Vascular Complications in Chuvash Polycythemia

ABSTRACT

Chuvash polycythemia is characterized by a homozygous 598C> T germline mutation in the von Hippel-Lindau gene (VHL), upregulation of hypoxia-inducible factor-1α during normoxia, and resulting augmentation of erythropoietin and several other hypoxia-controlled genes. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and usually originates from a single ancient event. Matched-cohort and case-control analyses have shown that VHL 598C> T homozygosity is associated with lower peripheral blood pressures, varicose veins, vertebral hemangiomas, lower white blood cell and platelet counts, and elevated serum concentrations of vascular endothelial growth factor and plasminogen activator inhibitor-1. These studies have also shown associations with arterial and venous thrombosis, major bleeding episodes, cerebral vascular events, and premature mortality. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL tumor predisposition syndrome have not been found, and no increased risk of cancer has been demonstrated. Retrospective analyses among patients with Chuvash polycythemia have not shown benefit for therapy with phlebotomy or aspirin, but these and other modes of therapy should be studied prospectively. Further investigation of the vascular complications of Chuvash polycythemia may increase our fundamental knowledge of thrombophilia, bleeding diatheses, and protection from cancer.

Polycythemia - VHL - thrombosis - bleeding - hypoxia-inducible factor - vascular endothelial growth factor

REFERENCES

• 1 Polyakova L A. Familial erythrocytosis among inhabitants of the Chuvash ASSR.  Problemi Gematologii i Perelivaniya Krovi. 1974;  10 30-36
• 2 Polyakova L A. Familial-Hereditary Erythrocytosis. Moscow: Scientific Research Institute of Hematology and Blood Transfusion. 1977
• 3 Ang S O, Chen H, Gordeuk V R et al.. Endemic polycythemia in Russia: mutation in the VHL gene.  Blood Cells Mol Dis. 2002;  28 57-21
• 4 Ang S O, Chen H, Hirota K et al.. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.  Nat Genet. 2002;  32 614-621
• 5 Safran M, Kaelin Jr W G. HIF hydroxylation and the mammalian oxygen-sensing pathway.  J Clin Invest. 2003;  111 779-783
• 6 Semenza G L. Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease.  Pediatr Res. 2001;  49 614-617
• 7 Gordeuk V R, Sergueeva A I, Miasnikova G Y et al.. Congenital disorder of oxygen-sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.  Blood. 2004;  103 3924-3932
• 8 Pastore Y D, Jelinek J, Ang S et al.. Mutation in the VHL gene in sporadic apparently congenital polycythemia.  Blood. 2003;  101 1591-1595
• 9 Pastore Y, Jedlickova K, Guan Y L et al.. Mutations of von Hippel-Lindau tumor suppressor gene and congenital polycythemia.  Am J Hum Genet. 2003;  73 412-419
• 10 Percy M J, McMullin M F, Jowitt S N et al.. Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry.  Blood. 2003;  102 1097-1099
• 11 Liu E, Percy M J, Amos C I et al.. The worldwide distribution of the VHL 598C> T mutation indicates a single founding event.  Blood. 2004;  103 1937-1940
• 12 Richards F M. Molecular pathology of von Hippel-Lindau disease and the VHL tumour suppressor gene.  Expert Rev Mol Med. 2001;  2001 1-27
• 13 Lonser R R, Glenn G M, Walther M et al.. von Hippel-Lindau disease.  Lancet. 2003;  361 2059-2067
• 14 Berlin N I. Diagnosis and classification of the polycythemias.  Semin Hematol. 1975;  12 339-351
• 15 Gruppo Italiano Studio Policitemia . Polycythemia vera: the natural history of 1214 patients followed for 20 years.  Ann Intern Med. 1995;  123 656-664
• 16 Spivak J L. Polycythemia vera: myths, mechanisms and management.  Blood. 2002;  100 4272-4290
• 17 Prchal J T. Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders.  Semin Hematol. 2001;  38 10-20
• 18 Prchal J T, Prchal J F, Semenza G L, Sokol L. Familial polycythemia.  Science. 1995;  268 1831-1832
• 19 Shibata J, Hasegawa J, Siemens H-J et al.. Hemostasis and coagulation at a hematocrit level of 0.85: functional consequences of erythrocytosis.  Blood. 2003;  101 4416-4422
• 20 Landolfi R, Marchioli R, Kutti J et al.. Efficacy and safety of low-dose aspirin in polycythemia vera.  N Engl J Med. 2004;  350 114-124
• 21 Clifford S C, Cockman M E, Smallwood A C et al.. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.  Hum Mol Genet. 2001;  10 1029-1038
• 22 Kondo K, Klco J, Nakamura E, Lechpammer M, Kaelin Jr W G. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.  Cancer Cell. 2002;  1 237-246
• 23 Turner K J, Moore J W, Jones A et al.. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation.  Cancer Res. 2002;  62 2957-2961