Department of Pediatrics, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA.
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), Houston, TX, USA.
Clin Appl Thromb Hemost. 2021 Jan-Dec;27:1076029621992128. doi: 10.1177/1076029621992128.
Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.
高血铁蛋白血症与脓毒症、噬血细胞性淋巴组织细胞增生症（HLH）、巨噬细胞活化综合征（MAS）和 2019 冠状病毒病（COVID-19）危重症患者的不良结局相关。尸检显示，死于脓毒症、HLH、MAS 或 COVID-19 的高血铁蛋白血症患者存在广泛的微血管血栓形成，其中富含血管性血友病因子（VWF）、血小板和/或纤维蛋白的微血栓。目前尚不清楚高血浆铁蛋白浓度是否会主动促进微血管血栓形成，或者它是否仅仅是这些患者的预后生物标志物。在这里，我们表明，重组铁蛋白重链蛋白（FHC）100000ng/ml 可显著增强人脐静脉内皮细胞（HUVEC）中 VWF 的分泌。与非危重病对照血浆的类似部分相比，从 HLH 危重病患者血浆中通过大小排阻色谱法分离的铁蛋白部分促进了 HUVEC 中 VWF 的分泌。此外，重组 FHC 可适度抑制 VWF 切割金属蛋白酶 ADAMTS-13 的活性。这些观察结果表明，明显的高血铁蛋白血症状态可通过诱导内皮细胞 VWF 分泌和降低 ADAMTS-13 活性来促进血栓形成和器官损伤。
