On‐pump Cardiac Surgery Enhances Platelet Renewal and Impairs Aspirin Pharmacodynamics: Effects of Improved Dosing Regimens

Abstract

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B within the 24-hour dosing interval and urinary TXA metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover.

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“…Identifying accelerated thrombopoiesis is potentially important because the associated reduced pharmacological response is modifiable by administering aspirin twice daily. [1][2][3][4]7 Three approaches have been used to identify patients with a reduced response to once-daily aspirin. 8,9 These are assays based on platelet aggregation, assays measuring thromboxane synthesis, and COX-1 acetylation assays.…”

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“…Consistent with this hypothesis, Cavalca et al recently reported impaired aspirin pharmacodynamics early after ONCAB that were associated with significant increases in immature platelets, total platelets, platelet mass, thrombopoieitin, IL‐6, glycocalicin, leukocytes, and high‐sensitivity CRP 32. IL‐6 can control inflammation through CRP and modulate megakaryocyte fragmentation, differentiation, and platelet release directly or through thrombopoieitin 32. Changes in thrombopoietic indexes were largely reversible 3 months after surgery 32.…”

“…In a study by Zimmermann et al,33 the antiplatelet effect of aspirin (100 mg/day started on day 1 after surgery) evaluated at day 5 was largely impaired after CPB but not after CABG without CPB; therefore, increased platelet turnover after CPB appears to contribute to transient aspirin “resistance” because an increased number of new platelets might be competent to form Thromboxane A 2 (TXA 2 ) within the 24‐hour dosing interval 33. Consistent with this hypothesis, Cavalca et al recently reported impaired aspirin pharmacodynamics early after ONCAB that were associated with significant increases in immature platelets, total platelets, platelet mass, thrombopoieitin, IL‐6, glycocalicin, leukocytes, and high‐sensitivity CRP 32. IL‐6 can control inflammation through CRP and modulate megakaryocyte fragmentation, differentiation, and platelet release directly or through thrombopoieitin 32.…”

“…A different and more clinically relevant way of assessing the potential hemostatic/prothrombotic differences related to ONCAB versus OPCAB is represented by studies of the pharmacodynamic response to antiplatelet drugs in these settings 32, 33. In a study by Zimmermann et al,33 the antiplatelet effect of aspirin (100 mg/day started on day 1 after surgery) evaluated at day 5 was largely impaired after CPB but not after CABG without CPB; therefore, increased platelet turnover after CPB appears to contribute to transient aspirin “resistance” because an increased number of new platelets might be competent to form Thromboxane A 2 (TXA 2 ) within the 24‐hour dosing interval 33.…”

“…IL‐6 can control inflammation through CRP and modulate megakaryocyte fragmentation, differentiation, and platelet release directly or through thrombopoieitin 32. Changes in thrombopoietic indexes were largely reversible 3 months after surgery 32. As shown by 3 independent studies, shortening the dosing interval (ie, twice‐daily dosing), but not doubling the dose, safely rescued the impaired antiplatelet effect of low‐dose aspirin and prevented platelet activation associated with acute inflammation and enhanced platelet turnover following cardiac surgery 32, 36, 37…”