To the Editor:
We read with great interest the recent publication by McCullough et al proposing a comprehensive management strategy for ambulatory patients with coronavirus disease 2019 (COVID-19).
1
The authors should be commended for proposing antiplatelet and antithrombotic therapy early in the disease.2
McCullough et al recommend 81 mg aspirin daily for high-risk, ambulatory patients with COVID-19.1
We suggest caution in relying on low-dose aspirin as chemoprophylaxis or treatment for immunothrombosis in COVID-19, especially in patients who are obese or elderly.Plasma thromboxane B2 levels are significantly increased,
2
and COX-2 expression is upregulated more than 50-fold in severe COVID-19.3
COX-2 is inducible and expressed in megakaryocytes and platelets.- Sharma A
- Garcia GJ
- Wang Y
- et al.
Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection.
Cell Rep Med. 2020; 1100052https://doi.org/10.1016/j.xcrm.2020.100052
4
Low-dose aspirin effectively inhibits COX-1 but not COX-2 activity.5
Increased expression of cytosolic phospholipase A2 and COX-2 in the obese or the elderly leads to increased generation of thromboxane A2 and resistance to aspirin.6
Among aspirin-naïve subjects, the median urinary 11-dehydro-thromboxane B2 levels was 1433 pg/mg creatinine in the obese compared with 505 pg/mg creatinine in the nonobese, healthy controls (P < 0.01).7
Furthermore, among subjects taking aspirin, serum thromboxane B2 levels were positively correlated with body mass index (BMI) and body weight, suggesting that thromboxane generation in the obese is COX-2 dependent.7
The effect of aging on thromboxane generation was studied in 3261 aspirin-treated subjects: the baseline urinary thromboxane B2 levels increased with advancing age and were associated with higher risk of cardiovascular events (CHARISMA trial).8
Marked increase in thromboxane generation and COX-2 expression in severe COVID-19 raises the specter of aspirin resistance, especially in patients who are elderly or obese. Though increasingly recommended, the efficacy of low-dose aspirin remains to be demonstrated in ambulatory or hospitalized patients with COVID-19. The critical role of immunothrombosis in the pathogenesis, progression, and multiorgan failure in COVID-19 underlines an urgent need for effective antithrombotic therapies to reduce the risk of hospitalization, morbidity, and mortality.References
- Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection [e-pub ahead of print].Am J Med. 2021; (Accessed August 25, 2020): 16-22https://doi.org/10.1016/j.amjmed.2020.07.003
- Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients.Blood. 2020; 136: 1330-1341https://doi.org/10.1182/blood.2020007252
- Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection.Cell Rep Med. 2020; 1100052https://doi.org/10.1016/j.xcrm.2020.100052
- Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets.Proc Natl Acad Sci U S A. 2002; 99: 7634-7639https://doi.org/10.1073/pnas.112202999
- Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention.Cancer Metastasis Rev. 2017; 36: 289-303https://doi.org/10.1007/s10555-017-9675-z
- Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction.J Gerontol A Biol Sci Med Sci. 2004; 59: B876-B885https://doi.org/10.1093/gerona/59.9.b876
- Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation.J Thromb Haemost. 2019; 17: 885-895https://doi.org/10.1111/jth.14445
- Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid.Circulation. 2008; 118: 1705-1712https://doi.org/10.1161/circulationaha.108.768283
Article Info
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Funding: None.
Conflicts of Interest: None.
Authorship: Both authors had access to the data and a role in writing this manuscript.
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© 2021 Published by Elsevier Inc.
