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CASE REPORT

Essential Thrombocythemia Diagnosed in a Patient with Acute Myocardial


Infarction and Ischemic Strokes
INIMIOARA MIHAELA COJOCARU1,2, CRISTINA HEREA2, ANDREEA IONESCU2,
GABRIELA SOCOLIUC2, VIOLETA APIRA2, M. COJOCARU3
1

Carol Davila University of Medicine and Pharmacy, Department of Neurology,


2
Department of Neurology, Colentina Clinical Hospital,
3
Titu Maiorescu University, Faculty of Medicine, Department of Physiology,
Bucharest, Romania

We present the case of a 53-year-old man, diagnosed with infantile encephalopathy and spastic
tetraparesis, with a history of respiratory infections in the last 3 years, some of them complicated with
acute respiratory failure. In 2009 he presented with an acute myocardial infarction, thus being
hospitalized. Hypertension and hypercholesterolemia were also diagnosed. During hospitalization, he
presented also an acute respiratory infection. Routine blood tests demonstrated a constant raised
platelet count (>1000 109/L), and extensive investigation established the diagnosis of essential
thrombocythemia (ET) with JAK2 positive homozygotous type. The patients sister was diagnosed
with the same mutation. In 2009 he presented in our clinic for swallowing difficulties and tonicoclonic generalized seizures. CT-scan examination revealed multiple sequelar infarctions bilateral and
in cortico-subcortical regions. Hydroxyurea, double antiaggregation and anticonvulsivants were
administered followed by the improvement of the clinical state. ET is one of the chronic
myeloproliferative neoplasms characterized by a sustained platelet count > 450 109/L, presenting
with increased risk of thrombosis and hemorrhagic complications, especially in JAK2 positive
patients. Conclusion. ET is a cause of coronary and vascular cerebral events. ET should be
considered as a risk factor for thrombosis, especially in younger patients, therefore JAK2 gene should
be tested in highly suspicion patients, without being considered a routine investigation.
Key words: Essential thrombocythemia (ET), mutation V617F of JAK2 positive, acute
myocardial infarction, ischemic strokes.

Essential thrombocythemia (ET) is one of the


chronic myeloproliferative neoplasms. The concept
of myeloproliferative neoplasms (MPNs) has
evolved over the years from an initial five diseaseschronic myelogenous leukemia (CML), polycythemia
vera (PV), essential thrombocythemia (ET), chronic
idiopathic myelofibrosis and erythroleukemiaknown as myeloproliferative diseases to todays
MPNs which include CML, PV, ET, primary
myelofibrosis (PMF, formerly chronic idiopathic
myelofibrosis), chronic neutrophilic leukemia (CNL),
hypereosinophilic syndrome (chronic hypereosinophilic leukemia), mast cell disease, and unclassified
MPNs. The reviewed 2008 WHO classification
system for chronic myeloid neoplasms replaced the
terminology from disease to neoplasm in this large
group of myeloproliferative diseases in order to
reflect the neoplastic nature of these conditions [1].
Essential thrombocythemia (ET) is characterrised by a sustained thrombocytosis in peripheral
blood and increased numbers of large mature
megakaryocytes in the bone marrow. The white
cell count may be normal or raised, with a neutronphil leukocytosis [2].
ROM. J. INTERN. MED., 2013, 51, 1, 5361

ET presents an increased risk of thrombotic


and hemorrhagic complications, especially in JAK2
positive patients.
CASE PRESENTATION

We present the case of a 53-year-old man,


diagnosed with infantile encephalopathy and spastic
tetraparesis, with a history of respiratory infections
in the last 3 years, some of them complicated with
acute respiratory failure, for which he was
hospitalized in the ICU of Floreasca Emergency
Clinical Hospital.
On the 2nd of February 2009 the patients
family noticed that the patient presented psychomotor
agitation, groam, palidation, cold extremities, thus
being again hospitalized in Floreasca Emergency
Clinical Hospital where acute inferior myocardial
infarction, hypertension and hypercholesterolemia
were diagnosed. An antiplatelet therapy with hypotensive, cardioprotector, cholesterol lowering drugs
and diuretics was initiated.

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Inimioara Mihaela Cojocaru et al.

During hospitalization, he again developed


bronchopneumonia. He was referred to the Prof.
Dr. Matei Bal Institute for Infectious Diseases for
further investigations. Immunodepression syndrome
and autoimmune disease were infirmed.
Routine blood tests demonstrated a constant
raised platelet count (>1000 109/L).
The patient was referred to the Department of
Hematology of Fundeni Institute where a bone
marrow biopsy was done, that showed increased
cellularity, with a cluster of abnormally large
megakaryocytes, a finding typical of essential
thrombocytosis. The surrounding hemopoietic cells
were represented by a polymorphous population of
erythroid and myeloid precursors, with less than
5% blasts (Photos 1 and 2).
Genetic tests revealed V617F mutation of
JAK2 positive homozygotus type, consisting of
myeloproliferative neoplasm with essential thrombocythemia, thus hydrea therapy was initiated.
The patients sister was diagnosed with the
same mutation and the same type of disease.
In 2009 he was admitted in our clinic for
swallowing difficulties and tonico-clonic generalized
seizures.
The general clinical examination revealed
cachexia, the blood pressure was normal, slight
tachycardia.
The neurological examination showed a
foetal position, spastic tetraparesis, bilateral raised
jerks, left gaze palsy, sphincterian incontinence,
loss of verbal communication.
Platelet count was at 900 109/L.
CT-scan examination revealed multiple hypodense areas located in the occipital lobes corticosubcortical; right temporal and parietal lobe; frontal
lobes, in the right cerebellar lobe; thalamic and
right area lenticular lacunae were also observed.

The ventricular system was found to be enlarged,


mostly in the posterior horns, situated on the
midline. Global cortical atrophy (Photos 3 and 4).

Photo 1. Blood smear, OM 103, May-Grunwald Giemsa


stain Thrombocytosis.

Photo 2. Bone marrow biopsy, OM 103, May-Grunwald


Giemsa stain shows increased cellularity, with a cluster of
abnormally large megakaryocytes, a finding typical of
essential thrombocytosis. The surrounding hemopoietic cells
are a polymorphous population of erythroid and myeloid
precursors, with less than 5% blasts.

Photo 3 and 4. Cerebral CT scans Supra- and infratentorial infarctions.

Essential thrombocythemia in acute myocardial infarction and ischemic strokes

EEG revealed delta waves in all derivations.


ECG showed sequelar inferior myocardial
infarction, synus rhythm, slight tachycardia, QRS
axis at 50 degrees.
Cardiac ultrasound examination was normal.
Ultrasound examination of cervico-cerebral
arteries was normal.
The established diagnoses were: Myeloproliferative neoplasm. Essential thrombocythemia
(V617F mutation of JAK2 positive homozygotus
type). Infantile encephalopathy with spastic tetraparesis. Multi-infarct syndrome. Generalized epilepsy
with tonico-clonic seizures of mixed cause vascular
and encephalopathic. Sequelar inferior myocardial
infarction. Essential hypertension stage II risk
group C. Dyslipidemia with hypercholesterolemia.
Hydroxyurea, dual antiplatelet therapy (clopidogrel and aspirin), lowering cholesterol therapy
(statins), diuretic, hypotensor, cardioprotector, and
antiepileptic drugs (Carbamazepin 200 mg 2/d +
Orfiril 300 mg 2/d) were added to the previous
medication.
The clinical course improved, the patient was
free of seizures, and able to be nurished with soft
foods.
DISCUSSION

ET is one of the most frequently found


Phyladelphia negative myeloproliferative neoplasms.
The diagnosis is suggested by a platelet count >450
109/L, in the absence of any cause of thrombocytosis: inflammatory syndrome, iron deficiency,
or hypersplenism.
On a long term, the evolution towards
myelofibrosis, polyglobulia or acute myeloblastic
leukemia determines the maximal severity of ET,
but they are rare [2].
The TE diagnosis was established accurately
infirming that these could be the onset phase of
these diseases conform to WHO histological
criteria [1].
More recently, the discovery of V617F
mutation on the tyrosine kinase JAK2 gene in the
majority of polyglobulia cases [49] and in
approximately 50% TE cases permits the realization
of another subclassification of them, the forms that
carry the mutation on JAK2 being more close to
polyglobulia, presenting a higher haemoglobin
level [8].
Clinical features
Vascular complications in TE are very
frequent, both of arterial, venous and microcirculatory
type. The global annual incidence of thrombosis is

55

1.7% in people younger than 40 years, as compared


to 6.3% in patients of 4060 years and to 15.1% in
those over 60 years [10].
Arterial thrombosis was observed in approx.
40% of patients in the initial phase, their frequency
diminished during evolution, if the cytoreductor
treatment was initiated [10, 11]. As frequency, it
affects first the arteries with cephalic and cerebral
destination, then those of inferior limbs where a
subjacent obliterant arteriopathy is also present and
then the coronary arteries are affected.
Neurologically, transient or completed cerebral
strokes [12, 13], or spinal cord infarction [15, 17],
occlusive events of retinal arteries [12], optic or
vestibular neuropathy, more rarely dysarthria [16
18], gait disturbances, seizures [15], third nerve
palsy [19], neuromyotonia [20] and reversible acute
sensory-neural hearing loss [21] are observed.
Concerning the cardiac involvement, unstable
angor, ischemia and even myocardial infarction
[14] were present in 9.4% of patients, according to
some authors [22].
A prothrombotic state is present during the
natural evolution of ET.
Peripheral arteries may be also involved (by
thrombotic or thromboembolic mechanism), the
clinical features are described as intermittent
claudication of inferior limbs, pontage thrombosis
and stent thrombosis that may evolve towards
chronic ischemia [23].
Concerning the utero-placental circulation
thrombi may be discovered, inducing a vascular
insufficiency that can determine obstetrical events,
for example spontaneous abortions in the first
trimester of pregnancy occurring in 2636% of TE
cases, as compared to 1520% in normal pregnancies [24].
The venous thrombosis may involve profound
and superficial territories, with the complications
may present themselves as with pulmonary
embolias [14, 23] up to initial frequency 5% [10]
and then diminishes if cytoreducing therapy is
initiated [11]. The severity is maximal if cerebral
venous sinuses are involved [12, 14]. Sometimes
atypical sites can be involved: mesenteric vein,
portal vein, Budd-Chiari syndrome [25].
Microcirculation involvement is present
frequently [10, 1214]. TE patients have hypersensitive platelets that may spontaneously activate
and secrete prothrombotic factors such as thromboxane
and -thromboglobulin. The result is platelet
aggregates formation that occlude the microcirculation [26]. The clinical symptoms are migranous
headaches, visual symptoms as transient monocular
blindness, scintillating scotomas, reduced visual
acuity, dizziness sensations, non-myocardial infarction

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Inimioara Mihaela Cojocaru et al.

chest pain, acrosyndromes, livedo, with the special


mark that is the necrotic component digital
gangrene like during the blue toe syndrome [26].
Erythromelalgia, characterised by violent burning
aches in the plantar foot and erythrosic toes,
associated with raising of local hyperthermia, is a
rare feature, but suggestive for this condition [27].
This is a vasomotor problem consisting of acral
dysesthesia and erythema. It is a consequence of
abnormal platelet-endothelial interactions. Histopathological studies reveal platelet-rich arteriolar microthrombi with endothelial inflammation and intimal
proliferation [28].
Another less frequent presentation is bleeding.
The major risk factor is an extreme thrombocytosis
(>1500 109/L). Bleeding is frequently mucocutaneous, such as echymosis, episthaxis, gingival
bleeding, and menorrhagia. Gastrointestinal hemorrhage, albeit rare, might be serious.
Intracerebral hemorrhage is a severe complication [16]. While ET may cause primary
intracerebral hemorrhage, secondary hemorrhage
can be a complication of cerebral venous
thrombosis. The accuracy of the diagnosis is very
important, in order to avoid wrong therapeutical
decisions like withdrawal of antithrombotic
treatment in patients with hemorrhage secondary to
cerebral venous thrombosis.
Pathogenesis
Identification of V617F mutation of tyrosinkinase Janus 2 (JAK2) gene [3, 5, 6, 29] represented
an achievement in the understanding of myeloproliferative disorders.
The gene consists of a kinase domain (JAK
homology 1 or JH 1) and a catalytically inactive
pseudokinase domain with an important regulatory
function (JH2). The mutation is represented by
unique valine to phenylalanine substitution at
position 617 (V617F) in the JH2 domain which
negatively regulates JH1 and results in cytokine
independent activation and uncontrolled downstream hematopoietic proliferation.
In suspected cases of ET that are JAK2
negative, sceening for mutations in MPL (myeloproliferative leukemia virus oncogene) gene is
recommended. The c-MPL gene and its ligand,
thrombopoietin, regulates the proliferation and the
differentiation of megakaryocytes and of platelets.
The activation of MPL mutations has been linked
to familial thrombocytosis [30] and described in a
minority of patients with classical ET [31, 32].
More recently, mutation in a tumor suppressor gene,
TET2, has been identified in a variety of myeloid

neoplasms, but its specific roles have not yet been


fully evaluated [33, 34].
During the natural evolution of ET a
prothrombotic state is present due to the hyperactivity of different cell types: platelets, leukocytes,
vascular endothelial cells.
Platelets hyperactivation is suggested by
platelet aggregations on blood smears or by
platelets with numerous pseudopodes. Aggregability
tests may objectivate spontaneous platelet aggregation and paradoxically; a hypoaggregability in
vitro after stimulation with different inducers
(ADP, collagen), which is explained by degranulation of circulant platelets [35]. Raised synthesis
of thromboxane A2 was observed in vivo, noncorrelated to platelets count. This fact was
confirmed by measuring the urinary elimination of
its principal stable metabolite 23 dinorthromboxane [36]. High level of -thromboglobulin
(TG), normal constituent present in platelet
granules, reflects an in vivo raised secretion [37],
fact also suggested by the raised level of basal state
in the platelet membrane of the endogenous
thrombospondin found in the platelet membrane
during basal state [38, 39] or of P-selectin [39],
other intragranular constituents, or of CD36 [38,
40, 41].
Leukocytes
hyperactivation
involves
polynuclears, revealed in vivo by the expression of
membranary CD11b, raised in content of alkaline
phosphatase, in elastase or in myeloperoxidase [42,
43] and also in monocytes. The evaluation of
monocytes is possible by measuring the levels of
tissular factor present on their surface [44]. By
transcellular metabolism of arachidonic acid a
raised synthesis of thromboxane A2 by the platelets
favorises that of leukotrienes by polynuclears and
inversely [45].
The formation of mixed platelet-monocytes
or platelet-polynuclears aggregates is due to the
presence of activated platelets, polynuclears and
activated monocytes [44, 46, 47].
In TE there is a tendency towards activation
of vascular endothelial cell explained by raised
plasmatic level of markers, for example a von
Willebrand factor (vWF) and a plasminogen
activator (tPA), reflecting an acute process, or a
thrombomodulin, and a type 1 inhibitor of
plasminogen activator (PAI-1), reflecting a more
chronic process [48]. Other authors state that the
activation of vascular endothelial cell is due to the
same markers, or is the raised quetice of plasmatic
levels of soluble adhesines like sVCAM of endothelial origin [49, 50].

Essential thrombocythemia in acute myocardial infarction and ischemic strokes

A percent of activated platelets in JAK2


positive patients was reported statistically significant [44, 51, 52]. An acquired resistance of
activated protein C and a reduced level of protein S
were also observed [45, 46, 48, 53].
Bleeding is thought to be the result of an
acquired von Willebrand syndrome that occurs
when platelet counts exceed 1500 109/L. In the
presence of such an extreme thrombocytosis there
is a reduction in high molecular weight multimers
of vWF. This is a large multimeric glycoprotein
that plays a vital role in securing hemostasis by
mediating the initial adhesion of platelets to sites of
vascular injury and their subsequent aggregation.
Regulation of vWF size and function is based on
proteolytic modifications which can occur after
secretion from platelet granules into the bloodstream. This is mediated by a vWF cleaving

protease (ADAMTS13). The large multimeric forms


of vWF are most hemostatically effective. It is
thought that increased platelet number may facilitate
the interaction between platelet surface glycolproteins and vWF, inducing changes in vWF that
allow ADAMTS13 to access its cleavage site. The
interaction is enhanced at high platelet counts [54].
Investigations
Any patient with a persistent thrombocytosis
of >450 109/L requires investigations. The major
causes of thrombocytosis are listed in Table I, and
the WHO diagnostic criteria of ET in Table II.
Modifications of these criteria have been proposed
(Table III), meaning that bone marrow histology is
not always essential for patients harbouring
mutations to JAK2 or MPL [50].

Table I
Causes of thrombocytosis
Primary thrombocytosis
Essential thrombocythemia
Polycythemia vera
Idiopathic myelofibrosis
Chronic myeloid leukaemia
Myelodysplasia
Acute leukemia

57

Secondary thrombocytosis
Infection
Inflammation
Connective tissue disease
Iron deficiency
Surgery
Malignancy
Post-splenectomy
Hemolytic anemia
Blood loss

Table II
WHO criteria for the diagnosis of essential thrombocythemia
Diagnosis requires all four criteria
1. Sustained platelet count >450 109/L
2. Bone marrow biopsy showing proliferation mainly of the megakaryocytic
lineage with increased numbers of enlarged, mature megakaryocytes. No
significant increase or left shift of neutrophil granulopoiesis or
erythropoiesis
3. Not meeting WHO criteria for polycythemia vera, primary myelofibrosis,
BCR-ABL1 positive chronic myeloid leukemia or myelodysplastic
syndrome or other myeloid neoplasm
4. Demonstration of JAK2 V617F or other clonal marker, or in the absence
of JAK2 V617F, no evidence for reactive thrombocytosis
Table III
Suggested diagnostic criteria for essential thrombocythemia
Diagnosis requires A1-A3 or A1+A3-A5
A1 Sustained platelet count >450 109/L
A2 Presence of an acquired pathogenetic mutation (e.g., in JAK2 or MPL)
A3 No other myeloid malignancy, especially polycythemia vera, primary
myelofibrosis, chronic myeloid leukemia or myelodysplastic syndrome
A4 No reactive cause for thrombocytosis and normal iron stores
A5 Bone marrow trephine histology showing increased megakaryocytes with
prominent large hyperlobated forms; reticulin is generally not increased
(> 2 on a 04 scale)

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Inimioara Mihaela Cojocaru et al.

Management
In a TE patient with thrombotic events
conventional vascular risk factors need to be
evaluated: diabetes mellitus, hypercholesterolemia,
and hypertension, all being risk factors for
thrombosis [13, 55, 56]. Our patient presented with
many vascular risk factors: hypercholesterolemia,
hypertension, and sequelar myocardial infarction.
Active smoking also raises the thrombotic
risk [14, 55, 56].
Any predisposing condition to a thrombotic
risk by itself is susceptible to increase that of ET:
e.g., pregnancy, surgery, prolonged clinostatism, or
long time immobile position, administration of
oestroprogestatives or of substitutive hormonal
treatment. All these need to be avoided.
Therapeutically, the attitude is oriented
towards the individualization in ET patients of a
high risk vascular group: age > 60 years, with
history of thrombosis or strokes, persistent platelet
counts >1500 109/L [10, 57]. All these patients
will benefit from cytoreductive treatment (hydroxyurea) associated with low dose aspirin [11].
In the absence of the above factors patients
can be divided in low risk (age > 40 years) and
intermediate risk (age 4060 years) disease. Low
dose of aspirin is recommended (100160 mg/d).
In cases in which aspirin is not recommended,

clopidogrel can be used in order to alleviate


microvascular symptoms (erythromelalgia is very
sensitive to aspirin) [27, 28] or to provide some
protection from thrombotic complications.
Other therapeutical options include: alternative
cytoreductive agents-anagrelide or interferon
which are the preferred as second line therapies, or
busulfan or radioactive phosphorus, but these are
associated with a considerable risk for secondary
leukemia [58, 59].
In the case presented, not only infantile
encephalopathy was the cause of generalized
tonico-clonic seizures, as seemed to be initially, but
also the multiple sequelar cerebral ischemic lesions
whose clinical feature was silent until now. A
complex therapy was necessary to be administered,
addressed both to multiple vascular risk factors and
to convulsivant picture.
CONCLUSION

1) ET is a cause of coronary and vascular


cerebral events.
2) ET should be considered as a risk factor for
thrombosis, especially in younger patients, therefore JAK2 gene should be tested in high suspicion
patients, without being considered a routine investigation.

Se prezint cazul unui pacient de 53 ani diagnosticat cu encefalopatie


infantil i tetraparez spastic, cu antecedente de infecii respiratorii n ultimii
3 ani, unele dintre acestea complicate cu insuficien respiratorie acut. n 2009 a
prezentat infarct miocardic acut, fiind spitalizat pentru acesta. S-au mai
diagnosticat hipertensiune arterial i hipercolesterolemie. n timpul spitalizrii, a
prezentat, de asemenea, o infecie respiratorie acut. Investigaiile sanguine de
rutin au demonstrat un numr crescut constant de trombocite (>1000 109/l),
investigaia suplimentar stabilind diagnosticul de trombocitemie esenial (TE) cu
JAK2 pozitiv de tip homozigot. Sora pacientului a fost diagnosticat cu aceeai
mutaie. n 2009 pacientul a fost internat n clinica noastr pentru tulburri de
deglutiie i convulsii tonico-clonice generalizate. Examenul CT cerebral a relevat
multiple infarcte sechelare bilateral i la nivelul regiunilor cortico-subcorticale.
S-au administrat hidroxiuree, dubl antiagregare plachetar i anticonvulsivante,
urmate de ameliorarea strii clinice. TE este una dintre neoplaziile
mieloproliferative cronice caracterizate prin numr constant de trombocite >450
109/l, prezentnd risc crescut de complicaii trombotice i hemoragice, n special
la pacienii JAK2 pozitivi. Concluzie. TE reprezint o cauz pentru evenimentele
vasculare coronariene i cerebrale. TE ar trebui considerat factor de risc pentru
tromboz, n special la pacienii mai tineri, de aceea, gena JAK2 ar trebui testat
la pacienii cu mare suspiciune, fr a fi ns considerat ca investigaie de rutin.
Corresponding author: Senior lecturer Inimioara Mihaela Cojocaru MD, PhD Department of Neurology
Colentina Clinical Hospital, 1921, os. tefan cel Mare, 020125, Bucharest, Romania
E-mail: inimioaracojocaru@yahoo.com

Essential thrombocythemia in acute myocardial infarction and ischemic strokes

59

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Received February 13, 2013

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