Download PDF
Semin Thromb Hemost 2006; 32(3): 251-259
DOI: 10.1055/s-2006-939436
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

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

Raffaele Landolfi1 , 2 , Leonardo Di Gennaro2 , Linda Novarese2 , Carlo Patrono3
  • 1Professor
  • 2Institute of Internal Medicine and Geriatrics, Catholic University School of Medicine, Rome, Italy
  • 3Department of Pharmacology, University of Rome “La Sapienza,” Rome, Italy
Further Information

Publication History

Publication Date:
01 June 2006 (online)

    Permissions and Reprints

ABSTRACT

Polycythemia vera and essential thrombocythemia are chronic myeloproliferative disorders characterized by a relatively benign clinical course that may be complicated by arterial and venous thromboses. A thrombotic diathesis often manifests at diagnosis or in the preclinical phase of the myeloproliferative disease. Peculiar microcirculatory disturbances such as erythromelalgia and visual and hearing symptoms also commonly occur in these patients, and are highly responsive to aspirin. In a placebo-controlled trial in relatively low-risk polycythemic subjects, low-dose aspirin recently was shown to reduce the incidence of both arterial and venous thrombosis with a limited increase of the hemorrhagic risk. Due to its favorable benefit/risk profile, low-dose aspirin should be prescribed to all patients with polycythemia vera who have no contraindication to this treatment. Future studies should assess primarily the efficacy and safety of aspirin in essential thrombocythemia, and test the possible use of more aggressive antithrombotic strategies in high-risk polycythemic patients.

KEYWORDS

Polycythemia vera - essential thrombocythemia - aspirin - platelet activation - arterial thrombosis - venous thrombosis

REFERENCES

  • 1 Michiels J J, Barbui T, Finazzi G et al.. Diagnosis and treatment of polycythemia vera and possible future study designs of the PVSG.  Leuk Lymphoma. 2000;  36 239-253
    PubMedGoogle Scholar
  • 2 Vardiman J W, Harris N L, Brunning R D. The World Health Organization (WHO) classification of the myeloid neoplasms.  Blood. 2002;  100 2292-2302
    CrossrefPubMedGoogle Scholar
  • 3 Ania B J, Suman V J, Sobell J L et al.. Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989.  Am J Hematol. 1994;  47 89-93
    PubMedGoogle Scholar
  • 4 Mesa R A, Silverstein M N, Jacobsen S J et al.. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.  Am J Hematol. 1999;  61 10-15
    CrossrefPubMedGoogle Scholar
  • 5 Harrison C N. Current trends in essential thrombocythaemia.  Br J Haematol. 2002;  117 796-808
    CrossrefPubMedGoogle Scholar
  • 6 Spivak J L. Polycythemia vera: myths, mechanisms, and management.  Blood. 2002;  100 4272-4290
    CrossrefPubMedGoogle Scholar
  • 7 Chievitz E, Thiede T. Complications and causes of death in polycythemia vera.  Acta Med Scand. 1962;  172 513-523
    CrossrefPubMedGoogle Scholar
  • 8 Schafer A I. Bleeding and thrombosis in myeloproliferative disorders.  Blood. 1984;  64 1-12
    CrossrefPubMedGoogle Scholar
  • 9 Landolfi R, Rocca B, Patrono C. Bleeding and thrombosis in myeloproliferative disorders: mechanism and treatment.  Crit Rev Oncol Hematol. 1995;  20 203-222
    CrossrefPubMedGoogle Scholar
  • 10 Pearson T C, Weiherley-Mein G. Vascular occlusive episodes and venous hematocrit in primary proliferative polycythemia vera.  Lancet. 1978;  2 1219-1222
    PubMedGoogle Scholar
  • 11 Elliott M A, Tefferi A. Thrombosis and haemorrage in polycythemia vera and essential thrombocythemia.  Br J Haematol. 2005;  128 275-290
    CrossrefPubMedGoogle Scholar
  • 12 Michiels J J, Abels J, Steketee J et al.. Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.  Ann Intern Med. 1985;  102 466-471
    PubMedGoogle Scholar
  • 13 Michiels J J, Koudstaal P J, Mulder A H, van Vliet H HDM. Transient neurologic and ocular manifestations in primary thrombocythemia.  Neurology. 1993;  43 1107-1110
    PubMedGoogle Scholar
  • 14 Michiels J J, van Genderen P JJ, Jansen P H, Koudstaal P J. Atypical transient ischemic attacks in thrombocythemia of various myeloproliferative disorders.  Leuk Lymphoma. 1996;  22(suppl 1) 47-56
    PubMedGoogle Scholar
  • 15 Koudstaal P J, Koudstaal A. Neurologic and visual symptoms in essential thrombocythemia: efficacy of low-dose aspirin.  Semin Thromb Hemost. 1997;  23 365-370
    PubMedGoogle Scholar
  • 16 Scheffer M G, Michiels J J, Simoons M L, Roelandt J RCT. Thrombocythemia and coronary artery disease.  Am Heart J. 1991;  122 573-576
    CrossrefPubMedGoogle Scholar
  • 17 Van Genderen P J, Mulder P G, Waleboer M et al.. Prevention and treatment of thrombotic complications in essential thrombocythemia: efficacy and safety of aspirin.  Br J Haematol. 1997;  97 179-184
    CrossrefPubMedGoogle Scholar
  • 18 Gruppo Italiano Studio Policitemia . Polycythemia vera: the natural history of 1213 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
    PubMedGoogle Scholar
  • 19 Patrono C, Ciabattoni G, Pugliese F et al.. Estimated rate of thromboxane secretion into the circulation of normal humans.  J Clin Invest. 1986;  77 590-594
    PubMedGoogle Scholar
  • 20 Landolfi R, Ciabattoni G, Patrignani P et al.. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo.  Blood. 1992;  80 1965-1971
    CrossrefPubMedGoogle Scholar
  • 21 Rocca B, Ciabattoni G, Tartaglione R et al.. Increased thromboxane biosynthesis in essential thrombocythemia.  Thromb Haemost. 1995;  74 1225-1230
    PubMedGoogle Scholar
  • 22 Van Genderen P JJ, Prins F J, Mihiels J J, Schroer K. Thromboxane-dependent platelet activation in vivo precedes arterial thrombosis in thrombocythaemia: a rationale for the use of low-dose aspirin as an antithrombotic agent.  Br J Haematol. 1999;  104 438-441
    CrossrefPubMedGoogle Scholar
  • 23 Patrono C, Ciabattoni G, Patrignani P et al.. Eicosanoid biosynthesis and metabolism in myeloproliferative disorders.  Ann NY Acad Sci. 1994;  744 229-236
    PubMedGoogle Scholar
  • 24 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low dose aspirin in polycythemia vera.  N Engl J Med. 2004;  350 114-124
    CrossrefPubMedGoogle Scholar
  • 25 Vane J R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.  Nat New Biol. 1971;  231 232-235
    PubMedGoogle Scholar
  • 26 Burch J W, Stanford N, Majerus P W. Inhibition of platelet prostaglandin synthetase by oral aspirin.  J Clin Invest. 1978;  61 314-327
    PubMedGoogle Scholar
  • 27 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects.  J Clin Invest. 1982;  69 1366-1372
    CrossrefPubMedGoogle Scholar
  • 28 Smith W L. Prostanoid biosynthesis and mechanisms of action.  Am J Physiol. 1992;  263 181-191
    PubMedGoogle Scholar
  • 29 Patrono C, Ciabattoni G, Patrignani P et al.. Clinical pharmacology of platelet cyclooxygenase inhibition.  Circulation. 1985;  72 1177-1184
    PubMedGoogle Scholar
  • 30 FitzGerald G A, Oates J A, Hawiger J et al.. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.  J Clin Invest. 1983;  71 676-688
    PubMedGoogle Scholar
  • 31 Pedersen A K, FitzGerald G A. Dose-related kinetics of aspirin: presystemic acetylation of platelet cyclooxygenase.  N Engl J Med. 1984;  311 1206-1211
    PubMedGoogle Scholar
  • 32 Patrono C. Aspirin as an antiplatelet drug.  N Engl J Med. 1994;  330 1287-1294
    CrossrefPubMedGoogle Scholar
  • 33 Patrono C, Coller B, FitzGerald G A et al.. Platelet-active drugs: the relationship among dose, effectiveness and side effects: the Seventh ACCP conference on antithrombotic and thrombolytic therapy.  Chest. 2004;  126 234S-264S
    CrossrefPubMedGoogle Scholar
  • 34 Antithrombotic Trialist's Collaboration . Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;  324 71-86
    CrossrefPubMedGoogle Scholar
  • 35 Patrono C, Garcia Rodriguez L, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis.  N Engl J Med. 2005;  353 2373-2383
    CrossrefPubMedGoogle Scholar
  • 36 García Rodríguez L A, Hernández-Díaz S, de Abajo F J. Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies.  Br J Clin Pharmacol. 2001;  52 563-571
    CrossrefPubMedGoogle Scholar
  • 37 Patrono C, Bachmann F, Baigent C et al.. Expert consensus document on the use of antiplatelet agents.  Eur Heart J. 2004;  25 166-181
    CrossrefPubMedGoogle Scholar
  • 38 Peto R, Gray R, Collins R et al.. Randomised trial of prophylactic daily aspirin in British male doctors.  BMJ. 1988;  296 313-316
    CrossrefPubMedGoogle Scholar
  • 39 Steering Committee of the Physicians' Health Study Research Group . Final report on the aspirin component of the ongoing Physicians' Health Study.  N Engl J Med. 1989;  321 129-135
    CrossrefPubMedGoogle Scholar
  • 40 The Medical Research Councils' General Practice Framework . Thrombosis prevention trial: randomised trial of low intensity oral anticoagulation with warfarin and low-dose aspirin in primary prevention of ischaemic heart disease in men at increased risk.  Lancet. 1998;  351 233-241
    CrossrefPubMedGoogle Scholar
  • 41 Hansson L, Zanchetti A, Carruthers S G et al.. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.  Lancet. 1998;  351 1755-1762
    CrossrefPubMedGoogle Scholar
  • 42 Collaborative Group of the Primary Prevention Project . Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice.  Lancet. 2001;  357 89-95
    CrossrefPubMedGoogle Scholar
  • 43 Sanmuganathan P S, Ghahramani P, Jackson P R et al.. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.  Heart. 2001;  85 265-271
    CrossrefPubMedGoogle Scholar
  • 44 Ridker P M, Cook N R, Lee I M et al.. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.  N Engl J Med. 2005;  352 1293-1304
    CrossrefPubMedGoogle Scholar
  • 45 Van Genderen P JJ, Michiels J J, van Strik R, Lindemans J, van Vliet H HDM. Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.  Thromb Haemost. 1995;  73 210-214
    PubMedGoogle Scholar
  • 46 Van Genderen P JJ, Lucas I S, van Strik R et al.. Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.  Thromb Haemost. 1996;  76 333-338
    PubMedGoogle Scholar
  • 47 Michiels J J. Erythromelalgia and thrombocythemia: a disease of platelet prostaglandin metabolism.  Semin Thromb Hemost. 1997;  23 335-338
    PubMedGoogle Scholar
  • 48 Tartaglia A, Goldberg J, Berk P, Wasserman L. Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera.  Semin Hematol. 1986;  23 172-176
    PubMedGoogle Scholar
  • 49 Touraine F, Moldovan D, Touraine P, Chenot P, Bonnaud F. Aspirin and non steroidal anti-inflammatory drugs hypersensitivity review (2002-2004).  Allergy Immunol. 2005;  37 279-282
    PubMedGoogle Scholar
  • 50 Chan F K, Ching J Y, Hung L C et al.. Clopidogrel versus aspirin and omeprazole to prevent recurrent ulcer bleeding.  N Engl J Med. 2005;  352 238-244
    CrossrefPubMedGoogle Scholar
  • 51 Marchioli R, Finazzi G, Landolfi R et al.. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.  J Clin Oncol. 2005;  23 2224-2232
    CrossrefPubMedGoogle Scholar
  • 52 Harrison C N, Campbell P J, Buck G et al.. A randomized comparison of hydroxyurea with anagrelide in high-risk essential thrombocythemia.  N Engl J Med. 2005;  353 33-45
    CrossrefPubMedGoogle Scholar
  • 53 Michiels J J, Berneman Z, Schroyens W, van Vliet H HDM. Pathophysiology and treatment of platelet-mediated microvascular disturbances, major thrombosis and bleeding complications in essential thrombocythemia and polycythemia vera.  Platelets. 2004;  15 67-84
    CrossrefPubMedGoogle Scholar
  • 54 Michiels J J, Budde U, van der Planken M, Schroyens W, Bernaman Z. Acquired von Willebrand Syndromes: clinical features, aetiology, pathophysiology, classification and management.  Best Pract Res Clin Haematol. 2001;  14 401-436
    CrossrefPubMedGoogle Scholar
  • 55 Barbui T, Finazzi G. When and how to treat essential thrombocythemia.  N Engl J Med. 2005;  353(1) 85-86
    CrossrefPubMedGoogle Scholar
  • 56 Cortelazzo S, Viero P, Finazzi G et al.. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.  J Clin Oncol. 1990;  8 556-562
    PubMedGoogle Scholar
  • 57 Bauer K A. The thrombophilias: well-defined risk factors with uncertain therapeutic implications.  Ann Intern Med. 2001;  135 367-373
    PubMedGoogle Scholar
  • 58 Nicolaides A N. Thrombophilia and venous thromboembolism. International Consensus Statement.  Intern Angiol. 2005;  24 1-26
    PubMedGoogle Scholar
  • 59 Wehmeier A, Daum I, Jamin H, Schneider W. Incidence and clinical risk factors for bleeding and thrombotic complications in myeloproliferative disorders. A retrospective analysis of 260 patients.  Ann Hematol. 1991;  63 101-106
    CrossrefPubMedGoogle Scholar
  • 60 Van Genderen P JJ, Michiels J J. Erythromelalgic, thrombotic and hemorrhagic thrombocythemia.  Presse Med. 1994;  23 73-77
    PubMedGoogle Scholar
  • 61 Budde U, Schaefer G, Mueller N et al.. Acquired von Willebrand's disease in myeloproliferative syndrome.  Blood. 1984;  64 981-985
    PubMedGoogle Scholar
  • 62 Budde U, Dent J A, Berkovitz S D et al.. Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome.  Blood. 1986;  68 1213-1217
    PubMedGoogle Scholar
  • 63 Fabris F, Casonato A, Del Ben M G et al.. Abnormalities of von Willebrand factor in myeloproliferative disease: a relationship with bleeding diathesis.  Br J Haematol. 1986;  63 75-83
    CrossrefPubMedGoogle Scholar
  • 64 Van Genderen P JJ, Michiels J J, van der Poel-van de Luitgaarde S CAMP, van Vliet H HDM. Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia.  Ann Hematol. 1994;  69 81-84
    CrossrefPubMedGoogle Scholar
  • 65 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.  Lancet. 2000;  355 1295-1302
    CrossrefPubMedGoogle Scholar
  • 66 Grady D, Wenger N K, Herrington D et al.. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study.  Ann Intern Med. 2000;  132 689-696
    PubMedGoogle Scholar
  • 67 The ESPS . 2 Group. European Stroke Prevention Study 2. Efficacy and safety data. Secondary endpoints.  J Neurol Sci. 1997;  151 S1-S7
    PubMedGoogle Scholar
  • 68 Jacobson A K. Platelet ADP receptor antagonists: ticlopidine and clopidogrel.  Best Pract Res Clin Haematol. 2004;  17 55-64
    CrossrefPubMedGoogle Scholar
  • 69 Kralovics R, Passamonti F, Buser A S et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
    CrossrefPubMedGoogle Scholar
  • 70 James C, Ugo V, Le Couedic J-P et al.. A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera.  Nature. 2005;  434 1144-1148
    CrossrefPubMedGoogle Scholar
  • 71 Levine R L, Wadleigh M, Cools J et al.. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.  Cancer Cell. 2005;  7 387-397
    CrossrefPubMedGoogle Scholar
  • 72 Baxter E J, Scott L M, Campbell P J et al.. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
    CrossrefPubMedGoogle Scholar
  • 73 Campbell P J, Scott L M, Buck G et al.. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.  Lancet. 2005;  366 1945-1953
    CrossrefPubMedGoogle Scholar
  • 74 James C, Ugo V, Casadevall N, Constantinesco S N, Vainchenker W A. JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.  Trends Mol Med. 2005;  11 546-554
    CrossrefPubMedGoogle Scholar

Raffaele LandolfiM.D. 

Institute of Internal Medicine, Haemostasis Research Center, Catholic University School of Medicine

Largo Agostino Gemelli 8, 00168 Rome, Italy

Email: rlandolfi@rm.unicatt.it

      >