Aspirin for the Control of Platelet Activation and Prevention of Thrombosis in Essential Thrombocythemia and Polycythemia Vera: Current Insights and Rationale for Future Studies

Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2V617F-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2V617F-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene.

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Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature

Thrombosis and Haemostasis ◽

10.1055/s-0040-1720979 ◽

2020 ◽

Author(s):

Christophe Nicol ◽

Karine Lacut ◽

Brigitte Pan-Petesch ◽

Eric Lippert ◽

Jean-Christophe Ianotto

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasm ◽

Young Patients ◽

Lessons Learned ◽

Published Data ◽

Bleeding Events ◽

Future Studies ◽

Increased Risk

AbstractHemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially CALR-mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.

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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

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-2006-949664 ◽

2006 ◽

Vol 32 (6) ◽

pp. 589-604 ◽

Cited By ~ 85

Author(s):

Jan Michiels ◽

Zwi Berneman ◽

Wilfried Schroyens ◽

Guido Finazzi ◽

Ulrich Budde ◽

...

Keyword(s):

Polycythemia Vera ◽

Platelet Activation ◽

Von Willebrand Factor ◽

Essential Thrombocythemia ◽

Impaired Function ◽

Factor Interactions ◽

Von Willebrand ◽

Willebrand Factor

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Prevention of thrombosis in polycythemia vera and essential thrombocythemia

Haematologica ◽

10.3324/haematol.12604 ◽

2008 ◽

Vol 93 (3) ◽

pp. 331-335 ◽

Cited By ~ 29

Author(s):

R. Landolfi ◽

L. Di Gennaro

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Prevention Of Thrombosis

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Platelet activation and inhibition in polycythemia vera and essential thrombocythemia

Blood ◽

10.1182/blood-2012-10-429134 ◽

2013 ◽

Vol 121 (10) ◽

pp. 1701-1711 ◽

Cited By ~ 55

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.

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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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