In vivo prostacyclin biosynthesis and effects of different aspirin regimens in patients with essential thrombocythaemia

Summary

Essential thrombocythaemia (ET) is characterised by enhanced platelet generation and thrombosis. Once daily (od) aspirin incompletely inhibits platelet thromboxane (TX)A₂ production in ET. A twice daily (bid) dosing is necessary to fully inhibit TXA₂. Whether this dosing regimen affects in vivo prostacyclin (PGI₂) biosynthesis is unknown. PGI₂ biosynthesis was characterised in 50 ET patients on enteric-coated (EC) aspirin 100 mg od, by measuring its urinary metabolite, 2,3-dinor-6-keto-PGF_1α (PGI-M). Moreover, in a crossover study 22 patients poorly responsive to standard aspirin based on serum TXB₂ levels (>4 ng/ml) were randomised to different seven-day aspirin regimens: EC aspirin 100 mg od, 100 mg bid, 200 mg od, or plain as-pirin 100 mg od. PGI-M measured 24 hours after the last aspirin intake (EC, 100 mg od) was similar in patients and healthy subjects both on (n=10) and off (n=30) aspirin. PGI-M was unrelated to in vivo TXA₂ biosynthesis, and not affected by EC aspirin 100 mg bid or 200 mg od as compared to EC 100 mg od. PGI₂ biosynthesis in aspirin-treated ET patients appears unrelated to TXA₂ biosynthesis, and not affected by an improved aspirin regimen, demonstrating its vascular safety for future trials.

Keywords

Aspirin - prostacyclin - essential thrombocythaemia - platelets - thromboxane

^* Contributed equally as first authors.

• References

• 1 Patrono C, Rocca B, De Stefano V. Platelet activation and inhibition in polycy-thaemia vera and essential thrombocythaemia. Blood 2013; 121: 1701-1711.
• 2 Landolfi R, Marchioli R, Kutti J. et al. Efficacy and safety of low-dose aspirin in polycythaemia vera. N Engl J Med 2004; 350: 114-124.
• 3 Alvarez-Larran A, Cervantes F, Pereira A. et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocy-thaemia. Blood 2010; 116: 1205-1210. quiz 1387
• 4 De Stefano V, Za T, Rossi E. et al. Recurrent thrombosis in patients with polycy-thaemia vera and essential thrombocythaemia: incidence, risk factors, and effect of treatments. Haematologica 2008; 93: 372-380.
• 5 Palandri F, Polverelli N, Catani L. et al. Bleeding in essential thrombocythaemia: a retrospective analysis on 565 patients. Br J Haematol 2012; 156: 281-284.
• 6 TEAftEoM. Position paper on the regulatory requirements for the authorisation of low-dose modifie release ASA formulations in the secondary prevention of cardiovascular events. Doc Ref: EMEA/CPMP/EWP/282/02/final. 2009
• 7 Patrono C, Ciabattoni G, Pinca E. et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res 1980; 17: 317-327.
• 8 Dragani A, Pascale S, Recchiuti A. et al. The contribution of cyclooxygenase-1 and −2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythaemia: implications for antiplatelet therapy. Blood 2010; 115: 1054-1061.
• 9 Pascale S, Petrucci G, Dragani A. et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythaemia is explained by accelerated renewal of the drug target. Blood 2012; 119: 3595-3603.
• 10 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin “resistance”. J Am Coll Cardiol 2009; 53: 667-677.
• 11 Dillinger JG, Sideris G, Henry P, Bal dit Sollier C, Ronez E, Drouet L. Twice daily aspirin to improve biological aspirin efficacy in patients with essential thrombocythaemia. Thromb Res 2012; 129: 91-94.
• 12 Tefferi A. Overcoming “aspirin resistance” in MPN. Blood 2012; 119: 3377-3378.
• 13 McAdam BF, Catella-Lawson F, Mardini IA. et al. Systemic biosynthesis of pros-tacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-277.
• 14 Gryglewski RJ, Bunting S, Moncada S. et al. Arterial walls are protected against deposition of platelet thrombi by a substance (prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins 1976; 12: 685-713.
• 15 Topper JN, Cai J, Falb D. et al. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 1996; 93: 10417-10422.
• 16 Murata T, Ushikubi F, Matsuoka T. et al. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature 1997; 388: 678-682.
• 17 Yu Y, Ricciotti E, Scalia R. et al. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Translat Med 2012; 04: 132ra54.
• 18 Fitzgerald DJ, Roy L, Catella F. et al. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-989.
• 19 Fitzgerald DJ, Catella F, Roy L. et al. Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 1988; 77: 142-150.
• 20 Roy L, Knapp HR, Robertson RM. et al. Endogenous biosynthesis of prostacyc-lin during cardiac catheterisation and angiography in man. Circulation 1985; 71: 434-440.
• 21 FitzGerald GA, Smith B, Pedersen AK. et al. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-1068.
• 22 Knapp HR, Healy C, Lawson J. et al. Effects of low-dose aspirin on endogenous eicosanoid formation in normal and atherosclerotic men. Thromb Res 1988; 50: 377-386.
• 23 FitzGerald GA, Brash AR, Falardeau P. et al. Estimated rate of prostacyclin secretion into the circulation of normal man. J Clin Invest 1981; 68: 1272-1276.
• 24 Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Bahala N, Ember-son J, Merhi A, Abramson S. et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382: 769-779.
• 25 Kearney PM, Baigent C, Godwin J. et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Br Med J 2006; 332: 1302-1308.
• 26 Rocca B, Ciabattoni G, Tartaglione R. et al. Increased thromboxane biosynthesis in essential thrombocythaemia. Thromb Haemost 1995; 74: 1225-1230.
• 27 Swerdlow SH, Campo E, Harris NL. et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC 2008
• 28 Ciabattoni G, Pugliese F, Davi G. et al. Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70.
• 29 Morrow JD, Hill KE, Burk RF. et al. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalysed mechanism. Proc Natl Acad Sci USA 1990; 87: 9383-9387.
• 30 Ciabattoni G, Maclouf J, Catella F. et al. Radioimmunoassay of 11-dehydro-thromboxane B2 in human plasma and urine. Biochim Biophys Acta 1987; 918: 293-297.
• 31 Wang Z, Ciabattoni G, Creminon C. et al. Immunological characterisation of urinary 8-epi-prostaglandin F2 alpha excretion in man. J Pharmacol Experiment Therapeut 1995; 275: 94-100.
• 32 Blatnik M, Steenwyk RC. Quantification of urinary PGEm, 6-keto PGF(1alpha) and 2,3-dinor-6-keto PGF(1alpha) by UFLC-MS/MS before and after exercise. Prostaglan Lipid Mediators 2010; 93: 8-13.
• 33 Capone ML, Tacconelli S, Sciulli MG. et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation 2004; 109: 1468-1471.
• 34 Patrono C, Garcia Rodriguez LA, Landolfi R. et al. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353: 2373-2383.
• 35 Egan KM, Lawson JA, Fries S. et al. COX-2-derived prostacyclin confers athero-protection on female mice. Science 2004; 306: 1954-1957.
• 36 Garcia Rodriguez LA, Egan K, FitzGerald GA. Traditional nonsteroidal anti-inflammatory drugs and postmenopausal hormone therapy: a drug-drug interaction?. PLoS Med 2007; 04: e157.
• 37 Ali M, McDonald JW, Thiessen JJ. et al. Plasma acetylsalicylate and salicylate and platelet cyclooxygenase activity following plain and enteric-coated aspirin. Stroke 1980; 11: 9-13.
• 38 Cox D, Maree AO, Dooley M. et al. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006; 37: 2153-2158.
• 39 Grosser T, Fries S, Lawson JA. et al. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013; 127: 377-385.