Beruflich Dokumente
Kultur Dokumente
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.
54
55
56
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)
58
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,
59
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
TEFFERI A., VARDIMAN J.W., Classification and diagnosis of myeloproliferative neoplasms: criteria and point-of care
diagnostic algorithms. Leukemia 2008; 22: 1422.
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: 1523.
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: 75561.
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: 11448.
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: 105461.
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., DANDREEA A.,
FRHLING 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: 38797.
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: 177990.
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: 2278892.
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: 194553.
CORTELAZZO S., VIERO P., FINAZZI G., DEMILIO 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: 55662.
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): 14960.
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: 11326.
KOUDSTAAL P.J., KOUDSTAAL A., Neurologic and visual symptoms in essential thrombocythemia: efficacy of low-dose
aspirin Semin. Thromb. Hemost 1991; 23: 36570.
WATSON K.Y., KEY N., Vascular complication of essential thrombocythaemia: a link to cardiovascular risk factors. Br.
J. Haematol 1993; 83: 198203.
KESLER A,, ELLIS M.H., MANOR Y., GADOTH N., LISHNER M., Neurological complications of essential
thrombocythemia (ET). Acta Neurol. Scand 2000; 102: 299302.
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: 5138.
FAIVRE A., BONNEL S., LEYRAL G., GISSEROT O., ALLA P., VALANCE J., Essential thrombocythemia presenting as
spinal cord infarction. Presse Med 2009; 38: 11803.
MICHIELS J.J., KOUDSTAAL P.J., MULDER AH., VAN VLIET H.H., Transient neurologic and ocular manifestation in
primary thrombocythemia. Neurology 1993; 43: 110710.
PRABHAKARAN V.C., CHOHAN A., HUSAIN R., ANDREW N.C., Third nerve paralysis as a presenting sign of essential
thrombocythaemia. Eye (London) 2006; 20: 14834.
BENITO-LEON J., MARTIN E., VINCENT A., FERNANDEZ-LORENTE J., BLAS G., Neuromyotonia in association with
essential thrombocythaemia. J. Neurol. Sci 2000; 173: 789.
GRISELL D.L., MILLS G.M., Reversible acute sensorineural hearing loss associated with essential thrombocythosis. Arch. Int.
Med 1986; 146: 1813.
ROSSI C., RANDI M.L., ZERBINATI P., RINALDI V. GIROLAMIA., Acute coronary disease in essential thrombocythaemia
and polycythemia vera. J. Int. Med 1998; 244: 4953.
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: 3827.
HARRISON C., Pregnancy and its management in the Philadelphia negative myeloproliferative diseases. Br. J. Haematol 2005;
129: 293306.
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: 58791.
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: 53328544.
60
27. VAN GENDEREN P.J., MICHIELS J.J, Vascular complications in polycythemia vera. Semin. Thromb. Hemost 1997; 23: 44154.
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: 3338.
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: 105464.
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 cMPL gene, which encodes for the receptor for thrombopoietin. Blood 2004; 103: 4198200.
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: 34726.
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: 1419.
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: 22892301.
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: 90511.
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: 38190.
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: 122530.
37. BOUGHTON B.J., ALLINGTON M.J., KING A., Platelet and plasma tromboglobulin in myeloproliferative syndromes and
secondary thrombocytosis. Br. J. Haematol 1978; 40: 12532.
38. LEGRAND C., BELLUCCI S., DISDIER M., EDELMAN L., TOBELEM G., Platelet thrombospondin and glycoprotein IV
abnormalities in patients with essential thrombocythemia: effect of -Interferon treatment. Am. J. Hematol 1991; 38: 30713.
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: 1916.
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:
11624.
41. THIBERT V., BELLUCCI S., CRISTOFARI M., LEGRAND C., Increased platelet CD36 constitute a common marker in
myeloproliferative disorders. Br. J. Haematol 1995; 191: 61824.
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: 42616.
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:
238.
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: 16975.
45. MAUGERI N., EVANGELISTA V., CELARDO A., DELLELBA 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: 4506.
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: 52330.
47. JENSEN M.K., DE NULLY BROWN P., LUND B.V., NIELSEN O.J., HASSELBALCH H. C., Increased circulating plateletleukocyte aggregates in myeloproliferative disorders is correlated with previous thrombosis, platelet activation and platelet
count. Eur. J. Haematol 2001; 66: 14351.
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: 73642.
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: 4479.
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: 2539.
61
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: 75963.
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: 1028.
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: 40618.
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: 814.
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: 1504.
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: 748.
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: 21532.
58. WAGSTAFF A.J, KEATING G.M., Anagrelide: a review of its use in the management of essential thrombocythaemia. Drugs
2006; 66: 11131.
59. BRIERE J., GUILMIN F., Management of patients with essential thrombocythaemia: current concepts and perspectives. Pathol.
Biol. (Paris) 2001; 49: 17683.
Received February 13, 2013