Myeloproliferative disorders originate in the clonal expansion of a transformed pluripotential hematopoietic progenitor cell. This results in a group of syndromes that include polycythemia vera, essential thrombocythemia,
The article by Dr. Gilbert provides a comprehensive appraisal of the clinical aspects of essential thrombocythemia and polycythemia vera. The author reviews some of the previous work in the field that led to the current treatment recommendations, discusses newer treatment agents with platelet-lowering properties, and gives a balanced view of the attributes of both old and new treatment agents.
However, the diagnosis and management of polycythemia vera and essential thrombocythemia remain controversial. A lack of specific genetic markers has led to the development of complicated diagnostic criteria that are seldom used in routine clinical practice. I believe in a stepwise approach to reaching a working diagnosis rather than the application of a set of criteria that are not universally agreed upon. For example, one may suspect polycythemia vera if:
1. The hematocrit is above the upper limit of the reference interval (adjusted for sex and race);
2. There is a documented and persistent increase in hematocrit from a previous baseline; or
3. An upper normal hematocrit value is associated with a polycythemia vera-related feature such as aquagenic pruritus, large-vessel thrombosis, splenomegaly, erythromelalgia, microcytosis, or persistent leukocytosis or thrombocytosis.
In the absence of any of the above features, one can simply recheck the hematocrit in 3 to 6 months. However, if any of the aforementioned features are present, one can begin with a serum erythropoietin determination and continue the investigation for polycythemia vera with a bone marrow examination. Otherwise, a repeat hematocrit and serum erythropoietin determination in 3 to 6 months is reasonable. A bone marrow histologic examination that is complemented by recently described immunohistochemical markers is valuable in supporting a working diagnosis of polycythemia vera. With this strategy, measurement of the red cell mass to confirm a diagnosis of polycythemia vera is largely unnecessary.
A similar stepwise approach may be applied to the diagnosis of essential thrombocythemia. One should first exclude the possibility of reactive thrombocytosis by reviewing the patient’s history, previous platelet counts, the peripheral blood smear, and levels of serum ferritin and C-reactive protein. In the presence of nonreactive and persistent thrombocytosis, other chronic myeloid disorders must be excluded before a diagnosis of essential thrombocythemia can be established. The possibility of polycythemia vera should be pursued if the hematocrit is near or above the normal reference interval. Otherwise, a bone marrow examination is indicated to rule out the possibilities of chronic myeloid leukemia, the myelodysplastic syndrome, and either cellular or fibrotic phase agnogenic myeloid metaplasia. In other words, essential thrombocythemia remains a diagnosis of exclusion.
In general, drug therapy is discouraged in low-risk patients (age < 60 years and no history of thrombosis and a platelet count of < 1.5 million/mL and the absence of cardiovascular risk factors) with either polycythemia vera or essential thrombocythemia because of the low incidence of associated thrombohemorrhagic complications.[5,6] However, there is good evidence to support the use of hydroxyurea therapy in high-risk patients (age ³ 60 years or a history of thrombosis) with either polycythemia vera or essential thrombocythemia. What is not clearly known is whether:
1. Indeterminate-risk patients (ie, patients who are neither high- nor low-risk) require cytoreductive therapy;
2. Other platelet-lowering agents may be substituted for hydroxyurea;
3. Hydroxyurea is leukemogenic in these disorders; and
4. Thrombocythemia is a risk factor for thrombosis in polycythemia vera.
Similarly, the target platelet count during the treatment of high-risk patients has yet to be defined. Hopefully, ongoing and future trials will provide definitive answers to some of these questions.
At present, I consider interferon-alpha (Intron A, Roferon-A) for polycythemia vera and anagrelide (Agrylin) for essential thrombocythemia as alternative, but not superior, therapies for young patients (age < 60 years).[9,10] These new agents can also be used with reasonable safety in older patients who are intolerant of hydroxyurea. In women of childbearing age, no specific treatment is recommended for low-risk disease, and interferon-alpha is the preferred agent for high-risk disease.
Finally, our group recently reviewed the long-term experience with anagrelide in patients with essential thrombocythemia and found that thrombohemorrhagic complications continue to occur in patients with platelet counts above 400,000/µL. Accordingly, we recommend a target platelet count of 400,000/µL in patients who require treatment.
1. Tefferi A, Solberg LA, Silverstein MN: A clinical update inpolycythemia vera and essential thrombocythemia. Am J Med 109(2):141-149, 2000.
2. Tefferi A, Yoon SY, Li CY: Immunohistochemical staining formegakaryocyte c-mpl may complement morphologic distinction between polycythemiavera and secondary erythrocytosis. Blood 96(2):771-772, 2000.
3. Fairbanks VF, Klee GG, Wiseman GA,et al: Measurement of blood volume and redcell mass-re-examination of Cr-51 and I-125 methods. Blood Cells Mol Dis22(15):169-186, 1996.
4. Tefferi A, Ho TC, Ahmann GJ, et al: Plasma interleukin-6 andC-reactive protein levels in reactive vs clonal thrombocytosis. Am J Med97(4):374-378, 1994.
5. Berk PD, Wasserman LR, Fruchtman SM, et al: Treatment ofpolycythemia vera: A summary of clinical trials conducted by the polycythemiavera study group, in Wasserman LR, Berk PD, Berlin NI, et al (eds): PolycythemiaVera, pp 166-194. Philadelphia, WB Saunders, 1995.
6. Ruggeri M, Finazzi G, Tosetto A, et al: No treatment forlow-risk thrombocythemia: Results from a prospective study. Br J Haematol103:772-777, 1998.
7. Fruchtman SM, Mack K, Kaplan ME, et al: From efficacy tosafety-a Polycythemia Vera Study Group report on hydroxyurea in patients withpolycythemia vera. Semin Hematol 34(1):17-23, 1997.
8. Cortelazzo S, Finazzi G, Ruggeri M, et al: Hydroxyurea forpatients with essential thrombocythemia and a high risk of thrombosis. N Engl JMed 332(17):1132-1136, 1995.
9. Silver RT: Interferon alfa-effects of long-term treatmentfor polycythemia vera. Semin Hematol 34(1):40-50, 1997.
10. Anagrelide Study Group: Anagrelide, a therapy forthrombocythemic states: Experience in 577 patients. Am J Med 92(1):69-76, 1992.
11. Beressi AH, Tefferi A, Silverstein MN, et al: Outcomeanalysis of 34 pregnancies in women with essential thrombocythemia. Arch InternMed 155(11):1217-1222, 1995.
12. Storen EC, Tefferi A: Long-term use of anagrelide in youngpatients with essential thrombocythemia. Blood 97:863-866, 2001.