Essential Thrombocythemia in Young Adults

KRISTI J. McINTYRE, M.D.,* Division of Medical Oncology; H. CLARK HOAGLAND, M.D.,

MURRAY N. SILVERSTEIN, M.D., ROBERT M. PETITT, M.D., Division ofHematology
and Internal Medicine

Essential thrombocythemia is typically a disorder of adults in the sixth or seventh

decade of life and is characterized by frequent thrombohemorrhagic complications.
In young patients, the optimal management of complications is controversial. We
studied 56 young adults (33 female and 23 male patients) with a diagnosis of essential
thrombocythemia. The mean duration offollow-up was 4.68 years. The mean platelet
count at diagnosis was 1,328,000/mm3 Platelet aggregation studies in 21 patients
demonstrated hypoaggregation to epinephrine; spontaneous platelet aggregation
was present in 4. At diagnosis, 39 patients were asymptomatic, and thrombocytosis
was discovered incidentally. Throughout follow-up (up to 20 years), 24 patients
remained asymptomatic. Thrombotic complications developed in 24 patients; they
were life-threatening in only 3. The most common vaso-occlusive symptoms were
migraine headache (in 12 patients) and erythromelalgia (in 3). Minor hemorrhagic
complications occurred in six patients, and none was life-threatening. Serious
complications (one cerebral and two myocardial infarctions) occurred in three
patients, all of whom recovered. Two deaths occurred, neither of which was attrib-
utable to essential thrombocythemia. The treatment regimens used were chemother-
apy in 9 patients, antiaggregating agents in 7, radioactive phosphorus in 1, the newer
platelet-lowering agent anagrelide in 10, and only observation in 29. No treatment-
related acute leukemias developed. This series of young patients with essential
thrombocythemia, the largest to date, demonstrates a low incidence of life-threaten-
ing complications and a favorable long-term prognosis. Therapeutic recommenda-
tions should remain conservative, and potential leukemogens should be avoided
unless serious complications develop. Anagrelide maybe useful in young patients
with thrombocythemia who are symptomatic.

Essential thrombocythemia (ET) is a clonal! common. The incidence in Olmsted County in

myeloproliferative disorder characterized by a
sustained excessive production of platelets. This
disorder of unknown origin was first described
more than 50 years ago" and is considered un-
*Current address: Jackson, Mississippi.
Address reprint requests to Dr. H. C. Hoagland, Division of years, no increased risk of serious thrombo-
Hematology, Mayo Clinic, Rochester, MN 55905.
Mayo Clin Proc 66:149-154, 1991
southeastern Minnesota is 7 per million per
year. Typically, it occurs in adults in the sixth or
seventh decade oflife, and clinically it is associ-
ated with frequent thrombohemorrhagic com-
plications." In 1978, we reported the first series
of young patients with ET.4 In this group of nine
asymptomatic patients, followed up for 1 to 10
hemorrhagic complications was observed. This
149
150 ESSENTIAL THROMBOCYTHEMIA IN YOUNG ADULTS
finding distinctly contrasts with the natural
history of ET in older adults. The standard
treatment in older patients has been control of
thrombocytosis with potentially leukemogenic
chemotherapy or radioactive phosphorus to
reduce the rate of complications or death. We
concluded that a more conservative therapeutic
approach such as careful observation or antiag-
gregating agents should be used initially in
younger patients with ET because ofthe asymp-
tomatic nature of the disorder in this subset and
the possible deleterious effects of platelet-Iower-
ing therapies, such as alkylating agents and ra-
dioactive phosphorus.
With the widespread use of automated Coul-
ter counters, elevated platelet counts are being
noted incidentally in increasing numbers of
asymptomatic young patients who fulfill the
criteria for ET. In the literature, anecdotal
reports of life-threatening thrombohemorrhag-
ic complications in young adult patients have
caused controversy about appropriate therapeu-
tic managementr':" these reports warrant reex-
amination of the frequency and severity of com-
plications in this subset of patients with ET.
Additionally, the therapeutic dilemma is com-
pounded by a new platelet-lowering drug (ana-
grelide) without known leukemogenic potential
that is currently in the investigational stages
and may be considered for use in these young
adults. Therefore, we reviewed the records of 56
young adults with ET in an attempt to clarify the
natural history of the disorder, determine the
frequency and severity of complications, and
delineate appropriate management options.
PATIENTS
From 1969 to 1989, 56 young adults (younger
than 40 years of age) were newly diagnosed with
ET and underwent periodic follow-up. The cri-
teria for establishing the diagnosis of ET were
based on a modification of the definition re-
ported by the Polycythemia Vera Study Group 9, 10
and included (1) a platelet count persistently
more than 700,000/mm 3 , (2) atypical megakary-
ocytic hyperplasia in the bone marrow, (3) ab-
sence of known causes of reactive thrombocyto-
sis, and (4) exclusion of thrombocytosis related
Mayo Clin Proc, February 1991, Vol 66
to other myeloproliferative disorders (normal
erythrocyte volume with a hematocrit value less
than 46% and no Philadelphia chromosome).
METHODS
At initial evaluation, a bone marrow examina-
tion, peripheral blood cell count, and clinical
examination with an emphasis on initial symp-
toms were done on all patients. Results of
cytogenetic analysis were assessable in 28 ofthe
56 patients. Platelet aggregation studies with
epinephrine, adenosine diphosphate, collagen,
arachidonate, and ristocetin were performed on
25 patients. Spontaneous platelet aggregation
was assayed in 10 patients, and the bleeding
time was determined in 17 patients. A leukocyte
alkaline phosphatase score was obtained in 26
patients. Serum iron studies were performed in
28 patients; in the other 28 patients, no indirect
evidence of iron deficiency (hypochromia, low
mean corpuscular volume) was found.
Follow-up examinations included a clinical
assessment and peripheral blood cell count.
These studies were performed at various inter-
vals, asjustified by clinical need. Follow-up data
were also provided by family physicians.
Platelet counts were determined with phase
microscopy before 1978 and thereafter were
determined automatically on the Hemalog-8 and
Coulter ZBI counters. Bone marrow aspirate
and biopsy specimens were obtained with the
Jamshidi biopsy instrument, and smears were
assessed histologically. The cytologic focus was
on the morphologic features, size, and number of
megakaryocytes. When possible, Perls' Prus-
sian blue reagent and reticulin stains were used
to assess marrow iron stores and the degree of
marrow fibrosis, respectively. Cytogenetic analy-
sis was done on direct bone marrow prepara-
tions or 24-hour cultures. 11 Platelet aggregation
studies were done photometrically on a Bio/Data
aggregometer.P Platelet-rich plasma adjusted
to 250,000/mm3 was tested with the addition of
adenosine diphosphate, epinephrine, collagen,
arachidonate, and ristocetin. The spontaneous
platelet aggregation test was performed in ac-
cordance with the Breddin method. 13 The method
ofIvy was used to determine the bleeding time.P
Mayo Clin Proc, February 1991, Vol 66
Total erythrocyte mass was determined isotopi-
cally with radioactive chromium-51.
RESULTS
The median age of the 56 patients at diagnosis
was 29 years (range, 12 to 40 years). Consistent
with previously reported series.v" a female
preponderance was demonstrated (female:male
ratio, 1.4:1; 33 female and 23 male patients).
Mostpatients were asymptomatic at the time of
initial assessment; ET was found incidentally in
39 patients (70%) from routine blood cell counts.
The initial problem in four patients was minor
hemorrhaging, including a traumatic hematoma,
bleeding after a dental extraction, and gastroin-
testinal bleeding related to a peptic ulcer (two
patients). At the time of initial examination,
seven patients complained of vascular (mi-
grainelike) headaches. One patient had had a
myocardial infarction, and symptoms attribut-
able to splenomegaly and a spontaneous abor-
tion were present in one patient each (Table 1).
The duration of follow-up ranged from 5
months to 20 years (mean, 4.68 years). Twenty-
four (43%) of the patients remained asymptom-
atic throughout follow-up. Thrombotic compli-
cations occurred in 24 (43%) of the patients.
Table l.-Symptoms of Essential Thrombocythemia
in 56 Young Adults
Symptom
Thrombotic
Arterial
Cerebral infarction
Myocardial infarction
Transient ischemic attacks
Visual disturbance
Migraine headache
Erythromelalgia
Dizziness
Venous
Deep venous thrombosis
Priapism
Hemorrhagic
Epistaxis
Gastrointestinal bleeding
Postoperative bleeding
Posttraumatic bleeding
Spontaneous abortion
Asymptomatic
ESSENTIAL THROMBOCYTHEMIA IN YOUNG ADULTS 151
Disturbances of the microcirculation were the
most frequent thrombotic complications, occur-
ring in 21 (38%) ofthe patients. Cerebral distur-
bances were the most common of these; mi-
grainelike headaches occurred in 12 patients,
transient ischemic attacks in 2, blurred vision in
2, and dizziness in 2. Erythromelalgia occurred
in three patients. Thrombotic complications of
the large vessels occurred in five patients and
were arterial in three instances. A male patient
had a cerebral infarction, from which he fully
recovered. Two patients had myocardial infarc-
tions; one had normal and the other had athero-
sclerotic coronary arteries at cardiac catheter-
ization. Complications related to thrombosis
were noted in one patient with deep venous
thrombosis of a lower extremity. Hemorrhagic
complications occurred in only six (11%) of the
patients. These were all minor isolated bleeding
episodes that involved postoperative bleeding,
epistaxis, and gastrointestinal ulcers. Obstetric
complications were relatively infrequent. Of 16
pregnancies, 13 were uneventful and resulted in
live births, and 2 terminated in spontaneous
abortions (Table 1).
Ofthe 56 young patients, 2 died; neither ofthe
deaths was thought to be attributable to ET.
At initial During
examination follow-up
12 (21%) 24 (43%)
0 1
1 2
0 2
0 2
7 12
2 3
1 1
0 1
1 0
4 (7%) 6 (11%)
0 2
2 3
1 1
1 0
1 (2%) 2 (4%)
39 (70%) 24 (43%)
152 ESSENTIAL THROMBOCYTHEMIA IN YOUNG ADULTS Mayo Clin Proc, February 1991, Vol 66

One patient committed suicide, and one died of Table 2.-Initial Laboratory Data for 56 Young
autopsy-proven rupture of a cerebral berry an- Adults With Essential Thrombocythemia
eurysm. Physical examination at diagnosis re- Factor No. of patients
vealed that 20 (36%) of the patients had spleno- Platelet count/mm"
megaly. Splenomegaly developed in only one <1 million 22
additional patient during the follow-up period. 1 million-2 million 28
>2 million 6
None of the patients had clinical hepatomegaly. Leukocyte count/mm"
Treatment regimens during the 20-year pe- <10,000 47
riod included observation (29 patients), chemo- 10,000-15,000 9
therapy (hydroxyurea or busulfan; 9 patients), >15,000 o
Reticulin fibrosis 3
antiaggregating agents (aspirin or dipyridamole; Normal cytogenetic results 27/28
7 patients), radioactive phosphorus (1 patient), Platelet aggregation
and the newer selective platelet-lowering agent Normal 4/25
Abnormal
anagrelide (10 patients). Ofthe 24 patients who Epinephrine 21/25
remained asymptomatic throughout follow-up, Adenosine diphosphate 4/25
15 had observation only, 7 received anagrelide, Collagen 4/25
Spontaneous 4/10
and 2 were treated with aspirin. Of the 32 Abnormal bleeding time 3/17
symptomatic patients, 10 were not treated when
symptoms were minor. Antiaggregating agents
alone were used in 11 patients with minor neuro- other two. None ofthe 26 patients in whom the
logic symptoms (headaches and dysesthesias), leukocyte alkaline phosphatase level was deter-
and the frequency and severity of migrainelike mined had a low value. Marrow fibrosis was
headaches seemed to be reduced. Platelet-low- absent in all but three patients: two had grade
ering agents (anagrelide, hydroxyurea, and 1 and one had grade 3 reticulin staining. Only
radioactive phosphorus) were used in the other one cytogenetic abnormality, an isolated 5q-,
11 patients. was demonstrated. No Philadelphia chromo-
In one patient who was followed up for more some was observed in the 28 cases that were
than 17 years, the thrombocythemia underwent karyotyped. Platelet aggregation studies, which
conversion to polycythemia vera. No secondary were performed in 25 patients, revealed charac-
acute leukemias developed. Platelet counts teristic hypoaggregation to epinephrine in 21.
ranged from 711,000 to 2,571,000/mm 3 at diag- In addition, an abnormal response to collagen
nosis (mean, 1,328,000/mm3 ) ; 61% were more and to adenosine diphosphate was noted in four
than 1 million/mm". Nine patients had an in- patients each. Spontaneous platelet aggrega-
creased leukocyte count (between 11,000 and tion occurred in 4 of 10 patients tested. The
15,000/mm3 ) with slightly granulocytic imma- bleeding time was slightly prolonged (greater
turity (no blasts or promyelocytes) (Table 2). than 8 minutes) in 3 (18%) of the 17 patients in
Pronounced basophilia was not observed. At the whom it was studied.
time of diagnosis, the hematocrit values were
less than 46% in all the female patients and less DISCUSSION
than 52% in all the male patients. Bone marrow Our series of young patients with ET, the largest
evaluation revealed mild overall hypercellular- to date, affirms our original conclusion of more
ity in 49 patients. Megakaryocytic hyperplasia than a decade ago" that life-threatening throm-
was demonstrated in all patients. Iron stores bohemorrhagic complications in this subset of
were decreased or absent in five patients despite patients are uncommon. Indeed, most of our
normal hemoglobin concentrations and normal patients were asymptomatic at the time of ini-
mean corpuscular volumes. The results of se- tial assessment, and an extreme thrombocytosis
rum iron studies were normal in three of these was discovered incidentally on peripheral blood
patients, and such studies were not done in the cell counts. Almost a third of our patients re-
Mayo Clin Proc, February 1991, Vol 66
mained asymptomatic without control of throm-
bocytosis. In the past several years,even large
series of unselected patients with ET14-16 have
indicated that the natural history ofthis disease
is now more accurately characterized by long
asymptomatic intervals.
When symptoms did occur in our patients, the
spectrum was similar to that reported in series
of unselected patients,6,7,14,15,17-19 although the
frequency and distribution differed. Thrombotic
complications were more common than hemor-
rhagic problems. We chose to report minimal
nonspecific symptoms, and most of the throm-
botic complications were minor, transient dis-
turbances of the microvascular circulation
manifested by headaches of a vascular type
(migraine). Hemorrhagic phenomena were in-
frequent and minor in our young patients. This
observation is consistent with previous sugges-
tions''? that the lower incidence of coexisting
illness in this age-group correlates with a.lower
incidence of bleeding problems, in contrast to
older patients with ET.
The serious life-threatening complications that
occurred in three (5%) of our patients were all
arterial. The patients recovered completely and
were thereafter maintained on platelet-lower-
ing agents. Because one patient who had a
myocardial infarction also had coronary artery
atherosclerosis, it is difficult to attribute this
complication solely to ET. Interestingly, to date,
no definitive correlation exists between control
of thrombocytosis and a decrease in complica-
tions. The issue of obstetric complications is
both important and controversial. In our series
of young patients, with a preponderance of fe-
males, normal pregnancies were common. This
finding is in contrast to reports in previous
smaller series7,21,22 and to the widespread belief
that normal pregnancies in young women with
ET are rare. Spontaneous abortions occurred in
3 of the 16 pregnancies in our series. No prema-
ture deliveries or hemorrhagic complications
occurred. Of note, all three women who had
spontaneous abortions had subsequent normal
pregnancies. The issue of whether to attempt to
control thrombocytosis or to use antiaggregating
agents during pregnancy remains controversial.
ESSENTIAL THROMBOCYTHEMIA IN YOUNG ADULTS 153
A meta-analysis of four groups of young pa-
tients (including ours) yields a total of 123 pa-
tients. 7,19,23 All were younger than 40 years of
age (median age, 29.7 years). Sixty-three per-
cent were asymptomatic at the time of initial
investigation. "Significant" complications oc-
curred in 33%. Seven percent of complications
were clearly life-threatening and related to
thrombosis rather than to bleeding (cerebrovas-
cular accident in four patients, myocardial in-
farction in four, and portal and mesenteric vein
thrombosis in one). No case of acute leukemia
has developed in any of the four groups thus far.
On the basis of currently available laboratory
tests, predicting which patients are at risk for
serious life-threatening complications is not
possible. Most patients remain asymptomatic
for extended periods.
Therapeutic management of patients with ET
has been described as a "compromise"14,16 be-
tween accepting the risk of potentially serious
drug toxicities and the necessity of preventing
thrombohemorrhagic complications. This di-
lemma is even more pronounced in young pa-
tients with ET who are of childbearing age and
want to be protected from the infertility, terato-
genicity, and possible leukemogenesis associ-
ated with chemotherapeutic agents and radioac-
tive phosphorus. Recently, an alternative to
chemotherapeutic agents, anagrelide," has been
used in investigational clinical trials of unse-
lected patients with ET. It seems to control
thrombocytosis selectively (reducing the plate-
let count to less than 500,000/mm 3) with mini-
mal toxicity and no known leukemogenic poten-
tial. In our current series, 10 young patients
were initially treated with anagrelide and had
excellent control ofthrombocytosis. All patients
tolerated the drug and had no untoward side ef-
fects. Although the use of anagrelide holds
promise for the future, its use during pregnancy
has not been established. In our opinion, be-
cause of the favorable long-term prognosis and
the substantial number of asymptomatic young
patients with ET, treatment recommendations
in these patients should remain conservative.
We recommend careful observation in the young,
asymptomatic patient with ET. Antiplatelet
154 ESSENTIAL THROMBOCYTHEMIA IN YOUNG ADULTS
agents such as aspirin (100 mg/day) or dipyrida-
mole (75 mg three times a day) may be consid-
ered in patients with minor, non-life-threaten-
ing problems because, in our experience, these
symptoms seem to diminish with such treat-
ment. Control of thrombocytosis with chemo-
therapeutic agents or anagrelide should be re-
served for patients who have serious bleeding or
thrombotic complications. "Do no harm" should
still be the dictum.
ACKNOWLEDGMENT
We thank Michelle M. Ryks for secretarial as-
sistance and LeAnn M. Stee for editorial as-
sistance.
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