Increased transferrin protects from thrombosis in Chuvash erythrocytosis

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 VHLR200W mutation causes Chuvash erythrocytosis, a congenital disorder caused by augmented hypoxia‐sensing. Homozygous VHLR200W 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. VHLR200W 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.

Growing concerns about using hypoxia-inducible factor prolyl hydroxylase inhibitors for the treatment of renal anemia

“…The impact of hypoxia on thrombosis was attenuated using transferrin-specific antibodies, inhibitory peptides and transferrin knockdown [ 81 ]. However, this is in apparent contradiction with a recent observation in patients with Chuvash erythrocytosis in whom transferrin elevation were unexpectedly associated with reduced rather than increased thrombosis risk [ 82 ]. At present, it remains unclear whether high-dose iron supplementation contributes or not to thrombogenesis in patients with CKD receiving HIF-PHI treatment.…”

Targeting Pro-Oxidant Iron with Exogenously Administered Apotransferrin Provides Benefits Associated with Changes in Crucial Cellular Iron Gate Protein TfR in a Model of Intracerebral Hemorrhagic Stroke in Mice

“…Of note, we tested these parameters and obtained these negative results in two species, in physiological conditions, and in acute scenarios, all of which presented as very relevant for stroke. However, other studies tested the effects of transferrin on coagulation in other conditions, reporting either procoagulant effects, e.g., chronically elevated transferrin levels or blood processed much further than we did [33,34] or, in contrast, higher transferrin associated with protection from thrombosis [35].…”