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The lung is an important organ for platelet biogenesis.
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Smoking induces aggregation and attenuates mitochondrial respiration in platelets.
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Activated platelets and their mediators contribute to the pathogenesis of COPD.
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Antiplatelet therapy prevents the exacerbations and delays the progression of COPD.
Abstract
Platelets are essential mediators of inflammation and thrombosis. Chronic obstructive pulmonary disease (COPD) is a heterogeneous multisystem disease, causing significant morbidity and mortality worldwide. Recent evidence suggests that the lung is an important organ for platelet biogenesis. Cigarette smoking has been shown to induce platelet aggregation and decrease the capacity of mitochondrial electron transport system in platelets. Preclinical and clinical studies have suggested that platelets may contribute to the development of COPD through the 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, pathophysiological 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.
]. Chronic obstructive pulmonary disease (COPD) is a heterogeneous 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 [
]. 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 progression of COPD [
]. 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 [
]. Moreover, the use of aspirin has been shown to decrease the rate of acute exacerbations and delay the overall progression of COPD in recently published clinical studies [
]. Hence, the objectives of this review are to summarize the information on platelet biogenesis in lungs, to investigate the functions of platelets in the 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.[
] 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 [
]. Upon reaching their perivascular microenvironment, megakaryocytes develop extensions, structures described as proplatelets (2–4 μm) from which platelets fragment into bone marrow sinusoids [
]. 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 [
]. Some megakaryocytes are also found to reside in the pulmonary interstitium. These are phenotypically different and primarily express genes involved in immunity and inflammation [
Hemostasis is the primary physiological function of platelets in circulation. Upon injury to the vessel, the exposed subendothelial collagen and immobilized von Willebrand factor (vWF) interacts with the proteins on the platelet surface, such as integrins and glycoproteins Ib-IIa (GPIb-IIa) to mediate adhesion [
]. 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-granules, dense granules, and lysosomes) and to generate their own proteins through translation [
]. 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 [
]. Also, platelet microparticles (size 100–1000 nm) released from the platelets contain membrane constituents which are required for communication between leukocytes and vascular endothelial cells to mediate inflammation [
]. 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 enzymes). This occurs primarily in the lungs and liver, leading to the development of multiorgan failure [
]. Activated platelets have recently been shown to express CD154 that interacts with CD40 on endothelial cells to recruit leukocytes and participate in adaptive immunity. By expressing the CD40 ligand, platelets enhance antigen presentation, stimulate B cell differentiation and immunoglobulin class-switching, produce virus specific immunoglobulin G, and augment the response of CD8 cells [
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 megakaryocytes 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 megakaryocytes. These findings were more evident with increases in blood platelet counts [
]. 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 production 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 [
]. All these findings provide strong evidence suggesting that the lung is a major site of platelet biogenesis. Fig. 1 depicts the process of platelet formation, activation, and consequent release of mediators in the lung interstitium.
Fig. 1Biogenesis and Activation of Platelets in Lung
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 epinephrine or as a result of a smoking-induced increase in plasma catecholamines, mostly epinephrine, which is a well-studied stimulus of platelet aggregation[
]. 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 [
]. Chronic smoking reduces platelet lifespan significantly 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 [
]. 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 [
]. 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 regulators that act on multiple different signaling pathways during development of megakaryocytes [
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 [
]. 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 underlying the association may be independent of an increase in cardiovascular risk [
Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?.
]. A recently published large population study with data from the National Health and Nutrition Examination Survey showed that individuals with a self-reported diagnosis of emphysema had a significantly higher likelihood of having MPV lower than 10th percentile, compared to those who did not report the diagnosis.[
]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 aggregation in these patients [
]. Investigators have studied the potential utility of MPV in the prediction of exacerbations and development of pulmonary hypertension in patients with COPD [
]. An elevated PDW has also been associated with significantly lower forced expiratory flows in patients with stable COPD and was an independent risk factor for mortality in these patients, even after adjustment for potential confounding factors [
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.
Table 2Role of platelets in the pathogenesis of chronic obstructive pulmonary disease.
Effects on Lungs Relevant to COPD
Responsible Platelet Mediators
Likely Pathophysiologic Mechanisms
Loss of alveolar integrity
Platelet factor-4 (PF4) Platelet derived growth factor- A (PDGF-A)
Induction of human leukocyte elastase Abnormal alveolar septation
Generation of prothrombotic state and pulmonary vascular remodeling
P- Selectin CD 47 Beta- thromboglobulin Thromboxanes
Abnormal platelet activation Increased formation of platelet- monocyte aggregates Enhanced release of platelet mediators
Dysregulated response to hypoxia
Plasminogen activator inhibitor −1 (PAI-1)
Stimulation of release of platelet vesicles Increase in smoking-induced inflammation
Lung elastin was purified from hamster lungs to determine if human platelet factor 4 (PF4) stimulates the activity of human leukocyte elastase (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 [
]. 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 [
6.2 Prothrombotic state and pulmonary vascular remodeling
Following vascular injury, circulating platelets become activated, upregulating expression of cell surface receptors such as P-selectin ligand to facilitate adhesion to the arterial wall. Activated platelets release inflammatory chemokines and recruit inflammatory cells to form platelet-monocyte aggregates. Circulating platelet-monocyte aggregates are considered a sensitive measure of platelet activation. A study showed a significant increase in circulating platelet-monocyte aggregates in stable COPD patients compared with their well-matched controls. Aggregation increased further during an acute exacerbation in these patients. Platelet P-selectin expression and soluble P-selectin did not differ between groups in this study [
]. This increased propensity to form platelet aggregates may be partially explained by an increase in levels of integrin-associated proteins (e.g., CD47) noted in the serum of patients with severe acute exacerbation of COPD (AECOPD) [
]. In a recently published prospective, observational study, platelet reactivity (assessed with vasodilator-stimulated phosphoprotein assay) was significantly higher in patients with AECOPD, as compared to those with stable disease [
Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group.
Am. J. Respir. Crit. Care Med.1997; 156: 1794-1799
]. A study investigated platelet function by assessment of aggregate formation “in vivo” by measuring platelet aggregate ratio and blood concentrations of various platelet release products (e.g., β thromboglobulin and thromboxane B2) in patients with chronic airflow obstruction with and without hypoxemia. The platelet aggregate ratio (value approaches 1.0, in absence of platelet aggregation) was lower in the hypoxemic patients compared to the non-hypoxemic and control groups, although platelet release products were not increased in the peripheral blood. These findings suggest an increase in platelet activation and consequent platelet aggregate formation in patients with worsening hypoxemia and hypercapnia. Platelet aggregates may be trapped in the lung, resulting in the local release of mediators, leading to the structural remodeling of the pulmonary vasculature and consequent development of pulmonary hypertension, a common complication in patients with COPD [
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 [
]. Human platelets express HIF-2α, augmented by the exposure to hypoxia or other psychological stress. Hypoxia also stimulates platelets to synthesize plasminogen activator inhibitor (PAI)-1 and shed extracellular vesicles. These effects potentially induce a pro-thrombotic state associated with hypoxia. Platelets from patients with COPD and at high altitude were found to have higher expression of HIF-2α and PAI-1 than their healthy counterparts, indicating the potential role of platelet hypoxia signaling in the pathogenesis of COPD [
]. Several studies have suggested that PAI-1 may induce the progression of COPD through different mechanisms. It promotes inflammation caused by exposure to the cigarette smoke [
Plasminogen activator inhibitor-1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells.
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.2016; 11: 2369-2376
The role of antiplatelet therapy in patients with COPD has been evaluated in several clinical studies. The recently published Multi-Ethnic Study of Atherosclerosis (MESA) lung study included 4257 individuals (54% were smokers) with a mean age of 61 years. Aspirin use was noted to be regular (defined as 3 or more days a week) in 22% of study participants. The progression of percent emphysema (the percentage of emphysema-like lung below −950 Hounsfield units on cardiac and full-lung CT scans) was slower among patients who used aspirin regularly compared to those who did not. Regular aspirin use was associated with greater than 50% reduction in the rate of emphysema progression over 10 years. Results were similar with different doses (81 mg vs. 325 mg per day) of aspirin, with a greater magnitude of effect observed among those with airflow limitation; however, no association was found between aspirin use and change in lung function (measured by FEV1 or FEV1/FVC on spirometry). Beneficial effects on progression of emphysema seemed to be more prominent in men and current smokers [
Another cohort study evaluated the effect of aspirin on morbidity in 1698 patients with COPD, based on self-reported aspirin use. Aspirin users were matched one-to-one with nonusers, based on a propensity score. Patients on regular aspirin had significantly lower incidence rates of total AECOPD, although incidence of severe AECOPD did not differ significantly between the two groups. In this study, aspirin use was associated with a significantly improved quality of life (assessed with the St. George's Respiratory Questionnaire score) and lower odds of development of moderate-severe dyspnea (modified Medical Research Council questionnaire score ≥ 2) in patients [
Antiplatelet therapy with aspirin or clopidogrel was also correlated with a reduction in 1-year mortality in another observational study performed on 1343 spirometry confirmed COPD patients hospitalized with AECOPD [
Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?.
]. A large prospective national study from Sweden showed that use of antiplatelet medications was associated with a significant reduction of mortality risk in oxygen-dependent COPD patients [
]. In a retrospective cohort study with 206,806 patients hospitalized for AECOPD, aspirin use was found to be associated with significantly lower risk of in-hospital death and need for invasive mechanical ventilation [
]. Finally, a recently published meta-analysis of 5 studies with 11,117 patients concluded that antiplatelet therapy significantly lowers all-cause mortality in COPD patients, both in stable patients or in those with AECOPD. These results were consistent after meta-regression analysis with consideration for potential confounding factors [
ASA use was associated with - Lower incidence of total AECOPD (IRR 0.78; 95% CI, 0.65–0.94) with ASA use. - Lower SGRQ score and lower COPD Assessment Test score.
Harrison et al. 2014
Observational Cohort Study
1343
Spirometry confirmed COPD, Hospitalized for AECOPD
ASA or clopidogrel Dose- NR
One year all-cause mortality
ASA or clopidogrel treatment correlated with reduction in 1- year mortality (OR 0.63; 95% CI 0.47 to 0.85, p = 0.003).
Goto et al. 2018
Retrospective Cohort Study
206,686
Hospitalized for AECOPD
ASA Dose- NR
In-hospital death, Use of MV, Hospital length of stay
ASA users had - Lower inpatient mortality (OR 0.60; 95% 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 et al. 2016
Systematic Review and Meta-analysis
11,117
COPD
Any antiplatelet agent Dose- NR
All-cause mortality
Significantly lower all-cause mortality in patients on antiplatelet therapy (OR 0.81; 95%CI 0.75–0.88).
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 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 magnitude 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.
Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?.
Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group.
Am. J. Respir. Crit. Care Med.1997; 156: 1794-1799
Plasminogen activator inhibitor-1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells.
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.2016; 11: 2369-2376
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