Systemic Mastocytosis and Essential Thrombocythemia: Case Report and Literature Overview

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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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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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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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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Familiar Chronic Myeloproliferative Syndromes in First-Degree Relatives and Monozygotic Twins.

Blood ◽

10.1182/blood.v108.11.4908.4908 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4908-4908

Author(s):

Stefano Pulini ◽

Serena Rupoli ◽

Gaia Goteri ◽

Angela Tassetti ◽

Anna Rita Scortechini ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Low Dose ◽

Factor V Leiden ◽

Trephine Biopsy ◽

Bone Marrow Trephine ◽

First Degree Relatives ◽

Bone Marrow Trephine Biopsy ◽

Dose Aspirin ◽

Low Dose Aspirin

Abstract Chronic myeloproliferative syndromes (MPS) are clonal stem cell disorders resulting in excessive proliferation of one or more cell lineages. Rare families exist with first-degree relatives affected by MPS. Familial or hereditary essential thrombocythemia (HT) is described among children with primary thrombocytosis and it is inherited in an autosomal-dominant manner. In HT germ-line activating mutations of thrombopoietin (TPO) gene or its receptor, c-MPL can be recovered. A 31-year-old woman was first referred to our Clinic for an isolated high platelet count. On routine blood testing performed when she was 14 years old the platelet count was 1020 × 103/μl; at that time she refused other laboratory examinations, instrumental and histological diagnostic procedures and subsequent therapy and she remained asymptomatic. During the first pregnancy the platelet count went down to 500 × 103/μl but after the second it raised over one million per microliter. Bone marrow trephine biopsy showed clusters of megakaryocytes with hyperlobulated forms and platelet clumps; the caryotype was normal and bcr-abl rearrangements were negative. Leukocytic alkaline phosphatase was high, there was reduced platelet aggregation, the thrombophilic study didn’t demonstrate either factor V Leiden G1691A or prothrombin Gene G20210A mutations. During the follow up the platelet count remained under 1000 × 103/μl so that a watch-and-wait strategy seemed appropriate in this asymptomatic case and low-dose aspirin has been started. What is remarkable in this case is that it is a not-frequent example of HT since the patient’s father, sister and niece are all affected by essential thrombocytemia (ET); moreover the patient’s own little daughter is affected by neonatal thrombocytosis. The relatives are being treated only with low-dose aspirin, they are completely asymptomatic without thrombohemorrhagic events. Some authors report that HT appears to be a different disease from sporadic ET and with a more benign course. The somatic activating point mutation (V617F) in the JAK2 gene was not demonstrated in our patient; as for TPO and c-MPL mutations we are now completing the genetic study. Among other familiar chronic MPS we describe the occurrence of ET/PV and idiopathic myelofibrosis (IMF) in two monozygotic twin sisters. They both were diagnosed with MPS at the median age of 65 years old. The first had splenomegaly, thrombocytosis and erythrocytosis and was treated with aspirin, hydroxyurea and phlebotomy. The other, affected by IMF, had important epato-splenomegaly and the bone marrow trephine biopsy showed myelofibrosis with >90% collagen fibres. She received low dose hydroxyurea together with nandrolone decanoate; the organomegaly reduced and the hematic crasis improved. The JAK2 gene mutation was demonstrated only in the IMF patient. This second familial case strengthens the concept of a common pathogenesis of chronic MPS and suggests a genetic and hereditary etiology; moreover the occurrence of multiple disease phenotypes in a family is consistent with the theory of MPS as arising from clonal expansion of a pluripotential haematopoietic precursor cell that retains its pluripotentiality and produces an array of inter-related syndromes.

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Neurologic and Visual Symptoms in Essential Thrombocythemia: Efficacy of Low-Dose Aspirin

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-2007-996110 ◽

1997 ◽

Vol 23 (04) ◽

pp. 365-370 ◽

Cited By ~ 37

Author(s):

Peter Koudstaal ◽

Adriana Koudstaal

Keyword(s):

Essential Thrombocythemia ◽

Low Dose ◽

Visual Symptoms ◽

Dose Aspirin ◽

Low Dose Aspirin

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

Blood ◽

10.1182/blood.2019004596 ◽

2020 ◽

Vol 136 (2) ◽

pp. 171-182 ◽

Cited By ~ 10

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).

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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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