak et al., Case control study 964 Smoker (with and without Platelet Statistically significant increase (p < 0.0001) in platelet count
2009 COPD); no other comorbidities count with increasing severity of COPD
Harrison et al., Observational cohort 1343 Hospitalized patients for Platelet Thrombocytosis was associated with significant increase in 1-
2014 study AECOPD count year mortality (OR 1.53, 95% CI: 1.03–2.29, p = 0.030)
Steiropoulos Case control study 119 Stable COPD; Control- smokers MPV Significantly higher MPV in patients with COPD (p < 0.001),
et al., 2013 without airflow limitation compared to controls.
No correlation of MPV with indices of COPD severity.
Ball et al., 2019 Cross-sectional 17,969 Non-institutionalized adult MPV Individuals with emphysema had significantly higher adjusted
population study population in United States odds (OR 1.92, 95% CI: 1.11–3.31, p = 0.021) of having MPV
< 10th percentile.
Bialas et al., Retrospective cohort 79 Spirometry- proven COPD PDW High PDW was associated with - Lower FEF 25–75
2017 study - Reduced survival (adjusted HR 4.59, 95% CI: 1.1–19.19, p =
0.04)

3
H. Mallah et al. Respiratory Medicine 171 (2020) 106098

Table 2 cells [42,43]. Human platelets express HIF-2α, augmented by the

Role of platelets in the pathogenesis of chronic obstructive pulmonary disease. exposure to hypoxia or other psychological stress. Hypoxia also stimu­
Effects on Lungs Relevant to Responsible Platelet Likely Pathophysiologic lates platelets to synthesize plasminogen activator inhibitor (PAI)-1 and
COPD Mediators Mechanisms shed extracellular vesicles. These effects potentially induce a
Loss of alveolar integrity Platelet factor-4 (PF4) Induction of human pro-thrombotic state associated with hypoxia. Platelets from patients
Platelet derived leukocyte elastase with COPD and at high altitude were found to have higher expression of
growth factor- A Abnormal alveolar HIF-2α and PAI-1 than their healthy counterparts, indicating the po­
(PDGF-A) septation tential role of platelet hypoxia signaling in the pathogenesis of COPD
Generation of P- Selectin Abnormal platelet
prothrombotic state and CD 47 activation
[44]. Several studies have suggested that PAI-1 may induce the pro­
pulmonary vascular Beta- thromboglobulin Increased formation of gression of COPD through different mechanisms. It promotes inflam­
remodeling Thromboxanes platelet- monocyte mation caused by exposure to the cigarette smoke [45], and elevated
aggregates circulating PAI-1 levels have been associated with a decline in lung
Enhanced release of
function in patients with COPD [46].
platelet mediators
Dysregulated response to Plasminogen activator Stimulation of release of
hypoxia inhibitor − 1 (PAI-1) platelet vesicles 7. Antiplatelets in management of COPD
Increase in smoking-
induced inflammation The role of antiplatelet therapy in patients with COPD has been
evaluated in several clinical studies. The recently published Multi-
6.2. Prothrombotic state and pulmonary vascular remodeling Ethnic Study of Atherosclerosis (MESA) lung study included 4257 in­
dividuals (54% were smokers) with a mean age of 61 years. Aspirin use
Following vascular injury, circulating platelets become activated, was noted to be regular (defined as 3 or more days a week) in 22% of
upregulating expression of cell surface receptors such as P-selectin study participants. The progression of percent emphysema (the per­
ligand to facilitate adhesion to the arterial wall. Activated platelets centage of emphysema-like lung below − 950 Hounsfield units on car­
release inflammatory chemokines and recruit inflammatory cells to form diac and full-lung CT scans) was slower among patients who used aspirin
platelet-monocyte aggregates. Circulating platelet-monocyte aggregates regularly compared to those who did not. Regular aspirin use was
are considered a sensitive measure of platelet activation. A study associated with greater than 50% reduction in the rate of emphysema
showed a significant increase in circulating platelet-monocyte aggre­ progression over 10 years. Results were similar with different doses (81
gates in stable COPD patients compared with their well-matched con­ mg vs. 325 mg per day) of aspirin, with a greater magnitude of effect
trols. Aggregation increased further during an acute exacerbation in observed among those with airflow limitation; however, no association
these patients. Platelet P-selectin expression and soluble P-selectin did was found between aspirin use and change in lung function (measured
not differ between groups in this study [6]. This increased propensity to by FEV1 or FEV1/FVC on spirometry). Beneficial effects on progression
form platelet aggregates may be partially explained by an increase in of emphysema seemed to be more prominent in men and current
levels of integrin-associated proteins (e.g., CD47) noted in the serum of smokers [8].
patients with severe acute exacerbation of COPD (AECOPD) [36]. In a Another cohort study evaluated the effect of aspirin on morbidity in
recently published prospective, observational study, platelet reactivity 1698 patients with COPD, based on self-reported aspirin use. Aspirin
(assessed with vasodilator-stimulated phosphoprotein assay) was users were matched one-to-one with nonusers, based on a propensity
significantly higher in patients with AECOPD, as compared to those with score. Patients on regular aspirin had significantly lower incidence rates
stable disease [37]. Abnormal platelet activation may also be indicated of total AECOPD, although incidence of severe AECOPD did not differ
by finding of an increased level of beta-thromboglobulin during acute significantly between the two groups. In this study, aspirin use was
exacerbations [38]. associated with a significantly improved quality of life (assessed with
Biosynthesis of thromboxane- A2 by platelets is enhanced in patients the St. George’s Respiratory Questionnaire score) and lower odds of
with COPD[39]. A study investigated platelet function by assessment of development of moderate-severe dyspnea (modified Medical Research
aggregate formation “in vivo” by measuring platelet aggregate ratio and Council questionnaire score ≥ 2) in patients [9].
blood concentrations of various platelet release products (e.g., β Antiplatelet therapy with aspirin or clopidogrel was also correlated
thromboglobulin and thromboxane B2) in patients with chronic airflow with a reduction in 1-year mortality in another observational study
obstruction with and without hypoxemia. The platelet aggregate ratio performed on 1343 spirometry confirmed COPD patients hospitalized
(value approaches 1.0, in absence of platelet aggregation) was lower in with AECOPD [26]. A large prospective national study from Sweden
the hypoxemic patients compared to the non-hypoxemic and control showed that use of antiplatelet medications was associated with a sig­
groups, although platelet release products were not increased in the nificant reduction of mortality risk in oxygen-dependent COPD patients
peripheral blood. These findings suggest an increase in platelet activa­ [47]. In a retrospective cohort study with 206,806 patients hospitalized
tion and consequent platelet aggregate formation in patients with for AECOPD, aspirin use was found to be associated with significantly
worsening hypoxemia and hypercapnia. Platelet aggregates may be lower risk of in-hospital death and need for invasive mechanical venti­
trapped in the lung, resulting in the local release of mediators, leading to lation [48]. Finally, a recently published meta-analysis of 5 studies with
the structural remodeling of the pulmonary vasculature and consequent 11,117 patients concluded that antiplatelet therapy significantly lowers
development of pulmonary hypertension, a common complication in all-cause mortality in COPD patients, both in stable patients or in those
patients with COPD [31,40]. with AECOPD. These results were consistent after meta-regression
analysis with consideration for potential confounding factors [49].
Characteristics of studies evaluating the utility of antiplatelet therapy in
6.3. Dysregulation of hypoxia signaling the management of COPD are described in Table 3.

The nature of hypoxia signaling and regulation in humans has been
studied to improve the understanding of thrombus stabilization.
Hypoxia-inducible factor (HIF) is a heterodimeric deoxyribonucleic
acid-binding complex that regulates cellular response to hypoxia
through transcriptional modifications [41]. Hypoxia-inducible factor-1α
is ubiquitously expressed while HIF-2α and -3α are expressed by specific
8. Conclusions and future directions
Evidence of biogenesis of platelets in the lung makes a strong case for
extensive involvement of platelets in lung physiology and pathological
conditions. Several preclinical models have suggested that platelets have
crucial roles in the pathogenesis of COPD. Observations from recently

4
H. Mallah et al. Respiratory Medicine 171 (2020) 106098

Table 3
Studies on Use of Antiplatelet Drugs in Patients with Chronic Obstructive Pulmonary Disease
[ASA- Aspirin, [ASA- Aspirin, mg/d – milligrams per day, NR- Not reported, COPD- Chronic Obstructive Pulmonary Disease, AECOPD- Acute Exacerbation of COPD,
MV- Mechanical ventilation, OR- Odd’s Ratio, IRR- Incidence Rate Ratio, CI- Confidence interval].
Author Study Type Number of Important Baseline Name and Dose of Primary Outcomes of Key Findings in Results
& Year Participants characteristics of Antiplatelet Interest
Participants Medication

Aaron Longitudinal Cohort 4257 54% smokers, ASA Increase in “Percent- Regular ASA use was associated with 50%
et al. Study 22% regular ASA use, 81–325 mg/d Emphysema” on CT reduction in rate of emphysema progression
2018 No clinical scan (– 0.34%/10 years, 95% CI, − 0.60 to − 0.08;
cardiovascular disease P = 0.01) over 10 years.
Fawzy Observational Cohort 1698 COPD (FEV1/FVC < ASA Total number of ASA use was associated with - Lower
et al. Study-Propensity Score- 70%), Dose- NR moderate and severe incidence of total AECOPD (IRR 0.78; 95%
2019 Matched Analysis 45% reported daily AECOPD CI, 0.65–0.94) with ASA use.
ASA use - Lower SGRQ score and lower COPD
Assessment Test score.
Harrison Observational Cohort 1343 Spirometry confirmed ASA or clopidogrel One year all-cause ASA or clopidogrel treatment correlated
et al. Study COPD, Dose- NR mortality with reduction in 1- year mortality (OR
2014 Hospitalized for 0.63; 95% CI 0.47 to 0.85, p = 0.003).
AECOPD
Goto et al. Retrospective Cohort 206,686 Hospitalized for ASA In-hospital death, Use ASA users had
2018 Study AECOPD Dose- NR of MV, Hospital - Lower inpatient mortality (OR 0.60; 95%
length of stay CI 0.50–0.72; P < 0.001)
- Lower risk of invasive MV use (OR 0.64,
95% CI 0.55–0.73; P < 0.001)
- Shorter hospital stay.
Pavasini Systematic Review and 11,117 COPD Any antiplatelet All-cause mortality Significantly lower all-cause mortality in
et al. Meta-analysis agent patients on antiplatelet therapy (OR 0.81;
2016 Dose- NR 95%CI 0.75–0.88).

published cohort studies strongly indicate that antiplatelet agents may
attenuate disease progression in patients with COPD. Most of these
studies had patients on aspirin, and dosages varied within and across
studies. Aspirin users experienced significantly fewer AECOPD, less
radiographic progression, and reduced mortality. However, the magni­
tude of beneficial effects was comparable between low and high dose
groups in the study by Aaron et al. Future research should help improve
the understanding of the role of platelets in the pathophysiology of
COPD and estimate the effect of antiplatelet drugs on the rate of acute
exacerbations and overall mortality in these patients. Data on mortality
in COPD patients on aspirin deserve careful evaluation, since this
outcome may be confounded by the effect of antiplatelet medication on
concurrent cardiovascular diseases in many of these patients. Subgroup
analyses of large study cohorts could answer the outstanding questions
on the timing of initiation and choice of agents regarding antiplatelet
therapy in patients with COPD.
Author’s contributions
All the co-authors have significantly contributed to the manuscript
and approved the final version.
Funding source
None.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgement
None to declare.
References
[1] A.M. Hvas, Platelet function in thrombosis and hemostasis, Semin. Thromb.
Hemost. 42 (3) (2016) 183–184.
[2] C.N. Morrell, A.A. Aggrey, L.M. Chapman, K.L. Modjeski, Emerging roles for
platelets as immune and inflammatory cells, Blood 123 (18) (2014) 2759–2767.
[3] J.C. Hogg, W. Timens, The pathology of chronic obstructive pulmonary disease,
Annu. Rev. Pathol. 4 (2009) 435–459.
[4] E. Lefrancais, G. Ortiz-Munoz, A. Caudrillier, et al., The lung is a site of platelet
biogenesis and a reservoir for haematopoietic progenitors, Nature 544 (7648)
(2017) 105–109.
[5] S.A. Lonky, H. Wohl, Stimulation of human leukocyte elastase by platelet factor 4.
Physiologic, morphologic, and biochemical effects on hamster lungs in vitro,
J. Clin. Invest. 67 (3) (1981) 817–826.
[6] J.D. Maclay, D.A. McAllister, S. Johnston, et al., Increased platelet activation in
patients with stable and acute exacerbation of COPD, Thorax 66 (9) (2011)
769–774.
[7] S.N. Chaurasia, G. Kushwaha, P.P. Kulkarni, et al., Platelet HIF-2alpha promotes
thrombogenicity through PAI-1 synthesis and extracellular vesicle release,
Haematologica 104 (12) (2019) 2482–2492.
[8] C.P. Aaron, J.E. Schwartz, E.A. Hoffman, et al., A longitudinal cohort study of
aspirin use and progression of emphysema-like lung Characteristics on CT imaging:
the MESA lung study, Chest 154 (1) (2018) 41–50.
[9] A. Fawzy, N. Putcha, C.P. Aaron, et al., Aspirin use and respiratory morbidity in
COPD: a propensity score-matched analysis in subpopulations and intermediate
outcome measures in COPD study, Chest 155 (3) (2019) 519–527.
[10] E. Lefrancais, M.R. Looney, Platelet biogenesis in the lung circulation, Physiology
34 (6) (2019) 392–401.
[11] M. Ogawa, Differentiation and proliferation of hematopoietic stem cells, Blood 81
(11) (1993) 2844–2853.
[12] K.R. Machlus, J.E. Italiano Jr., The incredible journey: from megakaryocyte
development to platelet formation, J. Cell Biol. 201 (6) (2013) 785–796.
[13] R.M. Kaufman, R. Airo, S. Pollack, W.H. Crosby, Circulating megakaryocytes and
platelet release in the lung, Blood 26 (6) (1965) 720–731.
[14] K. Ghoshal, M. Bhattacharyya, Overview of platelet physiology: its hemostatic and
nonhemostatic role in disease pathogenesis, Sci. World J. 2014 (2014) 781857.
[15] E.I. Peerschke, W. Yin, B. Ghebrehiwet, Platelet mediated complement activation,
Adv. Exp. Med. Biol. 632 (2008) 81–91.
[16] S. Ball, K. Nugent, Microparticles in hematological malignancies: role in
coagulopathy and tumor pathogenesis, Am. J. Med. Sci. 355 (3) (2018) 207–214.
[17] V. Brinkmann, U. Reichard, C. Goosmann, et al., Neutrophil extracellular traps kill
bacteria, Science 303 (5663) (2004) 1532–1535.
[18] D.L. Sprague, B.D. Elzey, S.A. Crist, T.J. Waldschmidt, R.J. Jensen, T.L. Ratliff,
Platelet-mediated modulation of adaptive immunity: unique delivery of CD154
signal by platelet-derived membrane vesicles, Blood 111 (10) (2008) 5028–5036.
[19] D. Zucker-Franklin, C.S. Philipp, Platelet production in the pulmonary capillary
bed: new ultrastructural evidence for an old concept, Am. J. Pathol. 157 (1) (2000)
69–74.
[20] P.H. Levine, An acute effect of cigarette smoking on platelet function. A possible
link between smoking and arterial thrombosis, Circulation 48 (3) (1973) 619–623.

5
H. Mallah et al.
[21] J. Hung, J.Y. Lam, L. Lacoste, G. Letchacovski, Cigarette smoking acutely increases
platelet thrombus formation in patients with coronary artery disease taking aspirin,
Circulation 92 (9) (1995) 2432–2436.
[22] A.J. Bialas, K. Siewiera, C. Watala, et al., Mitochondrial functioning abnormalities
observed in blood platelets of chronic smoke-exposed Guinea pigs - a pilot study,
Int. J. Chronic Obstr. Pulm. Dis. 13 (2018) 3707–3717.
[23] J. Qiao, J.F. Arthur, E.E. Gardiner, R.K. Andrews, L. Zeng, K. Xu, Regulation of
platelet activation and thrombus formation by reactive oxygen species, Redox Biol
14 (2018) 126–130.
[24] S. Chen, Y. Su, J. Wang, ROS-mediated platelet generation: a microenvironment-
dependent manner for megakaryocyte proliferation, differentiation, and
maturation, Cell Death Dis. 4 (2013) e722.
[25] G. Cakmak, Z. Saglam, T. Saler, et al., Platelets: indicator of inflammation in COPD,
Int. J. Med. Med. Sci. 1 (5) (2009) 227–229.
[26] M.T. Harrison, P. Short, P.A. Williamson, A. Singanayagam, J.D. Chalmers,
S. Schembri, Thrombocytosis is associated with increased short and long term
mortality after exacerbation of chronic obstructive pulmonary disease: a role for
antiplatelet therapy? Thorax 69 (7) (2014) 609–615.
[27] A. Fawzy, N. Putcha, L.M. Paulin, et al., Association of thrombocytosis with COPD
morbidity: the SPIROMICS and COPDGene cohorts, Respir. Res. 19 (1) (2018) 20.
[28] P. Steiropoulos, N. Papanas, E. Nena, et al., Mean platelet volume and platelet
distribution width in patients with chronic obstructive pulmonary disease: the role
of comorbidities, Angiology 64 (7) (2013) 535–539.
[29] V.R. Biljak, D. Pancirov, I. Cepelak, S. Popovic-Grle, G. Stjepanovic, T.Z. Grubisic,
Platelet count, mean platelet volume and smoking status in stable chronic
obstructive pulmonary disease, Platelets 22 (6) (2011) 466–470.
[30] S. Ball, M. Arevalo, S. Wongsaengsak, J.A. Dennis, K. Nugent, Implications of mean
platelet volume in health and disease: a large population study on data from
National Health and Nutrition Examination Survey, Thromb. Res. 175 (2019)
90–94.
[31] J.A. Wedzicha, D. Syndercombe-Court, K.C. Tan, Increased platelet aggregate
formation in patients with chronic airflow obstruction and hypoxaemia, Thorax 46
(7) (1991) 504–507.
[32] I. Onder, S. Topcu, H.S. Dokmetas, C. Turkay, Z. Seyfikli, Platelet aggregation size
and volume in chronic obstructive pulmonary disease, Mater. Med. Pol. 29 (1–4)
(1997) 11–13.
[33] M.F. Mohamed, A. Ali, A. Abbas, M.S. Awad, M. Gouda, A.M. Sediq, Mean platelet
volume as a predictor of pulmonary hypertension in patients with stable COPD, Int.
J. Chronic Obstr. Pulm. Dis. 14 (2019) 1099–1108.
[34] A.J. Bialas, C. Pedone, W.J. Piotrowski, R. Antonelli Incalzi, Platelet distribution
width as a prognostic factor in patients with COPD - pilot study, Int. J. Chronic
Obstr. Pulm. Dis. 12 (2017) 2261–2267.
[35] H. Bostrom, K. Willetts, M. Pekny, et al., PDGF-A signaling is a critical event in lung
alveolar myofibroblast development and alveogenesis, Cell 85 (6) (1996) 863–873.
Respiratory Medicine 171 (2020) 106098
[36] L. Pan, Y.H. Yang, D.Q. Dong, [Integrin-associated proteins in blood plasma of
patients with acute exacerbation of chronic obstructive pulmonary disease],
Zhonghua Jiehe He Huxi Zazhi 33 (4) (2010) 265–267.
[37] M. Munoz-Esquerre, J.L. Ferreiro, D. Huertas, et al., Impact of acute exacerbations
on platelet reactivity in chronic obstructive pulmonary disease patients, Int. J.
Chronic Obstr. Pulm. Dis. 13 (2018) 141–148.
[38] J.F. Wu, Y.H. Yang, B.S. Pang, [Platelet factor 4 and beta-thromboglobulin in blood
plasma of patients with acute exacerbation of chronic obstructive pulmonary
disease], Zhonghua Yixue Zazhi 93 (18) (2013) 1378–1382.
[39] G. Davi, S. Basili, M. Vieri, et al., Enhanced thromboxane biosynthesis in patients
with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis
and Haemostasis Study Group, Am. J. Respir. Crit. Care Med. 156 (6) (1997)
1794–1799.
[40] M. Humbert, N.W. Morrell, S.L. Archer, et al., Cellular and molecular pathobiology
of pulmonary arterial hypertension, J. Am. Coll. Cardiol. 43 (12 Suppl S) (2004)
13S–24S.
[41] C.J. Schofield, P.J. Ratcliffe, Oxygen sensing by HIF hydroxylases, Nat. Rev. Mol.
Cell Biol. 5 (5) (2004) 343–354.
[42] P.H. Maxwell, M.S. Wiesener, G.W. Chang, et al., The tumour suppressor protein
VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis, Nature
399 (6733) (1999) 271–275.
[43] Q.F. Li, X.R. Wang, Y.W. Yang, H. Lin, Hypoxia upregulates hypoxia inducible
factor (HIF)-3alpha expression in lung epithelial cells: characterization and
comparison with HIF-1alpha, Cell Res. 16 (6) (2006) 548–558.
[44] S.N. Chaurasia, G. Kushwaha, P.P. Kulkarni, et al., Platelet HIF-2alpha promotes
thrombogenicity through PAI-1 synthesis and extracellular vesicle release,
Haematologica 104 (12) (2019) 2482–2492.
[45] X. Xu, H. Wang, Z. Wang, W. Xiao, Plasminogen activator inhibitor-1 promotes
inflammatory process induced by cigarette smoke extraction or
lipopolysaccharides in alveolar epithelial cells, Exp. Lung Res. 35 (9) (2009)
795–805.
[46] H. Wang, T. Yang, D. Li, et al., Elevated circulating PAI-1 levels are related to lung
function decline, systemic inflammation, and small airway obstruction in chronic
obstructive pulmonary disease, Int. J. Chronic Obstr. Pulm. Dis. 11 (2016)
2369–2376.
[47] M.P. Ekstrom, A.B. Hermansson, K.E. Strom, Effects of cardiovascular drugs on
mortality in severe chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care
Med. 187 (7) (2013) 715–720.
[48] T. Goto, M.K. Faridi, C.A. Camargo, K. Hasegawa, The association of aspirin use
with severity of acute exacerbation of chronic obstructive pulmonary disease: a
retrospective cohort study, NPJ Prim Care Respir Med 28 (1) (2018) 7.
[49] R. Pavasini, S. Biscaglia, F. d’Ascenzo, et al., Antiplatelet treatment reduces all-
cause mortality in COPD patients: a systematic review and meta-analysis, COPD 13
(4) (2016) 509–514.