Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3595-3603 ◽  
Author(s):  
Silvia Pascale ◽  
Giovanna Petrucci ◽  
Alfredo Dragani ◽  
Aida Habib ◽  
Francesco Zaccardi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Low Dose ◽  
Once Daily ◽  
Dosing Interval ◽  
Aspirin Dose ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Enteric Coated Aspirin ◽  
Enteric Coated

Abstract 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.

Increased Thromboxane Biosynthesis in Essential Thrombocythemia

1995 ◽  
Vol 74 (05) ◽  
pp. 1225-1230 ◽  
Author(s):  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Raffaele Tartaglione ◽  
Sergio Cortelazzo ◽  
Tiziano Barbui ◽  
...  
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Therapeutic Strategy ◽  
Low Dose ◽  
Thrombotic Risk ◽  
Dose Aspirin ◽  
Gender And Age ◽  
Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

scholarly journals A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia

Blood ◽  
2020 ◽  
Vol 136 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Bianca Rocca ◽  
Alberto Tosetto ◽  
Silvia Betti ◽  
Denise Soldati ◽  
Giovanna Petrucci ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Low Dose ◽  
Double Blind Trial ◽  
Double Blind ◽  
Thrombotic Risk ◽  
Once Daily ◽  
Blind Trial ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Cox 1

Abstract Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).

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

2020 ◽  
Vol 120 (10) ◽  
pp. 1442-1453
Author(s):  
Mariangela Scavone ◽  
Jessica Rizzo ◽  
Eti A. Femia ◽  
Gian Marco Podda ◽  
Elena Bossi ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Day Treatment ◽  
Poor Responders ◽  
Once Daily ◽  
Reticulated Platelets ◽  
Enteric Coated Aspirin ◽  
Serum Thromboxane ◽  
Enteric Coated

AbstractEssential 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.

Severe Thrombocytopenia Associated with Once-Daily Rifampin Therapy

1987 ◽  
Vol 21 (11) ◽  
pp. 882-884 ◽  
Author(s):  
Alice K. Pau ◽  
Melanie A. Fisher ◽  
Wanda Maldonado ◽  
Marc Lebel
Keyword(s):  
Platelet Count ◽  
Staphylococcus Epidermidis ◽  
Low Dose ◽  
High Dose ◽  
Intermittent Therapy ◽  
Severe Thrombocytopenia ◽  
Once Daily ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Immunological Reactions

Rifampin-induced thrombocytopenia has been recognized as an immunological reaction associated with intermittent high-dose therapy, and rarely seen with daily low-dose regimens. Our patient was a 33-year-old male with Marfan's syndrome who was given rifampin 600 mg/d po along with intravenous vancomycin for the treatment of Staphylococcus epidermidis endocarditis. His platelet count dropped from a baseline of 519000/mm3 to 4000/mm3 after four doses of rifampin. Petechiae were present on the lower extremities without the presence of other bleeding sites. Rifampin, low-dose aspirin, and dipyridamole were discontinued. His platelet count returned to normal nine days after discontinuation of therapy. With the increasing use of rifampin for the treatment of nontuberculosis infections, clinicians should recognize the possibility of this drug causing such serious immunological reactions as thrombocytopenia, hemolytic anemia, acute renal failure, and shock with daily or intermittent therapy. Extracto Rifampin es un agente antibacteriano el cual es utilizado ampliamente en el tratamiento de tuberculosis y de otras infecciones bacterianas. El fármaco puede causar reacciones inmunológicas severas que pueden resultar en trombocitopenia púrpura, anemia hemolítica, insuficiencia renal, y shock. Estas están usualmente asociadas a dosis altas administradas en una manera intermitente, y la descontinuación del fármaco usualmente resulta en resolución de la reacción. Los autores describen el caso de un hombre de 33 años de edad con el Síndrome de Marfan que desarrolla una trombocitopenia severa luego de la administración de 600 mg diarios de rifampin para el tratamiento de endocarditis causado por Staphylococcus epidermidis. El paciente recibió también conjuntamente con rifampin, vancomicina 1 gm iv q 12h, aspirina 600 mg po qd, dipyridamole 25 mg po tid, y propranolol 80 mg po q12h. Cuatro horas luego de la cuarta dosis de rifampin (Día numero 4) el paciente desarrolló petequias en las extremidades inferiores, y el contaje de plaquetas obtenido inmediatamente reveló una concentración de 4000/mm3, el cual refleja una disminución significativa en comparación con el contaje obtenido ocho días antes de 519000/mm3. Tanto rifampin como aspirina y dipyridamole fueron descontinuados. Una marcada trombocitopenia y petequias perduraron por una semana, otras fuentes de sangramiento fueron descartadas y no hubo ningún cambio significativo en el estado de coagulación o en el recuento sanguíneo. Las plaquetas regresaron a un nivel normal nueve días después de descontinuado el rifampin. Aunque las plaquetas aumentaron de 11000/mm3 a 36000/mm3 el día en que propranolol fue descontinuado, los autores expresan que esta respuesta es muy rápida para considerar a éste como el agente causante. Aunque no se puede establecer con certeza que la trombocitopenia fuera causada por rifampin o aspirina solamente, o por un efecto sinergístico de ambos, rifampin parece ser el agente causante más probable. Es importante reconocer el potencial que posee rifampin para causar reacciones adversas serias como trombocitopenia, anemia hemolítica, insuficiencia renal aguda, y shock. La terapia con rifampin debe de descontinuarse si alguna de estas ocurren y otras causas no se pueden identificar. Resume Les thrombocytopénies associées avec la rifampicine sont reconnues comme des réactions immunologiques rencontrées particulièrement avec des thérapies à hautes doses. Le cas décrit par les auteurs est celui d'un patient mâle agé de 33 ans présentant un syndrome de Marfan à qui on a administré 600 mg de rifampicine en dose unique quotidienne en combinaison avec vancomycine iv pour le traitement d'une endocardite à Staphylococcus epidermidis. Le décompte plaquettaire a chuté d'une valeur de 519000/ml à 4000/ml seulement quatre heures après la dose de rifampicine. Des pétéchies étaient apparentes au niveau des jambes en absence de saignements à d'autres sites. Rifampicine, acide acétylsalicylique à faible dose, et dipyridamole furent suspendus. Les plaquettes sont revenus a leur niveau normal neuf jours apres l'arrêt de la thérapie. Devant l'augmentation de l'utilisation de la rifampicine pour le traitement des infections non-tuberculeuses, les cliniciens devront reconnaître le potentiel de ce medicament à causer des réactions immunologiques sévères telles que thrombocytopénie, anémie hémolytique, insuffisance rénale et choc.

scholarly journals Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 528
Author(s):  
Mauro Cancian ◽  
Elisabetta Cosi ◽  
Marco Pizzi ◽  
Sandro Giannini ◽  
Irene Bertozzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Essential Thrombocythemia ◽  
Low Dose ◽  
Systemic Mastocytosis ◽  
Inflammatory Reactions ◽  
Zolendronic Acid ◽  
Literature Overview ◽  
Dose Aspirin ◽  
Low Dose Aspirin

Mastocytosis is a rare disease in which heightened amounts of mast cells accumulate in the skin, bone marrow, and other visceral organs. Upon activation, mast cells release a wide variety of preformed or newly synthesized mediators which can induce allergic symptoms and inflammatory reactions. Mastocytosis is diagnosed by biopsy and can be divided into cutaneous and systemic mastocytosis (SM). The first one affects the skin and is relatively benign, whilst SM, which involves bone marrow and other organs, may be aggressive and associate with both myelodisplastic and myeloproliferative diseases. Here we present a case of SM associated with essential thrombocythemia and complicated by severe osteoporosis, successfully treated with hydroxyurea, low-dose aspirin and zolendronic acid.

Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism

2015 ◽  
Vol 114 (09) ◽  
pp. 645-650 ◽  
Author(s):  
Rupert Bauersachs ◽  
Jan Beyer-Westendorf ◽  
Henri Bounameaux ◽  
Timothy Brighton ◽  
Alexander Cohen ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Anticoagulant Therapy ◽  
Low Dose ◽  
Double Blind ◽  
Once Daily ◽  
Safety Outcome ◽  
Dose Aspirin ◽  
Recurrent Venous Thromboembolism ◽  
Low Dose Aspirin ◽  
Recurrent Vte

SummaryPatients with unprovoked venous thromboembolism (VTE) are at high risk for recurrence. Although rivaroxaban is effective for extended VTE treatment at a dose of 20 mg once daily, use of the 10 mg dose may further improve its benefit-to-risk ratio. Low-dose aspirin also reduces rates of recurrent VTE, but has not been compared with anticoagulant therapy. The EINSTEIN CHOICE study is a multicentre, randomised, double-blind, active-controlled, event-driven study comparing the efficacy and safety of two once daily doses of rivaroxaban (20 and 10 mg) with aspirin (100 mg daily) for the prevention of recurrent VTE in patients who completed 6–12 months of anticoagulant therapy for their index acute VTE event. All treatments will be given for 12 months. The primary efficacy objective is to determine whether both doses of rivaroxaban are superior to aspirin for the prevention of symptomatic recurrent VTE, while the principal safety outcome is the incidence of major bleeding. The trial is anticipated to enrol 2,850 patients from 230 sites in 31 countries over a period of 27 months. In conclusion, the EINSTEIN CHOICE study will provide new insights into the optimal antithrombotic strategy for extended VTE treatment by comparing two doses of rivaroxaban with aspirin (clinicaltrials.gov NCT02064439).

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