Blood, Vol. 93 No. 2 (January 15), 1999:
pp. 415-416
INTRODUCTION: FOCUS ON HEMATOLOGY
Essential Thrombocythemia: Another "Heterogeneous Disease"
Better Understood?
By
Stephen D. Nimer
From the Division of Hematologic Oncology, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY.
 |
ARTICLE |
THE TWO GUIDING principles that I learned
during my medical training were that (1) disease presentations are
heterogeneous and (2) therapy must be "individualized." The
article by Harrison et al1 in this issue of BLOOD
addresses both of these issues by carefully defining the incidence of
clonal and nonclonal hematopoiesis in patients given the clinical
diagnosis of essential thrombocythemia (ET).
ET is one of the four myeloproliferative disorders (MPDs; with chronic
myelogenous leukemia [CML], polycythemia vera [PV], and
myelofibrosis [MF] constituting the others), but unlike CML, there is
no cytogenetic or molecular abnormality that definitively establishes
its diagnosis. Rather, the diagnosis of ET is made when a patient has
an elevated platelet count, increased numbers of megakaryocytes in the
bone marrow, no identifiable underlying abnormality known to cause
thrombocytosis, and the absence of findings suggestive of a different
MPD (see Table 1 for the current diagnostic
criteria of the Polycythemia Vera Study Group).
The treatment of ET is designed to prevent or reduce the risk of its
complications, which are most commonly related to vaso-occlusion or
hemorrhage and are often neurologic. There are no predictive tests to
determine who will develop hemostatic complications, but the risk
varies according to age, platelet count, duration of disease, prior
symptoms, and the presence or absence of other medical
conditions.2 The treatment of ET can vary from no treatment (ie, observation) or low-dose aspirin for low-risk patients, to treatment with hydroxyurea, 
-interferon, or Anagrelide, often in
combination with aspirin, for patients with
intermediate-risk or high-risk disease.3 ET can evolve into
myelofibrosis and, rarely, into acute leukemia (in roughly 3% to 5%
of cases).4
Myeloproliferative disorders such as ET are generally thought to be
stem cell disorders, yet clonality has not been universally found in
several analyses of ET patients. Clonality restricted to the
megakaryocytic lineage has been reported,5 but clonality can be difficult to demonstrate for a variety of reasons, as discussed in Harrison et al.1 Methodologies used to assess clonality have included analysis of G6PD isoenzymes, X-linked polymorphisms, and
DNA methylation patterns of X-linked genes.
In the report by Harrison et al,1 the investigators
examined X-chromosome inactivation patterns to assess clonality in a
population of 46 female patients with an elevated platelet count, in
whom secondary causes of thrombocythemia had been ruled out. This
group, and others, have previously shown that skewing of XCIPs occurs
commonly in females more than 65 years of age (by comparing the XCIP
pattern in neutrophils v T cells).6,7 Of the 46 patients with ET, they found 23 that were suitable for XCIP clonality
analysis. Ten of these patients (43%) clearly demonstrated clonal
hematopoiesis, whereas 57% had polyclonal disease, illustrating the
heterogeneity of patients given a clinical diagnosis of ET. The
incidence of clonality was not related to the age of the patient, the
platelet count, or the duration of disease. No patients in this series
developed acute myelogenous leukemia (AML), but 2 patients, both with clonal disease, developed myelofibrosis. The incidence of thrombotic, but not hemorrhagic, events appeared to be
less in patients with polyclonal hematopoiesis.
This report raises many important issues about the management of
patients with ET, and future studies will hopefully address whether
patients with clonal disease should be treated differently than those
with nonclonal disease. Studies of patients with familial ET suggest
that clonality is not required for the development of hemostatic
complications, although it may increase the risk of such events. The
risk of developing AML, and myelofibrosis, is probably higher in
patients with clonal disease; thus, the presence of clonal
abnormalities may guide the choice of cytoreductive treatment, avoiding
agents with leukemogenic potential.
Molecular abnormalities in the thrombopoietin (TPO) gene have recently
been found in several families with an autosomal dominant form of
hereditary thrombocythemia, suggesting at least one mechanism for
nonclonal ET. TPO is a major regulator of platelet production, and the
circulating level of TPO generally varies inversely with the number of
platelets in the blood and megakaryocytes in the bone marrow. In two
families with hereditary thrombocythemia (HT), abnormalities in the 5
UTR of the TPO gene were detected in affected but not unaffected
individuals, which generate aberrantly spliced TPO mRNAs and
overproduction of TPO. Affected individuals have an elevated platelet
count and an elevated TPO level.8,9 Elevated TPO levels
have also been found in nonfamilial ET and in reactive
thrombocytosis,10 but there has been only a limited search
for molecular defects in these individuals. Neither of these studies
examined hematopoietic progenitor cell clonality in HT, but a third
study has demonstrated polyclonal hematopoiesis in affected members of
an HT family.11 Recurrent hemostatic abnormalities have
been reported in some, but not all HT families; however, the clonality
of the hematopoietic progenitors in these instances was not described.
Although TPO administration itself does not appear to activate
platelets in vivo, hemostatic abnormalities could occur as a result of
chronic, persistent thrombocytosis and possibly the presence of other
risk factors.
Further study of patients with ET is necessary to confirm the findings
in Harrison et al1 and to address some of the questions raised in Table 2. This disorder remains a
diagnosis of exclusion, but someday it should be possible to identify
subgroups of patients who are particularly at risk for thrombotic or
hemorrhagic complications or progression to AML or MF, so that specific
algorithms can be applied to patient management. We may soon be able to
refer to thrombocytosis that is clonal as thrombocythemia vera and
consider all nonclonal disorders (whether due to increased TPO
production, iron deficiency, etc) as secondary thrombocythemia. Further
efforts to define the clonality and molecular abnormalities of ET and the other MPDs will allow us to better understand their heterogeneity and better individualize therapy.
| |
FOOTNOTES |
Address reprint requests to Stephen D. Nimer, MD, Division of
Hematologic Oncology, Department of Medicine, Memorial Sloan-Kettering
Cancer Center, 1275 York Ave, Box 575, New York, NY.
| |
REFERENCES |
1.
Harrison CN, Gale RE, Machin SJ, Linch DC:
A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications.
Blood
93:417, 1998[Abstract/Free Full Text]
2.
Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T:
Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.
J Clin Oncol
8:556, 1990[Abstract]
3.
Barbui T, Finazzi G, Dupuy E, Kiladjian JJ, Briere J:
Treatment strategies in essential thrombocythemia. A critical appraisal of various experiences in different centers.
Leuk Lymphoma
22:149, 1996 (suppl 1)
4.
Sterkers Y, Preudhomme C, Lai JL, Demory JL, Caulier MT, Wattel E, Bordessoule D, Bauters F, Fenaux P:
Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: High proportion of cases with 17p deletion.
Blood
91:616, 1998[Abstract/Free Full Text]
5.
El-Kassar N, Hetet G, Briere J, Grandchamp B:
Clonality analysis of hematopoiesis in essential thrombocythemia: Advantages of studying T lymphocytes and platelets.
Blood
89:128, 1997[Abstract/Free Full Text]
6.
Gale RE, Fielding AK, Harrison CN, Linch DC:
Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.
Br J Haematol
98:512, 1997[Medline]
[Order article via Infotrieve]
7.
Champion KM, Gilbert JG, Asimakopoulos FA, Hinshelwood S, Green AR:
Clonal haemopoiesis in normal elderly women: Implications for the myeloproliferative disorders and myelodysplastic syndromes.
Br J Haematol
97:920, 1997[Medline]
[Order article via Infotrieve]
8.
Kondo T, Okabe M, Sanada M, Kurosawa M, Suzuki S, Kobayashi M, Hosokawa M, Asaka M:
Familial essential thrombocythemia associated with one-base deletion in the 5-untranslated region of the thrombopoietin gene.
Blood
92:1091, 1998[Abstract/Free Full Text]
9.
Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC:
An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.
Nat Genet
18:49, 1998[Medline]
[Order article via Infotrieve]
10.
Cerutti A, Custodi P, Duranti M, Noris P, Balduini CL:
Thrombopoietin levels in patients with primary and reactive thrombocytosis.
Br J Haematol
99:281, 1997[Medline]
[Order article via Infotrieve]
11.
Jorgensen M, Raskind WH, Wolff J, Bachrach H, Kaushansky K:
Familial thrombocytosis associated with overproduction of thrombopoietin due to a novel splice donor site mutation.
Blood
92:205a, 1998 (abstr, suppl 1)
12.
Murphy S, Peterson P, Iland H, Laszlo J:
Experience of the Polycythemia Vera Study Group with essential thrombocythemia: A final report on diagnostic criteria, survival, and leukemic transition by treatment.
Semin Hematol
34:29, 1997[Medline]
[Order article via Infotrieve]
Top
Article
References
