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Aspirin Resistance in Obese and Elderly Patients with COVID-19?

      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).
      • McCullough PA
      • Kelly RJ
      • Ruocco G
      • et al.
      Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection [e-pub ahead of print].
      The authors should be commended for proposing antiplatelet and antithrombotic therapy early in the disease.
      • Hottz ED
      • Azevedo-Quintanilha IG
      • Palhinha L
      • et al.
      Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients.
      McCullough et al recommend 81 mg aspirin daily for high-risk, ambulatory patients with COVID-19.
      • McCullough PA
      • Kelly RJ
      • Ruocco G
      • et al.
      Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection [e-pub ahead of print].
      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,
      • Hottz ED
      • Azevedo-Quintanilha IG
      • Palhinha L
      • et al.
      Platelet activation and platelet-monocyte aggregates formation trigger tissue factor expression in severe COVID-19 patients.
      and COX-2 expression is upregulated more than 50-fold in severe COVID-19.
      • Sharma A
      • Garcia GJ
      • Wang Y
      • et al.
      Human iPSC-derived cardiomyocytes are susceptible to SARS-CoV-2 infection.
      COX-2 is inducible and expressed in megakaryocytes and platelets.
      • Rocca B
      • Secchiero P
      • Ciabattoni G
      • et al.
      Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets.
      Low-dose aspirin effectively inhibits COX-1 but not COX-2 activity.
      • Ornelas A
      • Zacharias-Millward N
      • Menter DG
      • et al.
      Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention.
      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.
      • Kim JW
      • Zou Y
      • Yoon S
      • et al.
      Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction.
      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).
      • Petrucci G
      • Zaccardi F
      • Giaretta A
      • et al.
      Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation.
      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.
      • Petrucci G
      • Zaccardi F
      • Giaretta A
      • et al.
      Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation.
      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).
      • Eikelboom JW
      • Hankey GJ
      • Thom J
      • et al.
      Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid.
      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

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        • Kelly RJ
        • Ruocco G
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        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
        • Hottz ED
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        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
        • 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
        • Rocca B
        • Secchiero P
        • Ciabattoni G
        • et al.
        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
        • Ornelas A
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        • Menter DG
        • et al.
        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
        • Kim JW
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        Vascular aging: molecular modulation of the prostanoid cascade by calorie restriction.
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        • Zaccardi F
        • Giaretta A
        • et al.
        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
        • Eikelboom JW
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        Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid.
        Circulation. 2008; 118: 1705-1712https://doi.org/10.1161/circulationaha.108.768283