Division of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
Department of Pediatric Oncology and Hematology, N. Ulianov Chuvash State University, Cheboksary, Chuvashia, Russia.
Am J Hematol. 2023 Oct;98(10):1532-1539. doi: 10.1002/ajh.27021. Epub 2023 Jul 12.
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.
von Hippel-Lindau 蛋白（VHL）对于细胞过程的缺氧调节至关重要。VHL 促进了缺氧诱导转录因子（HIFs）的蛋白水解清除，这些因子被氧依赖性 HIF-脯氨酰羟化酶修饰。VHL 纯合功能丧失突变导致 Chuvash 红细胞增多症，这是一种由增强的缺氧感知引起的先天性疾病。VHL 纯合导致 HIFs 的积累增加，从而增加促红细胞生成素基因的转录并提高血细胞比容。放血疗法可降低血细胞比容和高粘滞血症症状。然而，Chuvash 红细胞增多症的主要发病和死亡原因是血栓形成。放血疗法导致缺铁，这可能进一步提高 HIF 活性和转铁蛋白，最近转铁蛋白被认为是血栓形成的 HIF 调节的血浆铁转运体。我们假设转铁蛋白在 Chuvash 红细胞增多症中升高，并且缺铁导致其升高和血栓形成。我们在稳定状态下研究了 155 例患者和 154 例匹配的对照，并对他们进行了血栓形成的随访。基线时转铁蛋白升高，铁蛋白降低。VHL 纯合性和较低的铁蛋白与较高的促红细胞生成素和转铁蛋白相关。在 11 年的随访中，患者发生血栓形成的风险比对照增加了 8.9 倍。促红细胞生成素升高，但血细胞比容或铁蛋白升高与血栓形成风险无关。出乎意料的是，转铁蛋白升高与较低而不是较高的血栓形成风险相关。EPO 单核苷酸多态性（SNP）rs1617640 启动子的 A 等位基因与促红细胞生成素升高和血栓形成风险增加相关，而 TF SNP rs3811647 的内含子 A 等位基因与转铁蛋白升高和患者血栓形成保护相关。我们的研究结果表明，在 Chuvash 红细胞增多症中，转铁蛋白升高与血栓形成保护之间存在意外的因果关系。
