Thromb Haemost 2005; 93(01): 70-75
DOI: 10.1160/TH04-06-0394
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Elevated plasma osteoprotegerin levels are associated with venous thrombosis and bleeding in patients with polycythemia vera

Mathias Kees
1   Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University Vienna, Vienna, Austria
,
Franz Wiesbauer
2   Department of Internal Medicine II, Division of Cardiology, Medical University Vienna, Vienna, Austria
,
Bettina Gisslinger
1   Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University Vienna, Vienna, Austria
,
Renate Wagner
1   Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University Vienna, Vienna, Austria
,
Medhat Shehata
1   Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University Vienna, Vienna, Austria
,
Heinz Gisslinger
1   Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University Vienna, Vienna, Austria
› Author Affiliations
Financial support: This work has been kindly sponsored by the “Privatstiftung Unruhe”.
Further Information

Correspondence to:

Univ. Prof. Dr. Heinz Gisslinger
Medical University Vienna, Department of Internal Medicine I
Division of Hematology and Blood Coagulation
Währinger Gürtel 18–20
A-1090 Vienna, Austria
Phone: +43–1–40400–5464   
Fax: +43–1–4026930   

Publication History

Received 24 June 2004

Accepted after revision 04 October 2004

Publication Date:
14 December 2017 (online)

 

Summary

Patients with polycythemia vera (PV) have an increased risk for the development of thrombohemorrhagic complications. The pathogenesis of these complications is still unclear.An important role in vascular disease has recently been attributed to osteoprotegerin (OPG). It has been shown that various tissues of the cardiovascular system produce OPG, and there is growing evidence of an association between elevated serum OPG levels and cardiovascular morbidity.We evaluated if OPG was associated with an increased risk of venous thrombosis or bleeding complications in a cohort of 114 PV patients.The analysis consisted of a retrospective and a prospective part. In the retrospective univariate analysis,a one unit change in OPG caused the odds of venous thrombosis to increase by 40% (p=0.005) and the odds of bleeding to increase by 52% (p=0.001). Multivariate analysis only slightly attenuated the association to 33% (p=0.03) and 37% (p=0.013) for venous thrombosis and bleeding, respectively. OPG was also related to the development of the combined outcome of venous thrombosis and bleeding in the prospective analysis (log-rank-test: p=0.017).This is the first report that links the occurrence of venous thrombosis or bleeding to elevated OPG levels.


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  • References

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  • 2 Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood 2002; 100: 4272-90.
  • 3 Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219-22.
  • 4 Ruggeri M, Gisslinger H, Tosetto A. et al Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol 2002; 71: 1-6.
  • 5 Gisslinger H, Rodeghiero F, Ruggeri M. et al Homocysteine levels in polycythaemia vera and essential thrombocythaemia. Br J Haematol 1999; 105: 551-5.
  • 6 Michiels JJ. Erythromelalgia and thrombocythemia: a disease of platelet prostaglandin metabolism. Semin Thromb Hemost 1997; 23: 335-8.
  • 7 Neunteufl T, Heher S, Stefenelli T. et al Endothelial dysfunction in patients with polycythaemia vera. Br J Haematol 2001; 115: 354-9.
  • 8 Falanga A, Marchetti M, Evangelista V. et al Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96: 4261-6.
  • 9 Cines DB, Pollak ES, Buck CA. et al Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91: 3527-61.
  • 10 Jono S, Ikari Y, Shioi A. et al Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106: 1192-4.
  • 11 Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001; 86: 631-7.
  • 12 Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 2002; 22: 549-53.
  • 13 Simonet WS, Lacey DL, Dunstan CR. et al Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-19.
  • 14 Lacey DL, Timms E, Tan HL. et al Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-76.
  • 15 Fata JE, Kong YY, Li J. et al The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000; 103: 41-50.
  • 16 Bucay N, Sarosi I, Dunstan CR. et al osteoprotegerin- deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-8.
  • 17 Kim HH, Shin HS, Kwak HJ. et al RANKL regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. FASEB J 2003; 17: 2163-5.
  • 18 Collin-Osdoby P, Rothe L, Anderson F. et al Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 2001; 276: 20659-72.
  • 19 Zhang J, Fu M, Myles D et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 2002; 521: 180-4.
  • 20 Tan KB, Harrop J, Reddy M. et al Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 1997; 204: 35-46.
  • 21 Schoppet M, Sattler AM, Schaefer JR. et al Increased osteoprotegerin serum levels in men with coronary artery disease. J Clin Endocrinol Metab 2003; 88: 1024-8.
  • 22 Knudsen ST, Foss CH, Poulsen PL. et al Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol 2003; 149: 39-42.
  • 23 Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombo-cythemia. Semin Hematol 1999; 36: 9-13.
  • 24 Landolfi R, Marchioli R, Kutti J. et al Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114-24.
  • 25 Rothman K, Greenland S. Modern Epidemiology Philadelphia: Lippincott Williams & Wilkins; 1998: 255-7.
  • 26 Clayton D, Hills M. Statistical Models in Epidemiology. Oxford: Oxford University Press; 1993
  • 27 Chagraoui H, Tulliez M, Smayra T. et al Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO. Blood 2003; 101: 2983-9.
  • 28 Chagraoui H, Sabri S, Capron C. et al Expression of osteoprotegerin mRNA and protein in murine megakaryocytes. Exp Hematol 2003; 31: 1081-8.
  • 29 Malyankar UM, Scatena M, Suchland KL. et al Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000; 275: 20959-62.

Correspondence to:

Univ. Prof. Dr. Heinz Gisslinger
Medical University Vienna, Department of Internal Medicine I
Division of Hematology and Blood Coagulation
Währinger Gürtel 18–20
A-1090 Vienna, Austria
Phone: +43–1–40400–5464   
Fax: +43–1–4026930   

  • References

  • 1 Gruppo Italiano Studio Policitemia Polycythemia vera: the natural history of 1213 patients followed for 20 years. Ann Intern Med 1995; 123: 656-64.
  • 2 Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood 2002; 100: 4272-90.
  • 3 Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978; 2: 1219-22.
  • 4 Ruggeri M, Gisslinger H, Tosetto A. et al Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemia. Am J Hematol 2002; 71: 1-6.
  • 5 Gisslinger H, Rodeghiero F, Ruggeri M. et al Homocysteine levels in polycythaemia vera and essential thrombocythaemia. Br J Haematol 1999; 105: 551-5.
  • 6 Michiels JJ. Erythromelalgia and thrombocythemia: a disease of platelet prostaglandin metabolism. Semin Thromb Hemost 1997; 23: 335-8.
  • 7 Neunteufl T, Heher S, Stefenelli T. et al Endothelial dysfunction in patients with polycythaemia vera. Br J Haematol 2001; 115: 354-9.
  • 8 Falanga A, Marchetti M, Evangelista V. et al Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 2000; 96: 4261-6.
  • 9 Cines DB, Pollak ES, Buck CA. et al Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998; 91: 3527-61.
  • 10 Jono S, Ikari Y, Shioi A. et al Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002; 106: 1192-4.
  • 11 Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab 2001; 86: 631-7.
  • 12 Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprotegerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 2002; 22: 549-53.
  • 13 Simonet WS, Lacey DL, Dunstan CR. et al Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-19.
  • 14 Lacey DL, Timms E, Tan HL. et al Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-76.
  • 15 Fata JE, Kong YY, Li J. et al The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000; 103: 41-50.
  • 16 Bucay N, Sarosi I, Dunstan CR. et al osteoprotegerin- deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998; 12: 1260-8.
  • 17 Kim HH, Shin HS, Kwak HJ. et al RANKL regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. FASEB J 2003; 17: 2163-5.
  • 18 Collin-Osdoby P, Rothe L, Anderson F. et al Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 2001; 276: 20659-72.
  • 19 Zhang J, Fu M, Myles D et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Lett 2002; 521: 180-4.
  • 20 Tan KB, Harrop J, Reddy M. et al Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 1997; 204: 35-46.
  • 21 Schoppet M, Sattler AM, Schaefer JR. et al Increased osteoprotegerin serum levels in men with coronary artery disease. J Clin Endocrinol Metab 2003; 88: 1024-8.
  • 22 Knudsen ST, Foss CH, Poulsen PL. et al Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications. Eur J Endocrinol 2003; 149: 39-42.
  • 23 Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombo-cythemia. Semin Hematol 1999; 36: 9-13.
  • 24 Landolfi R, Marchioli R, Kutti J. et al Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004; 350: 114-24.
  • 25 Rothman K, Greenland S. Modern Epidemiology Philadelphia: Lippincott Williams & Wilkins; 1998: 255-7.
  • 26 Clayton D, Hills M. Statistical Models in Epidemiology. Oxford: Oxford University Press; 1993
  • 27 Chagraoui H, Tulliez M, Smayra T. et al Stimulation of osteoprotegerin production is responsible for osteosclerosis in mice overexpressing TPO. Blood 2003; 101: 2983-9.
  • 28 Chagraoui H, Sabri S, Capron C. et al Expression of osteoprotegerin mRNA and protein in murine megakaryocytes. Exp Hematol 2003; 31: 1081-8.
  • 29 Malyankar UM, Scatena M, Suchland KL. et al Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem 2000; 275: 20959-62.