AI Article Synopsis

  • VHL protein is crucial for managing cellular responses to low oxygen, and mutations in VHL lead to Chuvash erythrocytosis, a condition marked by high levels of erythropoietin and increased red blood cell count.
  • The study measured transferrin and ferritin levels in 155 Chuvash erythrocytosis patients compared to controls, discovering that patients had higher transferrin levels and lower ferritin, with transferrin elevation surprisingly linked to a lower risk of thrombosis.
  • The research also identified genetic variations associated with erythropoietin and transferrin levels, suggesting a complex relationship between anemia treatment, iron status, and thrombosis risk in affected individuals.

Article Abstract

Von Hippel-Lindau protein (VHL) is essential to hypoxic regulation of cellular processes. VHL promotes proteolytic clearance of hypoxia-inducible transcription factors (HIFs) that have been modified by oxygen-dependent HIF-prolyl hydroxylases. A homozygous loss-of-function VHL mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia-sensing. Homozygous VHL 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-regulated 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. VHL homozygosity and lower ferritin correlated with higher erythropoietin and transferrin. During 11 years of follow-up, risk of thrombosis increased 8.9-fold 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 EPO single nucleotide polymorphisms (SNP), rs1617640, associated with elevated erythropoietin and increased thrombosis risk, whereas the A allele of the intronic TF 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10529798PMC
http://dx.doi.org/10.1002/ajh.27021DOI Listing

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Article Synopsis
  • VHL protein is crucial for managing cellular responses to low oxygen, and mutations in VHL lead to Chuvash erythrocytosis, a condition marked by high levels of erythropoietin and increased red blood cell count.
  • The study measured transferrin and ferritin levels in 155 Chuvash erythrocytosis patients compared to controls, discovering that patients had higher transferrin levels and lower ferritin, with transferrin elevation surprisingly linked to a lower risk of thrombosis.
  • The research also identified genetic variations associated with erythropoietin and transferrin levels, suggesting a complex relationship between anemia treatment, iron status, and thrombosis risk in affected individuals.
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