Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms

Giuseppe Cella; Marina Marchetti; Fabrizio Vianello; Marina Panova-Noeva; Alfonso Vignoli; Laura Russo; Tiziano Barbui; Anna Falanga

doi:10.1160/TH09-09-0663

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2010; 104(01): 151-156
DOI: 10.1160/TH09-09-0663

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Nitric oxide derivatives and soluble plasma selectins in patients with myeloproliferative neoplasms

Authors

Giuseppe Cella

¹Cardiac, Thoracic and Vascular Sciences Dept, University of Padua, Padua, Italy
Marina Marchetti

²Division of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Ospedali Riuniti, Bergamo, Italy
Fabrizio Vianello

¹Cardiac, Thoracic and Vascular Sciences Dept, University of Padua, Padua, Italy
Marina Panova-Noeva

²Division of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Ospedali Riuniti, Bergamo, Italy

³Department of Biochemistry, Laboratory for Clinical Thrombosis and Haemostasis, Maastricht University, Netherlands
Alfonso Vignoli

²Division of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Ospedali Riuniti, Bergamo, Italy
Laura Russo

²Division of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Ospedali Riuniti, Bergamo, Italy
Tiziano Barbui

⁴Research Foundation, Ospedali Riuniti, Bergamo, Italy
Anna Falanga

²Division of Immunohematology and Transfusion Medicine & Hemostasis and Thrombosis Center, Ospedali Riuniti, Bergamo, Italy

Abstract

als PDF herunterladen

Summary

Essential thrombocythaemia (ET) and polycythaemia vera (PV) are characterised by a high incidence of thrombotic complications due to highshear stress of the vessel wall, blood hyperviscosity and hypoxaemia, all factors responsible for chronic endothelial dysfunction and platelet and leukocyte activation. We evaluated the activation status of vascular cells in 18 consecutive ET and 14 PV patients by measuring the plasma levels of the nitric oxide derivatives (NO_X) (i.e. nitrites and nitrates) and of soluble selectins of platelet (P-selectin), endothelial cell (P-selectin and E-selectin) and leukocyte (L-selectin) origin. The effect of hydroxyurea (HU) therapy on these parameters was also investigated. NO_X were significantly (p<0.01) increased in ET patients treated with HU (11.5 ± 2.6 nM) compared to non-HU treated ET (1.41 ± 0.3 nM) and to controls (4.78 ± 2.49 nM). Multivariate analysis confirmed HU therapy as an independent predictor of higher NO_X levels in ET. In addition, NO_X significantly correlated with haematocrit. Plasma P-selectin was significantly elevated in ET (350 ± 40 ng/10⁶ platelets) and PV (482 ± 53 ng/10⁶ platelets) patients compared to controls (120 ± 8 ng/106 platelets). In PV, also E-selectin (23.8 ± 4.2 ng/ml) was significantly increased compared to controls (11.2 ± 1.1 ng/ml; p<0.01). P-selectin was significantly correlated to platelet (R=0.33; p=0.01) and leukocyte count (R=0.6; p=0.000), while E-selectin (R=0.34; p=.014) and sL-selectin (R=0.3; p=0.03) were correlated with leukocyte count only. In the multivariate analysis, NO_X predicted increased levels of E-selectin in ET, but not in PV patients. Our data demonstrate that ET and PV are characterised by an altered pattern of soluble selectins and NO_X. HU-mediated increase of NOM_X levels could represent an additional antithrombotic mechanism of this drug.

Keywords

Nitric oxide - selectins - essential thrombocythemia - polycythemia vera - Hydroxyurea

PDF (168 kb)

Referenzen

References
1 Landolfi R, Rocca B, Patrono C. Bleeding and thrombosis in myeloproliferative disorders: mechanisms and treatment. Critical Rev Oncol Hematol 1995; 20: 203-222.
2 Falanga A, Marchetti M, Vignoli A. et al Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol 2005; 33: 523-530.
3 Falanga A, Marchetti M, Vignoli A. et al V617F JAK-2 mutation in patients with essential thrombocythemia: relation to platelet, granulocyte, and plasma hemostatic and inflammatory molecules. Exp Hematol 2007; 35: 702-711.
4 Falanga A, Marchetti M, Barbui T. et al Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils. Sem Hematol 2005; 42: 239-247.
5 Elliott MA, Tefferi A. Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 2005; 128: 275-290.
6 Cines DB, Pollak ES, Buck CA. et al Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91: 3527-3561.
7 Falanga A, Marchetti M, Evangelista V. et al Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and poly-cythemia vera. Blood 2000; 96: 4261-4266.
8 Freedman JE, Loscalzo J. Nitric oxide and its relationship to thrombotic disorders. J Thromb Haemost 2003; Jun 01 (06) 1183-8.
9 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101.
10 Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993; 14: 506-512.
11 Cella G, Bellotto F, Tona F. et al Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest 2001; 120: 1226-1230.
12 Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am J Hypertens 2001; 14: 44S-54S.
13 Blann AD, Tse W, Maxwell SJ. et al Increased levels of the soluble adhesion molecule E-selectin in essential hypertension. J Hypertens 1994; 12: 925-928.
14 Gearing AJ, Hemingway I, Pigott R. et al Soluble forms of vascular adhesion molecules, E-selectin, ICAM-1, and VCAM-1: pathological significance. Ann NY Acad Sci 1992; 667: 324-331.
15 Jilma B, Fasching P, Ruthner C. et al Elevated circulating P-selectin in insulin dependent diabetes mellitus. Thromb Haemost 1996; 76: 328-332.
16 Blann AD, Faragher EB, McCollum CN. Increased soluble P-selectin following myocardial infarction: a new marker for the progression of atherosclerosis. Blood Coagul Fibrinolysis 1997; 08: 383-390.
17 Michiels JJ, De Raeve H, Berneman Z. et al The 2001 World Health Organization and updated European clinical and pathological criteria for the diagnosis, classification, and staging of the Philadelphia chromosome-negative chronic myeloproliferative disorders. Semin Thromb Hemost 2006; 32: 307-340.
18 Keynes RG, Garthwaite J. Nitric oxide and its role in ischaemic brain injury. Curr Mol Med 2004; 04: 179-191.
19 Glover RE, Ivy ED, Orringer EP. et al Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea. Mol Pharmacol 1999; 55: 1006-1010.
20 Cortelazzo S, Finazzi G, Ruggeri M. et al Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. New Engl J Med 1995; 332: 1132-1136.
21 Rejto L, Huszka M, Kaplar M. et al Effects of in vitro platelet activation on platelet derived nitric oxide production in healthy humans and in chronic myeloproliferative diseases with elevated platelet counts. Platelets 2003; 14: 283-286.
22 Ferlito S, Gallina M. Nitrite, endothelin and E-selectin plasma levels after arginine infusion in normal and vasculopathic subjects. Minerva Cardioangiologica 1998; 46: 471-477.
23 Kayali Z, Herring J, Baron P. et al Increased plasma nitric oxide, L-arginine, and arginase-1 in cirrhotic patients with progressive renal dysfunction. J Gastroenterol Hepatol 2009; 24: 1030-1037.
24 Caimi G, Montana M, Calandrino V. et al Nitric oxide metabolites (nitrite and nitrate) in young patients with recent acute myocardial infarction. Clin Hemorheol Microcirculation 2008; 40: 157-163.
25 Shibata J, Hasegawa J, Siemens HJ. et al Hemostasis and coagulation at a hematocrit level of 0.85: functional consequences of erythrocytosis. Blood 2003; 101: 4416-4422.
26 Andre P. P-selectin in haemostasis. Br J Haematol 2004; 126: 298-306.
27 Karakantza M, Giannakoulas NC, Zikos P. et al Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera. Int J Hematol 2004; 79: 253-259.
28 Musolino C, Alonci A, Bellomo G. et al Myeloproliferative Disease: Markers of Endothelial and Platelet Status in Patients with Essential Thrombocythemia and Polycythemia Vera. Hematology (Amsterdam, Netherlands) 2000; 04: 397-402.
29 Jilma B, Eichler HG, Becherer A. et al Kinetics of circulating selectin levels during bone marrow aplasia. Eur J Haematol 1998; 61: 36-41.
30 Bang SM, Lee JS, Ahn JY. et al Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation. Thromb Haemost 2009; 101: 547-551.
31 Carobbio A, Finazzi G, Guerini V. et al Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. Blood 2007; 109: 2310-2313.