Cyclooxygenase (COX)-1 or -2 and prostaglandin (PG) synthases catalyze the formation of various PGs and thromboxane (TX) A ₂ . We have investigated the expression and activity of COX-1 and -2 during human megakaryocytopoiesis. We analyzed megakaryocytes from bone marrow biopsies and derived from thrombopoietin-treated CD34 ⁺ hemopoietic progenitor cells in culture. Platelets were obtained from healthy donors and patients with high platelet regeneration because of immune thrombocytopenia or peripheral blood stem cell transplantation. By immunocytochemistry, COX-1 was observed in CD34 ⁺ cells and in megakaryocytes at each stage of maturation, whereas COX-2 was induced after 6 days of culture, and remained detectable in mature megakaryocytes. CD34 ⁺ cells synthesized more PGE ₂ than TXB ₂ (214 ± 50 vs. 30 ± 10 pg/10 ⁶ cells), whereas the reverse was true in mature megakaryocytes (TXB ₂ 8,440 ± 2,500 vs. PGE ₂ 906 ± 161 pg/10 ⁶ cells). By immunostaining, COX-2 was observed in <10% of circulating platelets from healthy controls, whereas up to 60% of COX-2-positive platelets were found in patients. A selective COX-2 inhibitor reduced platelet production of both PGE ₂ and TXB ₂ to a significantly greater extent in patients than in healthy subjects. Finally, we found that COX-2 and the inducible PGE-synthase were coexpressed in mature megakaryocytes and in platelets. We conclude that both COX-isoforms contribute to prostanoid formation during human megakaryocytopoiesis and that COX-2-derived PGE ₂ and TXA ₂ may play an unrecognized role in inflammatory and hemostatic responses in clinical syndromes associated with high platelet turnover.

Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A₂ (TXA₂) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA₂ biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB₂ independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (β = 3.53, P = .001). Twenty-one aspirin-treated patients with serum TXB₂ ≥ 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric-coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB₂ reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB₂ excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB₂ only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose.

Arachidonic acid is one of the most abundant and ubiquitous ω-6 polyunsaturated fatty acid, present in esterified form in the membrane phospholipids of all mammalian cells and released from phospholipids by several phospholipases in response to various activating or inhibitory stimuli. Arachidonic acid is the precursor of a large number of enzymatically and non-enzymatically derived, biologically active autacoids, including prostaglandins (PGs), thromboxane (TX) A₂, leukotrienes, and epoxyeicosatetraenoic acids (collectively called eicosanoids), endocannabinoids and isoprostanes, respectively. Eicosanoids are local modulators of the physiological functions and pathophysiological roles of blood vessels and platelets. For example, the importance of cyclooxygenase (COX)-1-derived TXA₂ from activated platelets in contributing to primary haemostasis and atherothrombosis is demonstrated in animal and human models by the bleeding complications and cardioprotective effects associated with low-dose aspirin, a selective inhibitor of platelet COX-1. The relevance of vascular COX-2-derived prostacyclin (PGI₂) in endothelial thromboresistance and atheroprotection is clearly shown by animal and human models and by the adverse cardiovascular effects exerted by COX-2 inhibitors in humans. A vast array of arachidonic acid-transforming enzymes, downstream synthases and isomerases, transmembrane receptors, and specificity in their tissue expression make arachidonic acid metabolism a fine-tuning system of vascular health and disease. Its pharmacological regulation is central in human cardiovascular diseases, as demonstrated by biochemical measurements and intervention trials.

The success of trials that have shown net clinical benefits of antithrombotic drugs as well as the increasing prevalence of cardiovascular diseases in an ageing population have led to more widespread use of antiplatelet and anticoagulant drugs. At the same time, extremely low and high body weight (BW) are becoming more common due to a higher prevalence of frailty, associated with greater life expectancy, and the global epidemic of obesity, ‘globesity’, respectively.^1–3 These extreme BWs may affect cardiovascular risk as well as the pharmacokinetics of antithrombotic drugs, some of which have relatively narrow therapeutic windows.

Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.