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VHL promotes proteolytic clearance of hypoxia\u2010inducible transcription factors (HIFs) that have been modified by oxygen\u2010dependent HIF\u2010prolyl hydroxylases. A homozygous loss\u2010of\u2010function <jats:italic>VHL<\/jats:italic><jats:sup><jats:italic>R200W<\/jats:italic><\/jats:sup> mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia\u2010sensing. Homozygous <jats:italic>VHL<\/jats:italic><jats:sup><jats:italic>R200W<\/jats:italic><\/jats:sup> results in accumulation of HIFs that increase transcription of the erythropoietin gene and raise hematocrit. Phlebotomies reduce hematocrit and hyperviscosity symptoms. However, the major cause of morbidity and mortality in Chuvash erythrocytosis is thrombosis. Phlebotomies cause iron deficiency, which may further elevate HIF activity and transferrin, the HIF\u2010regulated plasma iron transporter recently implicated in thrombogenesis. We hypothesized that transferrin is elevated in Chuvash erythrocytosis, and that iron deficiency contributes to its elevation and to thrombosis. We studied 155 patients and 154 matched controls at steady state and followed them for development of thrombosis. Baseline transferrin was elevated, and ferritin reduced in patients. <jats:italic>VHL<\/jats:italic><jats:sup>R200W<\/jats:sup> homozygosity and lower ferritin correlated with higher erythropoietin and transferrin. During 11\u2009years of follow\u2010up, risk of thrombosis increased 8.9\u2010fold in patients versus controls. Erythropoietin elevation, but not hematocrit or ferritin, correlated with thrombosis risk. Unexpectedly, transferrin elevation associated with reduced rather than increased thrombosis risk. The A allele of the promoter <jats:italic>EPO<\/jats:italic> single nucleotide polymorphisms (SNP), rs1617640, associated with elevated erythropoietin and increased thrombosis risk, whereas the A allele of the intronic <jats:italic>TF<\/jats:italic> SNP, rs3811647, associated with higher transferrin and protection from thrombosis in patients. Our findings suggest an unexpected causal relationship between increased transferrin and protection from thrombosis in Chuvash erythrocytosis.<\/jats:p>","DOI":"10.1002\/ajh.27021","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T11:18:37Z","timestamp":1689160717000},"page":"1532-1539","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Increased transferrin protects from thrombosis in Chuvash erythrocytosis"],"prefix":"10.1002","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5169-7301","authenticated-orcid":false,"given":"Binal N.","family":"Shah","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7732-1385","authenticated-orcid":false,"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine University of Illinois at Chicago  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelina I.","family":"Sergueeva","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology and Hematology N. Ulianov Chuvash State University  Cheboksary Chuvashia Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina Y.","family":"Miasnikova","sequence":"additional","affiliation":[{"name":"Department of Hematology and Chemotherapy Chuvash Republic Clinical Hospital  Cheboksary Chuvashia Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-5469","authenticated-orcid":false,"given":"Tomas","family":"Ganz","sequence":"additional","affiliation":[{"name":"Pathology and Laboratory Medicine David Geffen School of Medicine University of California Los Angeles  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8019-2940","authenticated-orcid":false,"given":"Josef T.","family":"Prchal","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Utah, VAH, and Huntsman Cancer Institute  Salt Lake City Utah 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