ET, Stroke, Jantung

CASE REPORT

Essential Thrombocythemia Diagnosed in a Patient with Acute Myocardial Infarction and Ischemic Strokes

INIMIOARA MIHAELA COJOCARU1,2, CRISTINA HERŢEA2, ANDREEA IONESCU2, GABRIELA SOCOLIUC2, VIOLETA ŞAPIRA2, M. COJOCARU3

1“Carol Davila” University of Medicine and Pharmacy, Department of Neurology, 2Department 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 patient’s sister was diagnosed with the same mutation. In 2009 he presented in our clinic for swallowing difficulties and tonico-clonic 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 diseases-chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), chronic idiopathic myelofibrosis and erythroleukemia-known as myeloproliferative diseases to today’s MPNs which include CML, PV, ET, primary myelofibrosis (PMF, formerly chronic idiopathic myelofibrosis), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (chronic hypereo-sinophilic 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 character-rised 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 neutron-phil leukocytosis [2].

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 patient’s 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 hypo-tensive, cardioprotector, cholesterol lowering drugs and diuretics was initiated.

ROM. J. INTERN. MED., 2013, 51, 1, 53–61

Inimioara Mihaela Cojocaru et al. 2 54

During hospitalization, he again developed bronchopneumonia. He was referred to the “Prof. Dr. Matei Balş” 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 thrombo-cythemia, thus hydrea therapy was initiated.

The patient’s 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 hypo-

dense areas located in the occipital lobes cortico-subcortical; 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.

3 Essential thrombocythemia in acute myocardial infarction and ischemic strokes 55

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: Myeloproli-

ferative neoplasm. Essential thrombocythemia (V617F mutation of JAK2 positive homozygotus type). Infantile encephalopathy with spastic tetra-paresis. 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 (clo-pidogrel 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 thrombo-cytosis: 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 [4–9] 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

1.7% in people younger than 40 years, as compared to 6.3% in patients of 40–60 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 26–36% of TE cases, as compared to 15–20% in normal preg-nancies [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, 12–14]. TE patients have hyper-sensitive platelets that may spontaneously activate and secrete prothrombotic factors such as thromboxane and β-thromboglobulin. The result is platelet aggregates formation that occlude the microcircu-lation [26]. The clinical symptoms are migranous headaches, visual symptoms as transient monocular blindness, scintillating scotomas, reduced visual acuity, dizziness sensations, non-myocardial infarction


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. Histopatho-logical studies reveal platelet-rich arteriolar micro-thrombi 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 mucocuta-neous, such as echymosis, episthaxis, gingival bleeding, and menorrhagia. Gastrointestinal he-morrhage, albeit rare, might be serious.

Intracerebral hemorrhage is a severe com-plication [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 tyrosin-kinase Janus 2 (JAK2) gene [3, 5, 6, 29] represented an achievement in the understanding of myelo-proliferative 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 down-stream hematopoietic proliferation.

In suspected cases of ET that are JAK2 negative, sceening for mutations in MPL (myelo-proliferative 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 hyper-activity 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 aggre-gation and paradoxically; a hypoaggregability in vitro after stimulation with different inducers (ADP, collagen), which is explained by degranu-lation of circulant platelets [35]. Raised synthesis of thromboxane A2 was observed in vivo, non-correlated to platelets count. This fact was confirmed by measuring the urinary elimination of its principal stable metabolite 2–3 dinorthrom-boxane [36]. High level of β-thromboglobulin (βTG), normal constituent present in α 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 endo-thelial origin [49, 50].


A percent of activated platelets in JAK2 positive patients was reported statistically sig-nificant [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 blood-stream. 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 glycol-proteins 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 Secondary thrombocytosis

Essential thrombocythemia Polycythemia vera Idiopathic myelofibrosis Chronic myeloid leukaemia Myelodysplasia Acute leukemia

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 0–4 scale)


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 (hydroxy-urea) 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 40–60 years) disease. Low dose of aspirin is recommended (100–160 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 α 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, there-fore JAK2 gene should be tested in high suspicion patients, without being considered a routine inves-tigation.

Se prezintă cazul unui pacient de 53 ani diagnosticat cu encefalopatie

infantilă şi tetrapareză spastică, cu antecedente de infecţii respiratorii în ultimii 3 ani, unele dintre acestea complicate cu insuficienţă respiratorie acută. În 2009 a prezentat infarct miocardic acut, fiind spitalizat pentru acesta. S-au mai diagnosticat hipertensiune arterială şi hipercolesterolemie. În timpul spitalizării, a prezentat, de asemenea, o infecţie respiratorie acută. Investigaţiile sanguine de rutină au demonstrat un număr crescut constant de trombocite (>1000 × 109/l), investigaţia suplimentară stabilind diagnosticul de trombocitemie esenţială (TE) cu JAK2 pozitivă de tip homozigot. Sora pacientului a fost diagnosticată cu aceeaşi mutaţie. În 2009 pacientul a fost internat în clinica noastră pentru tulburări de deglutiţie şi convulsii tonico-clonice generalizate. Examenul CT cerebral a relevat multiple infarcte sechelare bilateral şi la nivelul regiunilor cortico-subcorticale. S-au administrat hidroxiuree, dublă antiagregare plachetară şi anticonvulsivante, urmate de ameliorarea stării clinice. TE este una dintre neoplaziile mieloproliferative cronice caracterizate prin număr constant de trombocite >450 × 109/l, prezentând risc crescut de complicaţii trombotice şi hemoragice, în special la pacienţii JAK2 pozitivi. Concluzie. TE reprezintă o cauză pentru evenimentele vasculare coronariene şi cerebrale. TE ar trebui considerată factor de risc pentru tromboză, în special la pacienţii mai tineri, de aceea, gena JAK2 ar trebui testată la pacienţii cu mare suspiciune, fără a fi însă considerată ca investigaţie de rutină.

Corresponding author: Senior lecturer Inimioara Mihaela Cojocaru MD, PhD Department of Neurology “Colentina” Clinical Hospital, 19–21, Şos. Ştefan cel Mare, 020125, Bucharest, Romania E-mail: [email protected]


REFERENCES

1. TEFFERI A., VARDIMAN J.W., Classification and diagnosis of myeloproliferative neoplasms: criteria and point-of care diagnostic algorithms. Leukemia 2008; 22: 14–22.

2. LENGFELDER E., HOCHHAUS A., KRONAWITTER U., HOCHE D., QUEISSER W., JAHN-EDER M., BURKHARDT R., REITER A., ANSANI A., HEHLMANN R., Should a platelet limit of 600 x 109/l be used as a diagnosis criterion in primary thrombocythemia? An analysis of the natural course including early stages. Br. J. Haematol 1998; 100: 15–23.

3. PASSAMONTI F., RUMI E., PUNGOLINO E., MALABABRBA L., BERTAZZONI P., VALENTINI M., ORLANDI F., ARCAINI L., BRUSAMOLINA E., PASUTO C.M., CAZZOLA M., MORRA E., LAZZARINO M., Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. Am. J. Med 2004; 117: 755–61.

4. JAMES C., UGO V., CAMPBELL P.J., LE COUEDIC J.P., STAERK J., DELHOMMEAU F., LACOUT C., GARCON L., RADOVA H., BERGER R., BENNANCEUR-GRISCELLI A., VILLEVAL J.L., CONSTANTINESCU S., CASADEVALL N., VAINCHEKER W., A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature 2005; 434: 1144–8.

5. BAXTER E.J., SCOTT L.M., CAMPBELL P.J., EAST C., FOUROUCLAS N., SWANTON S., SCOTT M.A., ERBER W.N., GREEN A.P., Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–61.

6. LEVINE L.R., WADLEIGH M., COOLS J., EBERT B.L., WERNIG G., HUNTLY B.J., BOGGON T.J., WLODARSKA I., CLARK J.J., MOORE S., ADELSPERGER J., KOO S., LEE J.C., GABRIEL S., MERCHER T., D’ANDREEA A., FRÖHLING S., DOHNER K., MARYNEN P., VANDENBERGHE P., MESA R.A., TEFFERI A., GRIFFIN J.D., ECK M.J., SELLERS W.R., MEYERSON M., GOLUB T.R., LEE S.J., GILLILAND D.G., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–97.

7. KRALOVICS R., PASSAMONTI F., BUSER A.S., TEO S.S., TIEDT R., PASSWEG J.R., TICHELLI A., CAZZOLA M., SKODA R.C., A gain-of-function mutation of JAK2 in myeloproliferative disorder. N. Engl. J. Med 2005; 352: 1779–90.

8. ZHAO R., XING S., LI Z., FU X., LI Q., KRANZ S.B., ZHAO Z.J., Identification of an acquired JAK2 mutation in polycythemia vera. J. Biol. Chem 2005; 280: 22788–92.

9. CAMPBELL P.J., SCOTT L.M, BUCK G., WHEATLEY K,, EAST C.L., MARSDEN J.T., DUFFY A., BOYD E.M., BENCH A.J., SCOTT M.A., VASSILIOU G.S., MILLIGAN D.W., SMITH S.R., ERBER W.N., BAREFORD D., WILKINS B.S., REILLY J.T., Definition of subtypes of essential thrombocythemia and relation to polycythemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005; 366: 1945–53.

10. 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 1990; 8: 556–62.

11. BARBUI T., FINAZZI G., DUPUY E., KILADJIAN J.J., BRIERE J., Treatment strategies in essential thrombocythemia. A critical appraisal of various experiences in different centres. Leuk. Lymphoma 1996; 22 (Suppl 1): 149–60.

12. CORTELAZZO S., FINAZZI G., RUGERRI M., VESTRI O., GALLI M., RODEGHIERO F, BARBUI T., Hydroxyureea in the treatment of patients with essential thrombocythemia at high risk of thrombosis: a prospective randomised trial. N. Engl. J. Med 1995; 332: 1132–6.

13. KOUDSTAAL P.J., KOUDSTAAL A., Neurologic and visual symptoms in essential thrombocythemia: efficacy of low-dose aspirin Semin. Thromb. Hemost 1991; 23: 365–70.

14. WATSON K.Y., KEY N., Vascular complication of essential thrombocythaemia: a link to cardiovascular risk factors. Br. J. Haematol 1993; 83: 198–203.

15. KESLER A,, ELLIS M.H., MANOR Y., GADOTH N., LISHNER M., Neurological complications of essential thrombocythemia (ET). Acta Neurol. Scand 2000; 102: 299–302.

16. JABAILY J., ILAND H.J., LASZLO J., MASSEY E.W., FAGUET G.B., BRIERE J., LANDAW A., PISCIOTTA A.V., Neurological complications of essential thrombocythemia. Ann. Int. Med 1983; 99: 513–8.

17. FAIVRE A., BONNEL S., LEYRAL G., GISSEROT O., ALLA P., VALANCE J., Essential thrombocythemia presenting as spinal cord infarction. Presse Med 2009; 38: 1180–3.

18. MICHIELS J.J., KOUDSTAAL P.J., MULDER AH., VAN VLIET H.H., Transient neurologic and ocular manifestation in primary thrombocythemia. Neurology 1993; 43: 1107–10.

19. PRABHAKARAN V.C., CHOHAN A., HUSAIN R., ANDREW N.C., Third nerve paralysis as a presenting sign of essential thrombocythaemia. Eye (London) 2006; 20: 1483–4.

20. BENITO-LEON J., MARTIN E., VINCENT A., FERNANDEZ-LORENTE J., BLAS G., Neuromyotonia in association with essential thrombocythaemia. J. Neurol. Sci 2000; 173: 78–9.

21. GRISELL D.L., MILLS G.M., Reversible acute sensorineural hearing loss associated with essential thrombocythosis. Arch. Int. Med 1986; 146: 1813.

22. ROSSI C., RANDI M.L., ZERBINATI P., RINALDI V. GIROLAMIA., Acute coronary disease in essential thrombocythaemia and polycythemia vera. J. Int. Med 1998; 244: 49–53.

23. HACHULLA E., ROSE C., TRILLOT N., CAULIER-LELEU M.T., PASTUREL-MICHON V., Devant quelles manifestations vasculaires rechercher un syndrome myeloproliferatif ? J. Mal. Vasc 2000; 25: 382–7.

24. HARRISON C., Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br. J. Haematol 2005; 129: 293–306.

25. DENNINGER M.H., CHAIT Y., CASADEVALL N., HILLAIRE S., GUILLAIN M.C., ERLINGER S., BRIERE J, VALLA D., Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology 2000; 31: 587–91.

26. MICHIELS J.J, BWERNEMAN Z., SCHROYENS W., KOUDSTAAL J., LINDEMANS J., NEUMANN H.A., VAN VLIET H.H., Platelet-mediated erythromelalgic, cerebral, ocular, and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and coumadine-resistant arterial thrombophilia. Platelets 2006; 17: 53328–544.


27. VAN GENDEREN P.J., MICHIELS J.J, Vascular complications in polycythemia vera. Semin. Thromb. Hemost 1997; 23: 441–54. 28. VAN GENDEREN P.J., LUCAS I.S., VAN STRIK R., Erythromelalgia in essential thrombocythemia is characterized by

platelet activation and endothelial cell damage but not by thrombin generation. Thromb. Haemost 1996; 76: 333–8. 29. BAXTER E.J., SCOTT L.M., CAMPBELL P.J., EAST C., FOUROUCLAS N., SWANTOM S., VASSILIOU G.S., BENCH

A.J., BOYD E.M., CURTIN N., SCOT M.A., ERBER W.N., GREEN A.R., SWANTON S., Acquired mutation in the tyrosine kinase JAK2 in human myeloproliferative disorders Lancet 2005; 365: 1054–64.

30. DING J., KOMATSU H., WAKITA A., KATO-URANISHI M., ITO M., SATOH A., TSUBOI K., NITTA M., MIYAZAKI H., IIDA S., UEDA R.M., Famililal essential thrombocythaemia associated with a dominant positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198–200.

31. PARDANANI A.D., LEVINE R.S., LASHO T., PIKMAN Y, MESA R.A, WADLEIGH M., STEENSMA D.P., ELLIOTT M.A., WOLANSKYJ A.P., HOGAN W.J., MCCLURE R.F., LITZOW M.R., GILLILAND D.G., TEFFERI A., MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–6.

32. BEER P.A., CAMPBELL P.J., SCOTT L.M., BENCH A.J, ERBER W.N., BAREFORD D., WILKINS B.S., REILLY J.T., HASSELBALCH H.C., BOWMAN R., WHEATLEY K., BUCK G., HARRISON C. N., GREEN A.R., MPL mutations in myeloproliferative disorder: analysis of the PT-1 cohort. Blood 2008; 112: 141–9.

33. DELHOMMEAU F., DUPONT S., DELLA VALLE V., JAMES C., TRANNOY S., MASSE A., KOSNIDER O., LE COUEDIC J.P., ROBERT F., ALBERDI A., LECLUSE Y., PLO I., DREYFUS F.J., ROBERT F., MARZAC C., CASADEVALL N., LACOMBE C., ROMANA S.P., DESSEN P., SOULIER J., VIGUIE F., FONTENAY M., MARZAC C., VAINCHENKER W., BERNARD O.A., Mutation in TET2 in myeloid cancers. N. Engl. J. Med 2009; 360: 2289–2301.

34. TEFFERI A., PARDANANI A.D., LIM K.H., LIM K.H., ABDEL-WAHAB O., LASHO T.L., PATEL J., GANGAT N., FINKE C.M., SCHWAGER S., MULLALLY A., LI C.Y., HANSON C.A., MESA R., BERNARD O., DELHOMMEAU F., VAINCHENKER W., GILLILAND D.G., LEVINE R.L., TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009; 23: 905–11.

35. BELLUCCI S., MICHIELS J.J, The role of JAK2 V617F mutation, spontaneous erythropoiesis and megakaryocytopoiesis, hypersensitive platelets, activated leukocytes, and endothelial cells in the etiology of thrombotic manifestations in polycythemia vera and essential thrombocythemia. Semin. Thromb. Hemost 2006; 32: 381–90.

36. ROCCA B., CIABATTONI G., TARTAGLIONE R., CORTELAZZO S., BARBUI T., PATRONO C., LANDOLFI R. Increased thromboxane biosynthesis in essential thrombocythemia. Thromb. Haemost 1995; 74: 1225–30.

37. BOUGHTON B.J., ALLINGTON M.J., KING A., Platelet and plasma tromboglobulin in myeloproliferative syndromes and secondary thrombocytosis. Br. J. Haematol 1978; 40: 125–32.

38. LEGRAND C., BELLUCCI S., DISDIER M., EDELMAN L., TOBELEM G., Platelet thrombospondin and glycoprotein IV abnormalities in patients with essential thrombocythemia: effect of α-Interferon treatment. Am. J. Hematol 1991; 38: 307–13.

39. GRIESSHAMMER M., BENEKE H., NUSSBAUMER B., GRUNEWALD M., BANGERTER M., BERGMANN L., Increased platelet surface expression of P-selectin and thrombospondin as markers of platelet activation in essential thrombocythemia. Thromb. Res 1999; 96: 191–6.

40. JENSEN M.K., DE NULLY BROWN P., LUND B.V., NIELSEN O.J., HASSELBALCH H.C., Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders. Br. J. Haematol 2000; 100: 116–24.

41. THIBERT V., BELLUCCI S., CRISTOFARI M., LEGRAND C., Increased platelet CD36 constitute a common marker in myeloproliferative disorders. Br. J. Haematol 1995; 191: 618–24.

42. FALANGA A., MARCHETTI M., EVANGELISTA V., VIGNOLI A., LICINI M., BALICCO M., MANARINI S., FINAZZI G., CERLETTI C., BARBUI T., Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96: 4261–6.

43. BURGALETA C., GONZALES N., CEZAR J., Increased CD11/CD18 expression and altered metabolic activity on polymorphonuclear leukocytes from patients with polycythemia vera and essential thrombocythemia. Acta Hematol 2002; 108: 23–8.

44. ARELLANO-RODRIGO E., ALVAREZ-LARAN A., REVERTER J.C., VILLAMOR N., COLOMER D., CERVANTES F., Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica 2006; 91: 169–75.

45. MAUGERI N., EVANGELISTA V., CELARDO A., DELL’ELBA G., MARTELLI N., PICCARDONI P., DE GAETANO G., CERLETTI C., Polymorphonuclear leukocyte-platelet interaction. Role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis. Thromb. Haemost 1994; 72: 450–6.

46. FALANGA A., MARCHETTI M., VIGNOLI A., BALDUCCI D., BARBUI T., Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp. Hematol 2005; 33: 523–30.

47. JENSEN M.K., DE NULLY BROWN P., LUND B.V., NIELSEN O.J., HASSELBALCH H. C., Increased circulating platelet-leukocyte aggregates in myeloproliferative disorders is correlated with previous thrombosis, platelet activation and platelet count. Eur. J. Haematol 2001; 66: 143–51.

48. BELLUCCI S., IGNATOVA E., JAILLET N., BOFFA M.C., Platelet hyperactivation in patients with essential thrombocythemia is not associated with vascular endothelial celll damage as judged by the level of plasma thrombomodulin, protein S, PAI-1, t-PA, and vWF. Thromb. Haemost 1993; 70: 736–42.

49. BLANN A., CAINE G., BAREFORD D., Abnormal vascular, platelet and coagulations markers in primary thrombocythemia are not reversed by treatments that reduce the platelet count. Platelets 2004; 15: 447–9.

50. KARAKANTZA M., GIANNAKOULAS N.C., ZIKOS P., SAKELLAROPOULOS G., KOURAKLIS A., AKTYRI A., METALLINOS I.C, THEODORI E., ZOUMBOS N.C, MANIATIS A. Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia. Int. J. Hematol 2004; 79: 253–9.


51. BARBUI T., CAROBBIO A., RAMBALDI A., FINAZZI G., Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood 2009; 114: 759–63.

52. ARELLANO-RODRIGO E., ALVAREZ-LARAN A., REVERTER J.C., COLOMER D., VILLAMOR N., BELLOSILLO B., CERVANTES F., Platelet turnover, coagulation factors, and soluble markers of platelet and endothelial activation in essential thrombocythemia: Relationship with thrombosis occurrence and JAK2 V617F allele burden. Am. J. Hematol 2009; 84: 102–8.

53. MARCHETTI M., CASTOLDI E., SPRONK H.M., VAN OERLE R., BALDUCCI D., BARBUI T., ROSING J., TEN CATE H., FALANGA A., Thrombin generation and activated protein C resistance in patients with essential thrombocythemia and polycythemia Blood 2008; 112: 4061–8.

54. VAN GENDEREN P.J., MICHIELS J.J., VAN DER POEL-VAN DE LUYTGAARDE S.C., VAN VLIET H.H., Acquired von Willebrand disease as a cause of recurrent mucocutaneous bleeding in primary thrombocythemia: relationship with platelet count. Ann. Hematol 1994; 69: 81–4.

55. BESSES C., CERVANTES F., PERREIRA A., FLORENSA L., SOLE F., HERNANDEZ-BOLUDA J.C., WOESSNER S., SANS-SABRAFEN J., ROZMAN C., MONTSERRAT E., Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients. Leukemia 1999; 13: 150–4.

56. JANTUNEN R., JUVONEN E., IKKALA E., OKSANRN K., RUUTU T., The predictive value of vascular risk factors and gender for the development of thrombotic complications in essential thrombocythemia. Ann. Hematol 2001; 80: 74–8.

57. BARBUI T., BAROSI G., GROSSI A., GUGLIOTTA L., LIBERATO LN., MARCHETTI M., MAZZUCCONI M.G., RODEGHIERO F., TURA S., Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004, 89: 215–32.

58. WAGSTAFF A.J, KEATING G.M., Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs 2006; 66: 111–31.

59. BRIERE J., GUILMIN F., Management of patients with essential thrombocythaemia: current concepts and perspectives. Pathol. Biol. (Paris) 2001; 49: 176–83.

Received February 13, 2013

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