Unfractionated heparin inhibits histone-mediated coagulation activation and thrombosis in mice

Introduction: Histones play pivotal roles in the pathophysiology of sepsis. Different studies have reported that unfractionated heparin (UFH) can improve histone-mediated organ dysfunction. However, in such studies, UFH was usually pretreated or injected with histones concurrently, which was obviously inconsistent with clinical practice. Therefore, this study aimed to figure out whether UFH can inhibit histone-induced coagulation activation and thrombosis when histones have caused coagulation disorder already.

Methods: Male C57/BL6 mice of average weight ~22 g were randomly divided into three groups. The histone group was injected with histones 50 mg/kg through the tail vein. The histone + UFH group was injected with UFH (400 U/kg) through the tail vein 1 h or 6 h after the induction of histones. The control group was injected with equal volume of sterile saline. The lungs were harvested 3 h after UFH administration. In survival studies, mice were treated with UFH (800 U/kg, n = 10) or sterile saline (n = 10) intravenously after histones (75 mg/kg) injection and observed for 7 days.

Results: 1) UFH improved survival rate in mice injected with lethal doses of histones; 2) UFH alleviated histone-induced lung injury and pulmonary edema; 3) UFH improved histone-induced endothelial cell injury; 4) UFH improved histone-mediated high expression of TF, PAI-1, fibrinogen and low expression of TM.

Conclusion: UFH can effectively attenuate histone-induced lung injury, coagulation activation and thrombosis.

Keywords: Coagulation activation; Histone; Lung injury; Unfractionated heparin.