Induced normothermia ameliorates the procoagulant host response in human endotoxaemia

Abstract

Background: Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers. Methods: Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg À1 ) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37 C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model. Results: In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x10 9 L À1 ([95%CI:27-107]; p¼0.002), aPTT (mean difference:3s [95%CI:1-5]; p¼0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p¼0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide. Conclusion:In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.

Magnesium Sulfate Ameliorates Histone-Induced Coagulation Dysfunction and Lung Damage in Mice

“…Extracellular histones have been proposed as significant mediators in sepsis pathogenesis, with several experiments demonstrating that extracellular histones can induce endothelial cell injury and impaired coagulation (5,33). In mouse models, intravenous histone administration provokes perturbations in the coagulation system similar to sepsis-induced consumptive coagulopathy and DIC, including endothelial damage, increased concentrations of TF and vWf, subsequently leading to PLT activation, extensive thrombosis, and coagulation factor depletion, thereby presenting as low PLT counts and prolonged PT and aPTT (2,24,(34)(35)(36). One study reported that circulating histone levels were higher in septic patients who developed DIC (6); however, the relationship between histones and various significant coagulation parameters (e.g., PLT counts, PT, aPTT, D-dimer, and fibrinogen) remains unclear.…”

“…Magnesium (Mg 2+ ) is an essential nutrient that maintains normal cellular physiological activity and homeostasis in the body through more than 300 biochemical reactions (8,9). Previous studies on Mg 2+ and magnesium sulfate (MgSO 4 ) have shown an anticoagulant effect with reduced PLT aggregation, blood clotting, and thrombosis (2,(10)(11)(12). A retrospective observational study has hinted that low Mg 2+ levels are associated with active coagulation and inhibition of fibrinolysis in septic patients; however, whether Mg 2+ is a factor affecting coagulation in sepsis is unclear (13).…”

“…Recent advances demonstrate that extracellular histones are significant mediators of sepsis, with the ability to induce endothelial cell injury, activate PLTs, and promote thrombin formation, which are responsible for DIC and MOF (4)(5)(6). The mouse model of extracellular histone-induced injury is characterized by endothelial damage and excessive coagulation activation, with increased concentrations of tissue factor (TF) and von Willebrand factor (vWf ), bearing a strong resemblance to sepsis-associated coagulopathy (2,7). In addition, circulating histone levels are higher in septic patients who develop DIC (6); however, the relationship between circulating histones and laboratory markers reflecting coagulation in septic patients and mice has not been reported.…”

“…Despite advances in defining the pathogenesis of sepsis, it remains a leading cause of death in critically ill patients (1). In sepsis, a dysregulated host immune response causes the acute activation of coagulation, microthrombosis, and platelet (PLT) and coagulation factor depletion, ultimately contributing to disseminated intravascular coagulation (DIC) and multiorgan failure (MOF) with no specific treatment currently available (2). Therefore, we aimed to explore a promising and aggressive therapeutic means of targeting pathological coagulation in sepsis (3).…”

Complementary Sets of Autoantibodies Induced by SARS-CoV-2, Adenovirus and Bacterial Antigens Cross-React with Human Blood Protein Antigens in COVID-19 Coagulopathies

“…), etc., which revealed that some of the most common autoantigen targets in COVID-19-associated coagulopathies, such as CL, PF4 and β2GP, have significant mimics with these bacteria but do not have significant mimics with SARS-CoV-2 and especially its spike protein [ 40 ] (summarized in Figure 1 ). Since some bacterial infections, especially GAS , Staphylococci, Klebsiella and Clostridia , are themselves associated with increased risks of coagulopathies [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ], these results suggested that preceding or concomitant bacterial co-infections may support the induction of a variety of COVID-19 autoimmune coagulopathies through anamnestic secondary cross-reactivity or bystander activation of complementary autoimmune mechanisms to those activated by SARS-CoV-2. Conversely, if a pre- or co-existing bacterial infection were necessary to induce autoimmune coagulopathies, then the absence of such infections among the vast majority of vaccinees might explain the extremely infrequent occurrence of vaccine-induced thrombotic events [ 62 , 63 ].…”