Department of Critical Care Medicine, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China; Department of Critical Care Medicine, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Nanjing Road 288, Tianjin 300020, China.
Department of Critical Care Medicine, the First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.
Thromb Res. 2024 Dec;244:109176. doi: 10.1016/j.thromres.2024.109176. Epub 2024 Oct 14.
Heparin-binding protein (HBP) levels have been linked to organ failure and may represent an inflammatory biomarker of sepsis. We found disseminated intravascular coagulation (DIC) is associated with higher HBP levels in patients and in in vivo and in vitro models. This prospective, single-center observational study investigated the effects and underlying mechanisms of HBP on the coagulation cascade in sepsis.
538 patients with sepsis from June 2016 to December 2019 were enrolled. Mechanisms underlying HBP and the coagulation system were investigated in human umbilical vein endothelial cells (HUVEC) and C57 mice.
Increased HBP was associated with sepsis-induced DIC. The optimal cutoff value was 37.5 ng/mL (sensitivity: 56 %, specificity: 65 %). Antithrombin-III (AT-III) activity, plasmin-a2 plasmin inhibitor complex (PIC), procalcitonin (PCT), hemoglobin, and HBP ≥37.5 ng/mL were associated with of DIC occurrence. In HUVECs &C57 mice models, Western blotting, qPCR, and immunohistochemistry analysis showed that the binding between HBP and TGF-β receptor 2 (TGFBR2) caused elevation of plasminogen activator inhibitor-1 (PAI-1) levels. Furthermore, we found that mice stimulated with HBP had higher levels of fibrinogen and D-dimer in the blood. HBP treatment caused the accumulation of fibrinogen in mice lung tissue. Treatment with TGFBR2-small interfering RNAs inhibited the effects.
Patients with sepsis having HBP ≥37.5 ng/mL at admission were more likely to develop DIC. HBP upregulates the expression of fibrinogen and PAI-1 via TGFBR2 and the TGF-β signalling pathway.
肝素结合蛋白 (HBP) 水平与器官衰竭有关，可能是脓毒症的炎症生物标志物。我们发现弥散性血管内凝血 (DIC) 与患者以及体内和体外模型中 HBP 水平升高有关。这项前瞻性、单中心观察性研究调查了 HBP 对脓毒症凝血级联的影响及其潜在机制。
纳入了 2016 年 6 月至 2019 年 12 月期间的 538 例脓毒症患者。在人脐静脉内皮细胞 (HUVEC) 和 C57 小鼠中研究了 HBP 和凝血系统的潜在机制。
HBP 增加与脓毒症诱导的 DIC 相关。最佳截断值为 37.5ng/mL（灵敏度：56%，特异性：65%）。抗凝血酶-III (AT-III) 活性、纤溶酶-α2 纤溶酶抑制剂复合物 (PIC)、降钙素原 (PCT)、血红蛋白和 HBP≥37.5ng/mL 与 DIC 发生相关。在 HUVEC 和 C57 小鼠模型中，Western blot、qPCR 和免疫组织化学分析表明，HBP 与 TGF-β 受体 2 (TGFBR2) 结合导致纤溶酶原激活物抑制剂-1 (PAI-1) 水平升高。此外，我们发现用 HBP 刺激的小鼠血液中纤维蛋白原和 D-二聚体水平升高。HBP 处理导致小鼠肺组织中纤维蛋白原的积累。用 TGFBR2 小干扰 RNA 处理可抑制这些作用。
入院时 HBP≥37.5ng/mL 的脓毒症患者更有可能发生 DIC。HBP 通过 TGFBR2 和 TGF-β 信号通路上调纤维蛋白原和 PAI-1 的表达。
