Patients with Essential Thrombocythemia may be Poor Responders to Enteric-Coated Aspirin, but not to Plain Aspirin

Abstract

Essential thrombocythemia (ET) patients are treated with aspirin (acetylsalicylic acid [ASA]) to prevent thrombosis. Previous studies showed that serum thromboxane (Tx) B₂ was high 24 hours after enteric-coated (EC)-ASA in ET patients, due to increased number of noninhibited reticulated platelets (RPs), consequent to high platelet turnover, and that ASA should be given twice a day to ET patients. We studied ET patients (n = 17) and healthy subjects (n = 10) on 100 mg EC-ASA once daily; experiments were repeated after 14-day treatment with 100 mg plain-ASA once daily. Serum TxB₂, plasma ASA, and salicylic acid (SA) were measured before the morning dose and up to 8 hours thereafter. Blood activity of ASA-deacethylating esterases, in vitro inhibition of collagen-induced TxB₂ production by ASA (10–1,000 µM), and number of RP were measured. TxB₂ inhibition by ASA in vitro and esterases activities were normal in all subjects. EC-ASA elicited highly variable responses; 6 ET patients were poor responders, as their serum TxB₂ was high after EC-ASA; their plasma levels of ASA and SA were low/undetectable. In contrast to EC-ASA, plain ASA decreased serum TxB₂ and increased plasma ASA and SA in all subjects. Serum TxB₂ was high in ET patients at 24 hours and significantly correlated with RP count (but not RP percentage) and platelet count. Plain ASA should be used in ET patients to inhibit platelets efficiently. The identification of ET patients who might benefit from twice a day ASA could simply be based on their platelet count: since their platelet turnover is not increased, ET patients with normalized platelet count should not need twice a day ASA treatment.

Keywords

essential thrombocythemia - platelets - aspirin - thromboxane - thrombosis

• References

• 1 Rumi E, Cazzola M. How I treat essential thrombocythemia. Blood 2016; 128 (20) 2403-2414
• 2 Hultcrantz M, Björkholm M, Dickman PW. , et al. Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: a population-based cohort study. Ann Intern Med 2018; 168 (05) 317-325
• 3 Barbui T, Tefferi A, Vannucchi AM. , et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 2018; 32 (05) 1057-1069
• 4 Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J 2018; 8 (01) 2
• 5 Tefferi A, Pardanani A. Essential thrombocythemia. N Engl J Med 2019; 381 (22) 2135-2144
• 6 Michiels JJ, Berneman Z, Schroyens W, Finazzi G, Budde U, van Vliet HH. The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera. Semin Thromb Hemost 2006; 32 (06) 589-604
• 7 Malpass TW, Savage B, Hanson SR, Slichter SJ, Harker LA. Correlation between prolonged bleeding time and depletion of platelet dense granule ADP in patients with myelodysplastic and myeloproliferative disorders. J Lab Clin Med 1984; 103 (06) 894-904
• 8 Rendu F, Lebret M, Nurden A, Caen JP. Detection of an acquired platelet storage pool disease in three patients with a myeloproliferative disorder. Thromb Haemost 1979; 42 (02) 794-796
• 9 Swart SS, Pearson D, Wood JK, Barnett DB. Functional significance of the platelet alpha2-adrenoceptor: studies in patients with myeloproliferative disorders. Thromb Res 1984; 33 (05) 531-541
• 10 Lussana F, Femia EA, Pugliano M. , et al. Evaluation of platelet function in essential thrombocythemia under different analytical conditions. Platelets 2020; 31 (02) 179-186
• 11 Michiels JJ, Berneman Z, Gadisseur A, Lam KH, De Raeve H, Schroyens W. Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera. Acta Haematol 2015; 133 (01) 56-63
• 12 Falanga A, Marchetti M, Vignoli A, Balducci D, Barbui T. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol 2005; 33 (05) 523-530
• 13 Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, Villamor N, Colomer D, Cervantes F. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 2006; 91 (02) 169-175
• 14 Maugeri N, Malato S, Femia EA. , et al. Clearance of circulating activated platelets in polycythemia vera and essential thrombocythemia. Blood 2011; 118 (12) 3359-3366
• 15 Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010; 24 (06) 1128-1138
• 16 Lussana F, Caberlon S, Pagani C, Kamphuisen PW, Büller HR, Cattaneo M. Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: a systematic review. Thromb Res 2009; 124 (04) 409-417
• 17 Klampfl T, Gisslinger H, Harutyunyan AS. , et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369 (25) 2379-2390
• 18 Nangalia J, Massie CE, Baxter EJ. , et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369 (25) 2391-2405
• 19 Boyd EM, Bench AJ, Goday-Fernández A. , et al. Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis. Br J Haematol 2010; 149 (02) 250-257
• 20 Rocca B, Ciabattoni G, Tartaglione R. , et al. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb Haemost 1995; 74 (05) 1225-1230
• 21 Landolfi R, Ciabattoni G, Patrignani P. , et al. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo. Blood 1992; 80 (08) 1965-1971
• 22 Landolfi R, Marchioli R, Kutti J. , et al; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350 (02) 114-124
• 23 Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353 (22) 2373-2383
• 24 Spivak JL. Myeloproliferative Neoplasms. N Engl J Med 2017; 376 (22) 2168-2181
• 25 Harrison C, Barbui T. Aspirin in low-risk essential thrombocythemia, not so simple after all?. Leuk Res 2011; 35 (03) 286-289
• 26 Frelinger III AL, Furman MI, Linden MD. , et al. Residual arachidonic acid-induced platelet activation via an adenosine diphosphate-dependent but cyclooxygenase-1- and cyclooxygenase-2-independent pathway: a 700-patient study of aspirin resistance. Circulation 2006; 113 (25) 2888-2896
• 27 Dragani A, Pascale S, Recchiuti A. , et al. The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy. Blood 2010; 115 (05) 1054-1061
• 28 Pascale S, Petrucci G, Dragani A. , et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119 (15) 3595-3603
• 29 Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect of enteric coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke 2006; 37 (08) 2153-2158
• 30 Maree AO, Curtin RJ, Dooley M. , et al. Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease. J Am Coll Cardiol 2005; 46 (07) 1258-1263
• 31 Barbui T, Barosi G, Birgegard G. , et al; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29 (06) 761-770
• 32 Finazzi G. How to manage essential thrombocythemia. Leukemia 2012; 26 (05) 875-882
• 33 Tamayo SG, Rickman LS, Mathews WC. , et al. Examiner dependence on physical diagnostic tests for the detection of splenomegaly: a prospective study with multiple observers. J Gen Intern Med 1993; 8 (02) 69-75
• 34 Sirok D, Patfalusi M, Szeleczky G, Somorjai G, Greskovits D, Monostory K. Robust and sensitive LC/MS-MS method for simultaneous detection of acetylsalicylic acid and salicylic acid in human plasma. Microchem J 2018; 136: 200-208
• 35 Zhou G, Marathe GK, Hartiala J. , et al. Aspirin hydrolysis in plasma is a variable function of butyrylcholinesterase and platelet-activating factor acetylhydrolase 1b2 (PAFAH1b2). J Biol Chem 2013; 288 (17) 11940-11948
• 36 Rocca B, Tosetto A, Betti S. , et al. A randomized, double-blind trial of three aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia. Blood 2020; 136 (02) 171-182
• 37 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. J Thromb Haemost 2019; 17 (06) 885-895
• 38 McCall M, Peace A, Tedesco AF, Foley D, Conroy RM, Cox D. Weight as an assay-independent predictor of poor response to enteric aspirin in cardiovascular patients. Platelets 2020; 31 (04) 530-535
• 39 Peace A, McCall M, Tedesco T. , et al. The role of weight and enteric coating on aspirin response in cardiovascular patients. J Thromb Haemost 2010; 8 (10) 2323-2325
• 40 Bhatt DL, Grosser T, Dong JF. , et al. Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus. J Am Coll Cardiol 2017; 69 (06) 603-612
• 41 Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet 1996; 348 (9039): 1413-1416