Background Low molecular-weight heparin (LMWH) is routinely administered to burn patients for thromboprophylaxis. Some studies have reported heparin resistance, yet the mechanism(s) and prevalence have not been systematically studied. We hypothesized that nucleosomes, composed of histone structures with associated DNA released from injured tissue and activated immune cells in the form of neutrophil extracellular traps (NETs or NETosis), neutralize LMWH resulting in suboptimal anticoagulation, assessed by reduction in anti-factor Xa activity. Methods Blood was sampled from >15% total body surface area (TBSA) burn patients receiving LMWH on days 5, 10 and 14. Peak anti-factor Xa (AFXa) activity, anti-thrombin (ATIII) activity, cell-free DNA (cfDNA) levels and nucleosome levels were measured. Mixed effects regression was adjusted for multiple confounders, including injury severity and ATIII activity, and was used to test the association between nucleosomes and AFXa. Results A total of 30 patients with severe burns were included. Mean TBSA 43% (SD 17). Twenty-three (77%) patients were affected by heparin resistance (defined by AFXa activity <0.2 IU/mL). Mean peak AFXa activity across samples was 0.18 IU/mL (SD 0.11). Mean ATIII was 81.9% activity (SD 20.4). Samples taken at higher LWMH doses were found to have significantly increased AFXa activity, though the effect was not observed at all doses, at 8000 IU no samples were heparin resistant. Nucleosome levels were negatively correlated with AFXa (r = −0.29, p = 0.050) consistent with the hypothesis. The final model, with peak AFXa as the response variable, was adjusted for nucleosome levels (p = 0.0453), ATIII activity (p = 0.0053), LMWH dose pre-sample (p = 0.0049), drug given (enoxaparin or tinzaparin) (p = 0.03), and other confounders including severity of injury, age, gender, time point of sample. Conclusions Heparin resistance is a prevalent issue in severe burns. Nucleosome levels were increased post-burn, and showed an inverse association with AFXa consistent with the hypothesis that they may interfere with the anticoagulant effect of heparin in vivo and contribute to heparin resistance. Accurate monitoring of AFXa activity with appropriate therapy escalation plans are recommended with dose adjustment following severe burn injury.

中文翻译：

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严重热损伤中的肝素抵抗：一项前瞻性队列研究

背景 低分子量肝素 (LMWH) 常规用于烧伤患者预防血栓形成。一些研究报告了肝素抵抗，但其机制和患病率尚未系统研究。我们假设核小体由组蛋白结构和从受损组织释放的相关DNA组成，并以中性粒细胞胞外陷阱（NETs或NETosis）的形式激活免疫细胞，中和LMWH，导致抗凝效果不佳，通过抗Xa因子活性降低来评估。方法 从第 5、10 和 14 天接受 LMWH 的全身表面积 (TBSA) 烧伤患者中采集血液样本。峰值抗 Xa 因子 (AFXa) 活性、抗凝血酶 (ATIII) 活性、无细胞 DNA测量了 (cfDNA) 水平和核小体水平。混合效应回归针对多种混杂因素进行了调整，包括损伤严重程度和 ATIII 活性，并用于测试核小体和 AFXa 之间的关联。结果共纳入30例严重烧伤患者。平均 TBSA 43% (SD 17)。二十三名(77%)患者受到肝素抵抗(定义为AFXa活性＜0.2IU/mL)的影响。样品的平均峰值 AFXa 活性为 0.18 IU/mL (SD 0.11)。ATIII 平均活性为 81.9% (SD 20.4)。在较高 LWMH 剂量下采集的样本被发现显着增加了 AFXa 活性，尽管并非在所有剂量下都观察到这种效果，但在 8000 IU 时，没有样本出现肝素抗性。核小体水平与 AFXa 呈负相关（r = -0.29，p = 0.050），与假设一致。最终模型以 AFXa 峰值作为响应变量，根据核小体水平 (p = 0.0453)、ATIII 活性 (p = 0.0053)、样品前 LMWH 剂量 (p = 0.0049)、给药药物（依诺肝素或亭扎肝素）进行调整（ p = 0.03），以及其他混杂因素，包括伤害严重程度、年龄、性别、样本时间点。结论 肝素抵抗是严重烧伤中普遍存在的问题。烧伤后核小体水平增加，并与 AFXa 呈负相关，这与它们可能干扰体内肝素的抗凝作用并导致肝素抵抗的假设一致。建议通过适当的治疗升级计划准确监测 AFXa 活性，并在严重烧伤后调整剂量。