Platelets play an important role in chronic obstructive pulmonary disease (COPD), and antiplatelet therapy may delay progression of the lung disease, decrease the risk for acute exacerbations, improve quality of life, and even reduce all-cause mortality, according to a recent review published in Respiratory Medicine.1  

Platelets are primarily produced in the bone marrow, but data suggest that the lung may serve as an additional major site of platelet biogenesis. The effects of platelets on elastase activity and loss of alveolar integrity, formation of platelet aggregates associated with prothrombotic state and pulmonary vascular remodeling, and dysregulated response to hypoxia, may all contribute to the pathogenesis of COPD.1

Patients with COPD have been found to have higher platelet counts, and thrombocytosis has been identified as a potential risk factor for increased morbidity and mortality in patients with COPD.1,2 Previous studies have reported that patients with COPD have increased levels of inflammatory markers, as well as elevated levels of metabolites of thromboxane A2, which is secreted by activated platelets.3,4

Smoking has a major effect on platelets as it can reduce platelet lifespan, increase platelet response to aggregation through direct and indirect effects of nicotine, and alter platelets mitochondrial respiratory parameters with increased generation of reactive oxygen species that have a vital role in regulation of platelets signaling pathways.1


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The Role of Aspirin in COPD

Aspirin, an antiplatelet that blocks the conversion of arachidonic acid, has both systemic and local effects, including platelets inactivation and anti-inflammatory properties.5

The Multi-Ethnic Study of Atherosclerosis (MESA)-Lung study was the first study to suggest that aspirin use may slow emphysema progression. The study included more than4000 patients aged 45 to 84 years and evaluated the percentage of emphysema-like lung characteristics on computed tomography (CT).6 Regular aspirin use, defined as aspirin use 3 days or more per week, was associated with a more than 50% reduction in the rate of emphysema progression on imaging over 10 years.  The results were similar in ever smokers and in individuals using low-dose (81 mg) or full-strength (300-325 mg) aspirin.6 Aaron et al noted that inhibition of platelet activation by aspirin was the most likely explanation for the beneficial effect of antiplatelet therapy on the chronic lung disease.6

Aspirin therapy was also associated with a lower rate of COPD exacerbation, as patients who received aspirin had a 22% lower incidence of any acute exacerbation during 3 years of follow-up (adjusted incidence rate ratio, 0.78; 95% CI, 0.65-0.94) compared with patients who did not receive aspirin. Furthermore, daily aspirin use was associated with fewer respiratory symptoms, including exacerbation risk and dyspnea, and better quality of life.5

Additionally, several studies have reported aspirin treatment may be associated with reduced all-cause mortality in patients with COPD. Harrison et al conducted an observational cohort study of patients hospitalized for acute exacerbation of COPD and reported a reduction 1 year all-cause mortality risk in patients on aspirin or clopidogrel (odds ratio [OR], 0.63; 95% CI, 0.47-0.85; P =.003).2 Goto et al also completed a retrospective study of patients hospitalized for acute exacerbation of COPD and reported a lower inpatient mortality in patients treated with aspirin (OR, 0.60; 95% CI-0.50-0.72; P <.001), along with a lower rate of invasive mechanical ventilation (OR, 0.64; 95% CI, 0.55-0.73; P <.001).7  However, this potential survival benefit of aspirin treatment in patients with COPD was not evident in other studies.8,9,

In a 2016 systematic review and meta-analysis, all-cause mortality risk was significantly lower in patients with COPD  on antiplatelet therapy (OR, 0.81; 95% CI, 0.75-0.88), with consistent findings in outpatients and in those with acute exacerbation of COPD.10

Newer Antiplatelet Therapies

While aspirin was the most commonly used antiplatelet in the aforementioned studies, in the study by Harrision et al, 91 patients were treated with clopidogrel and data showed that aspirin or clopidogrel treatment correlated with a reduction in 1-year mortality.2 Campo et al suggested that newer antiplatelets, including prasugrel and ticagrelor, may produce a stronger platelet inhibition and improve outcomes in patients with COPD patients.8 However, the use of the anticoagulant, warfarin, was not associated with a significant difference in overall mortality.2

Antiplatelet therapy, especially aspirin, should be considered for patients with COPD, with or without ischemic heart disease, as treatment may slow disease progression, respiratory morbidity, and all-cause mortality. Thrombocytosis was found to be an independent risk factor for mortality in patients with acute exacerbation of COPD, and antiplatelet therapy may be associated with a survival benefit.2

It is important to note that the benefits of antiplatelet therapy are based on data from retrospective and observational studies. Additional studies may better characterize the role of platelets and antiplatelet therapy in patients with COPD.

“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,” wrote the researchers.1

References

1. Mallah H, Ball S, Sekhon J, Parmar K, Nugent K. Platelets in chronic obstructive pulmonary disease: aAn update on pathophysiology and implications for antiplatelet therapy. Respir Med. 2020;171:106098.

2. Harrison MT, Short P, Williamson PA, Singanayagam A, Chalmers JD, Schembri S. Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy? Thorax. 2014;69(7):609-615.

3. Agusti A, Edwards LD, Rennard SI, et al; for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5):e37483.

4. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest. 1982;69(6):1366-1372.

5. Fawzy A, Putcha N, Aaron CP, et al. Aspirin use and respiratory morbidity in COPD: a propensity score-matched analysis in subpopulations and intermediate outcome measures in COPD study. CHEST. 2019;155(3):519-527.

6. Aaron CP, Schwartz JE, Hoffman EA, et al. A longitudinal cohort study of aspirin use and progression of emphysema-like lung characteristics on CT imaging: the MESA Lung study. CHEST. 2018;154(1):41-50.

7. Goto T, Faidi MK, Camargo CA, Hasegawa K. The association of aspirin use with severity of acute exacerbation of chronic obstructive pulmonary disease : a retrospective cohort study. NPJ Prim Care Respir Med. 2018;28(1):7.

8. Campo G, Pavasini R, Malagù M, et al. Relationship between troponin elevation, cardiovascular history and adverse events in patients with acute exacerbation of COPD. COPD. 2015;12(5):560-567.

9. Søyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J. 2007;29(2):279-283.

10. Pavasini R, Biscaglia S, Ascenzo F, et al. Antiplatelet treatment reduces all-cause mortality in COPD patients : a systematic review and meta-analysis. COPD. 2016;13(4):509-514.