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.

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

1987 ◽  
Vol 57 (01) ◽  
pp. 062-066 ◽  
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.

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.

scholarly journals Low-dose aspirin does not lower in vivo platelet activation in healthy smokers

1998 ◽  
Vol 102 (5) ◽  
pp. 1229-1231 ◽  
Author(s):  
Pernerstorfer ◽  
Stohlawetz ◽  
Stummvoll ◽  
Kapiotis ◽  
Szekeres ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Low Dose ◽  
Dose Aspirin ◽  
Low Dose Aspirin

Thromboxane A2 Signaling Regulates Heterogeneous Platelet Activation Following Laser-Induced Injury In Mouse Cremaster Arterioles

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1055-1055
Author(s):  
Jian Shen ◽  
Fei Yang ◽  
Yujun Shen ◽  
Ying Yu ◽  
Timothy J. Stalker ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Vascular Injury ◽  
Low Dose ◽  
Thromboxane A2 ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Platelet Accumulation ◽  
Cox 1 ◽  
Platelet Mass

Abstract Background A recent study demonstrated that platelet accumulation following vascular injury in vivo is hierarchically organized resulting in a structure comprised of a core of fully-activated platelets that is overlaid with an unstable shell of less activated platelets (Stalker et al, Blood, 2013). This structure results from different elements of the platelet signaling network giving rise to regions that differ in platelet activation state, packing density, and stability. It was thus proposed that regional differences in platelet activation reflect regional differences in the distribution of platelet agonists. This provides new insights into heterogeneous platelet activation during platelet accumulation in vivo. Thromboxane A2 (TxA2), a dominant prostanoid product of cyclooxygenase 1 (COX-1) generated in platelets, plays an important role in the maintenance of vascular hemostasis and is a major therapeutic target of anti-platelet therapy. But its contribution to the regional architecture of a platelet mass is unknown. Approach To determine the contribution of TxA2 activity to the hierarchical organization of a thrombus, multicolor intravital microscopy was used to observe platelet accumulation and activation in thromboxane A2 receptor knockout (TP-/-) and low dose aspirin treated WT mice following laser-induced injury in mouse cremaster arterioles. Results TP-/- mice showed reduced total platelet (CD41) accumulation following vascular injury, consistent with a previous report (Yu et al, Sci Transl Med, 2012). The peak CD41 area in TP-/- mice was significantly reduced relative to WT mice (p=0.004). Interestingly, the core area of the thrombus in which the platelets are fully activated (P-selectin+), was not significantly different in TP-/- compared to WT during thrombus formation. This suggests that TxA2 signaling via the TP receptor primarily influences platelet recruitment and retention in the outer shell region of a platelet mass, but not full platelet activation in the core region. Aspirin inhibits TxA2 production through acetylation of COX-1, and is widely used as both primary and secondary prevention of cardiovascular diseases. We treated WT mice with aspirin in their drinking water (30 mg/L) for more than 1 week to mimic the effect of low dose aspirin treatment in humans (Yu et al, J Clin Invest, 2005). Similar to our findings in TP-/- mice, we found that aspirin treatment reduced total platelet accumulation following laser-induced injury in vivo (p<0.05). The decrease in peak platelet accumulation caused by aspirin was observed in the shell region at early time points (up to 2 min post-injury). In contrast to our findings in the TP-/- mice, low dose aspirin also resulted in reduced platelet activation and core region formation at later timepoints (p<0.05), suggesting that COX-1 may contribute to full platelet activation independent of TP receptor signaling. Conclusion Our studies show for the first time the role of TxA2 signaling in producing the hierarchical structure of a platelet mass formed in response to vascular injury. Our data indicate that TxA2signaling is critical for recruitment and/or retention of platelets prior to robust platelet activation including alpha granule secretion. These findings further highlight the importance of discrete spatial localization of platelet agonists within an evolving platelet plug in order to achieve the optimal hemostatic response. (This study was supported by National Natural Science Foundation of China 81170132 to Li Zhu) Disclosures: No relevant conflicts of interest to declare.

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).

scholarly journals Obesity is associated with impaired responsiveness to once‐daily low‐dose aspirin and in vivo platelet activation

2019 ◽  
Vol 17 (6) ◽  
pp. 885-895 ◽  
Author(s):  
Giovanna Petrucci ◽  
Francesco Zaccardi ◽  
Alberto Giaretta ◽  
Viviana Cavalca ◽  
Esmeralda Capristo ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Low Dose ◽  
Once Daily ◽  
Dose Aspirin ◽  
Low Dose Aspirin

Platelet activation and inhibition in polycythemia vera and essential thrombocythemia

Blood ◽  
2013 ◽  
Vol 121 (10) ◽  
pp. 1701-1711 ◽  
Author(s):  
Carlo Patrono ◽  
Bianca Rocca ◽  
Valerio De Stefano
Keyword(s):  
Polycythemia Vera ◽  
Antiplatelet Therapy ◽  
Platelet Activation ◽  
Essential Thrombocythemia ◽  
Low Dose ◽  
Treatment Guidelines ◽  
Bleeding Complications ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
The Individual

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.

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.

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