Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 10)

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Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 10)

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Complications Perhaps no other condition in clinical medicine has caused otherwise astute physicians to intervene inappropriately more often than thrombocytosis, particularly if the platelet count is 1 x 106/µL. It is commonly believed that a high platelet count causes intravascular stasis and thrombosis; however, no controlled clinical study has ever established this association, and in patients younger than age 60, the incidence of thrombosis was not greater in patients with thrombocytosis than in age-matched controls. To the contrary, very high platelet counts are associated primarily with hemorrhage due to acquired von Willebrand disease. This is not meant to imply that an...

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  1. Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 10) Complications Perhaps no other condition in clinical medicine has caused otherwise astute physicians to intervene inappropriately more often than thrombocytosis, particularly if the platelet count is >1 x 106/µL. It is commonly believed that a high platelet count causes intravascular stasis and thrombosis; however, no controlled clinical study has ever established this association, and in patients younger than age 60, the incidence of thrombosis was not greater in patients with thrombocytosis than in age-matched controls. To the contrary, very high platelet counts are associated primarily with hemorrhage due to acquired von Willebrand disease. This is not meant to imply that an elevated platelet count cannot cause symptoms in a patient with ET, but rather that the focus should be on the patient, not the platelet count. For example,
  2. some of the most dramatic neurologic problems in ET are migraine-related and respond only to lowering of the platelet count, while other symptoms such as erythromelalgia respond simply to platelet cyclooxygenase 1 inhibitors such as aspirin or ibuprofen, without a reduction in platelet number. Still others may represent an interaction between an atherosclerotic vascular system and a high platelet count, and others may have no relationship to the platelet count whatsoever. Recognition that PV can present with thrombocytosis as well as the discovery of previously unrecognized causes of hypercoagulability (Chap. 111) make the older literature on the complications of thrombocytosis unreliable. Essential Thrombocytosis: Treatment Survival of patients with ET is not different than for the general population. An elevated platelet count in an asymptomatic patient without cardiovascular risk factors requires no therapy. Indeed, before any therapy is initiated in a patient with thrombocytosis, the cause of symptoms must be clearly identified as due to the elevated platelet count. When the platelet count rises above 1 X 10 6/µL, a substantial quantity of high-molecular-weight von Willebrand multimers are removed from the circulation and destroyed by the platelets, resulting in an acquired form of von Willebrand disease. This can be identified by a reduction in ristocetin cofactor activity. In this situation, aspirin could promote hemorrhage. Bleeding in this situation usually responds to ε-aminocaproic acid, which can be given prophylactically before and after elective surgery. Plateletpheresis is at best
  3. a temporary and inefficient remedy that is rarely required. Importantly, ET 32 patients treated with P or alkylating agents are at risk of developing acute leukemia without any proof of benefit; combining either therapy with hydroxyurea increases this risk. If platelet reduction is deemed necessary on the basis of symptoms refractory to salicylates alone, IFN-α, the quinazoline derivative, anagrelide, or hydroxyurea can be used to reduce the platelet count, but none of these is uniformly effective nor without significant side effects. Hydroxyurea and aspirin are more effective than anagrelide and aspirin for prevention of TIAs but not more effective for the prevention of other types of arterial thrombosis and actually less effective for venous thrombosis. Normalizing the platelet count does not prevent either arterial or venous thrombosis. Risk of gastrointestinal bleeding is also higher when aspirin is combined with anagrelide. As more clinical experience is acquired, ET is more benign than previously thought. Evolution to acute leukemia is more likely to be a consequence of therapy than of the disease itself. In managing patients with thrombocytosis, the physician's first obligation is to do no harm. Further Readings Buss DH et al: The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: An analysis of 129 cases. Am J Hematol
  4. 20:365, 1985 [PMID: 3865532] Elliot MA et al: Thrombosis and hemorrhage in polycythemia vera and essential thrombocythaemia. Br J Haematol 128:275, 2005 Levine RL, Gilliland DG: JAK-2 mutations and their relevance to myeloproliferative disease. Curr Opin Hematol 14:43, 2007 [PMID: 17133099] Reilly JT: Idiopathic myelofibrosis: Pathogenesis to treatment. Hematol Oncol 24:56, 2006 [PMID: 16477581] Spivak JL: Polycythemia vera: Myths, mechanisms, and management. Blood 100:4272, 2002 [PMID: 12393615] Vainchenker W et al: A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. Hematology (Am Soc Hematol Educ Program):195, 2005 Bibliography
  5. Barosi G et al: Diagnostic and clinical relevance of the number of circulating CD34+ cells in myelofibrosis with myeloid metaplasia. Blood 98:3249, 2001 [PMID: 11719361] Bessman JD: Microcytic polycythemia: Frequency of nonthalassemic causes. JAMA 238:2391, 1977 [PMID: 578867] Cervantes F: Modern management of myelofibrosis. Br J Haematol 128:583, 2005 [PMID: 15725078] Cervantes F et al: Myelofibrosis with myeloid metaplasia in young individuals: Disease characteristics, prognostic factors and identification of risk groups. Br J Haematol 102:684, 1998 [PMID: 9722294] Harrison CN et al: Hydroxyurea compared with anagrelide in high-risk essential thrombocythaemia. N Engl J Med 353:33, 2005 [PMID: 16000354] Johansson PL et al: An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: A study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 129:701, 2005
  6. [PMID: 15916693] Jones A et al: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106:2162, 2005 [PMID: 15920007] Kaushansky K: The molecular mechanisms that control thrombopoiesis. J Clin Invest 115:3339, 2005 [PMID: 16322778] Kessler CM, Klein HG: Untreated thrombocythemia in chronic myeloproliferative disorders. Br J Haematol 50:157, 1982 [PMID: 6976793] Kiladjian JJ et al: High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood 108:2037, 2006 [PMID: 16709929] Lamy T et al: Inapparent polycythemia vera: An unrecognized diagnosis. Am J Med 102:14, 1997 [PMID: 9209196] Landolfi R et al: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350:114, 2004 [PMID: 14711910]
  7. Mesa R et al: Durable responses to thalidomide-based drug therapy for myelofibrosis with myeloid metaplasia. Mayo Clin Proc 79:883, 2004 [PMID: 15244384] Murphy S et al: Template bleeding time and clinical hemorrhage in myeloproliferative disease. Arch Intern Med 138:1251, 1978 [PMID: 277084] Rondelli D et al: Allogeneic stem-cell transplantation with reduced- intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 105:4115, 2005 [PMID: 15671439] Ruggeri M et al: No treatment for low-risk thrombocythaemia: Results of a prospective study. Br J Haematol 103:772, 1998 [PMID: 9858229] Garcia-Manero G et al: Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative disorders. Am J Hematol 60:130, 1999 [PMID: 9929105] Sedlacek SM et al: Essential thrombocythemia and leukemic transformation. Medicine 65:353, 1986 [PMID: 3465986]
  8. Silver RT: Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107:451, 2006 [PMID: 16804923] Tefferi A et al: Cytogenetic findings and their clinical relevance in myelofibrosis with myelopid metaplasia. Br J Haematol 113:763, 2001 [PMID: 11380468] Vardiman JW et al: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100:2292, 2002 [PMID: 12239137] a

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