Platelet activation and inhibition in polycythemia vera and essential thrombocythemia

Abstract Persistently enhanced platelet activation has been characterized in polycythemia vera (PV) and essential thrombocythemia (ET) and shown to contribute to a higher risk of both arterial and venous thrombotic complications. The incidence of major bleeding complications is also somewhat higher in PV and ET than in the general population. Although its efficacy and safety was assessed in just 1 relatively small trial in PV, low-dose aspirin is currently recommended in practically all PV and ET patients. Although for most patients with a thrombosis history the benefit/risk profile of antiplatelet therapy is likely to be favorable, in those with no such history this balance will depend critically on the level of thrombotic and hemorrhagic risks of the individual patient. Recent evidence for a chemopreventive effect of low-dose aspirin may tilt the balance of benefits and harm in favor of using aspirin more broadly, but the potential for additional benefits needs regulatory scrutiny and novel treatment guidelines. A clear pharmacodynamic rationale and analytical tools are available for a personalized approach to antiplatelet therapy in ET, and an improved regimen of low-dose aspirin therapy should be tested in a properly sized randomized trial.

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Increased Thromboxane Biosynthesis in Essential Thrombocythemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649916 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1225-1230 ◽

Cited By ~ 71

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.

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PB2196 ANTIPLATELET THERAPY IN ESSENTIAL THROMBOCYTHEMIA: LABORATORY STUDY OF LOW-DOSE ASPIRIN

HemaSphere ◽

10.1097/01.hs9.0000567264.48027.4a ◽

2019 ◽

Vol 3 (S1) ◽

pp. 984-985

Author(s):

R. Cacciola ◽

V. Vecchio ◽

E. Gentilini Cacciola ◽

E. Cacciola

Keyword(s):

Antiplatelet Therapy ◽

Laboratory Study ◽

Essential Thrombocythemia ◽

Low Dose ◽

Dose Aspirin ◽

Low Dose Aspirin

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Cytoreduction Plus Low-Dose Aspirin Versus Cytoreduction in Monotherapy As Primary Prophylaxis of Thrombosis in Patients with Essential Thrombocythemia.

Blood ◽

10.1182/blood.v120.21.2828.2828 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2828-2828

Author(s):

Alberto Alvarez-Larrán ◽

Arturo Pereira ◽

Eduardo Arellano-Rodrigo ◽

Juan Carlos Hernández-Boluda ◽

Francisco Cervantes ◽

...

Keyword(s):

Antiplatelet Therapy ◽

Essential Thrombocythemia ◽

Low Dose ◽

Conflicts Of Interest ◽

Previous History ◽

Primary Prophylaxis ◽

Dose Aspirin ◽

Mutational Status ◽

Low Dose Aspirin ◽

History Of

Abstract Abstract 2828 Antiplatelet therapy with low-dose aspirin is commonly used in combination with cytoredution for the prevention of thrombosis in patients with high-risk essential thrombocythemia (ET), as determined by age > 60 years and/or previous history of thrombosis. However, it is uncertain whether low-dose aspirin adds any benefit to cytoreductive therapy in patients without a history of thrombosis. In this study, the probability of thrombosis and bleeding was retrospectively analyzed in 248 patients with ET (median age: 66 years; 83 males, 165 females) treated with cytoreduction plus low-dose aspirin (n=170) or with cytoreduction only (n=78). Patients with a history of thrombosis or bleeding, as well as those receiving anticoagulant therapy, were excluded from the study. The indication of cytoreduction was age > 60 years (n=198), extreme thrombocytosis (n=37), microvascular disturbances (n=6), and others (n=7) First-line cytoreductive therapy consisted of hydroxyurea (n=216), anagrelide (n=27), interferon-α (n=4), and busulfan (n=1). During a median follow-up of 7.4 years (range: 0.1–26), a total of 28 thromboses (arterial, n=22; venous, n=6) were registered. At 5 years, the probability of thrombosis in patients receiving cytoreduction plus low-dose aspirin or cytoreduction only was 8% and 17%, respectively (p=0.006). No significant differences were observed depending on gender, presence of cardiovascular risk factors, JAK2 V617F mutational status, WBC count at diagnosis or type of cytoreductive therapy. At multivariate analysis, patients not receiving antiplatelet therapy were found to have a higher risk of thrombosis (HR: 3.3, 95%CI: 1.3–7.9, p=0.009). During the study period, a total of 13 major hemorrhagic events were registered (digestive, n=7, intracranial, n=3, others, n=3). At 5 years, the probability of major bleeding in patients receiving cytoreduction plus low-dose aspirin or cytoreduction as monotherapy was 6% and 4%, respectively (p=0.1). In conclusion, in patients with ET receiving cytoreductive therapy as primary prophylaxis of thrombosis, the addition of low-dose aspirin reduces the risk of thrombosis without increasing the risk of bleeding. Disclosures: No relevant conflicts of interest to declare.

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Investigation of the Interaction of Blood Platelets with the Coagulation System at the Site of Plug Formation In Vivo in Man - Effect of Low-Dose Aspirin

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651063 ◽

1987 ◽

Vol 57 (01) ◽

pp. 062-066 ◽

Cited By ~ 36

Author(s):

P A Kyrle ◽

J Westwick ◽

M F Scully ◽

V V Kakkar ◽

G P Lewis

Keyword(s):

Platelet Activation ◽

Thrombin Generation ◽

Low Dose ◽

Bleeding Time ◽

Blood Platelets ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Plug Formation ◽

Granule Release

SummaryIn 7 healthy volunteers, formation of thrombin (represented by fibrinopeptide A (FPA) generation, α-granule release (represented by β-thromboglobulin [βTG] release) and the generation of thromboxane B2 (TxB2) were measured in vivo in blood emerging from a template bleeding time incision. At the site of plug formation, considerable platelet activation and thrombin generation were seen within the first minute, as indicated by a 110-fold, 50-fold and 30-fold increase of FPA, TxB2 and PTG over the corresponding plasma values. After a further increase of the markers in the subsequent 3 minutes, they reached a plateau during the fourth and fifth minute. A low-dose aspirin regimen (0.42 mg.kg-1.day-1 for 7 days) caused >90% inhibition of TxB2formation in both bleeding time blood and clotted blood. At the site of plug formation, a-granule release was substantially reduced within the first three minutes and thrombin generation was similarly inhibited. We conclude that (a) marked platelet activation and considerable thrombin generation occur in the early stages.of haemostasis, (b) α-granule release in vivo is partially dependent upon cyclo-oxygenase-controlled mechanisms and (c) thrombin generation at the site of plug formation is promoted by the activation of platelets.

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No correlation of intensity of phlebotomy regimen with risk of thrombosis in polycythemia vera: evidence from European Collaboration on Low-Dose Aspirin in Polycythemia Vera and Cytoreductive Therapy in Polycythemia Vera clinical trials

Haematologica ◽

10.3324/haematol.2017.165126 ◽

2017 ◽

Vol 102 (6) ◽

pp. e219-e221 ◽

Cited By ~ 10

Author(s):

Tiziano Barbui ◽

Alessandra Carobbio ◽

Arianna Ghirardi ◽

Arianna Masciulli ◽

Alessandro Rambaldi ◽

...

Keyword(s):

Clinical Trials ◽

Polycythemia Vera ◽

Low Dose ◽

Dose Aspirin ◽

European Collaboration ◽

Low Dose Aspirin

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P2Y12 Inhibitors Exacerbate Low-dose Aspirin-induced Small Bowel Injury in Dual Antiplatelet Therapy

Internal Medicine ◽

10.2169/internalmedicine.7292-21 ◽

2021 ◽

Vol 60 (22) ◽

pp. 3517-3523

Author(s):

Yukiko Handa ◽

Shinya Fukushima ◽

Motoyasu Osawa ◽

Takahisa Murao ◽

Osamu Handa ◽

...

Keyword(s):

Small Bowel ◽

Antiplatelet Therapy ◽

Low Dose ◽

Dual Antiplatelet Therapy ◽

Bowel Injury ◽

Small Bowel Injury ◽

P2y12 Inhibitors ◽

Dose Aspirin ◽

Low Dose Aspirin

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Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview

Medicina ◽

10.3390/medicina55090528 ◽

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.

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Inflammation, oxidative stress and platelet activation in aspirin-treated critical limb ischaemia: Beneficial effects of iloprost

Thrombosis and Haemostasis ◽

10.1160/th10-07-0499 ◽

2011 ◽

Vol 105 (02) ◽

pp. 321-328 ◽

Cited By ~ 15

Author(s):

Chiara Cuccurullo ◽

Dario Di Michele ◽

Giuseppe Laurora ◽

Giuseppe Sgrò ◽

Paolo Di Ruscio ◽

...

Keyword(s):

Oxidative Stress ◽

Platelet Activation ◽

Low Dose ◽

Arterial Disease ◽

Critical Limb Ischaemia ◽

Limb Ischaemia ◽

Beneficial Effects ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Iloprost Infusion

SummaryPlatelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB2 and 8-iso-PGF2α excretion rate, as in vivoindexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB2 [499 (277 – 807) vs. 380 (189 – 560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF2α [533 (316 – 842) vs. 334 (196 – 540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005 – 3015) vs. 948 (845 – 2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8 – 35.9) vs. 43.7 (33.0 – 75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF2α and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.

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

Blood ◽

10.1182/blood-2011-06-359224 ◽

2012 ◽

Vol 119 (15) ◽

pp. 3595-3603 ◽

Cited By ~ 125

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.

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