Unfractioned Heparin for Treatment of Sepsis Caused by Abdominal Infection
Status:
Not yet recruiting
Trial end date:
2023-07-30
Target enrollment:
Participant gender:
Summary
Sepsis is the leading cause of death in intensive care units and a major public health
concern in the world. Heparin, a widely used anticoagulant medicine to prevent or treat
thrombotic disorders, has been demonstrated to prevent organ damage and lethality in
experimental sepsis models. However, the efficacy of heparin in the treatment of clinical
sepsis is not consistent. Caspase-11, a cytosolic receptor of LPS, triggers lethal immune
responses in sepsis. Recently, we have revealed that heparin prevents cytosolic delivery of
LPS and caspase-11 activation in sepsis through inhibiting the heparanase-mediated glycocalyx
degradation and the HMGB1- LPS interaction, which is independent of its anticoagulant
properties. In our study, it is found that heparin treatment could prevent lethal responses
in endotoxemia or Gram-negative sepsis, while caspase-11 deficiency or heparin treatment
failed to confer protection against sepsis caused by Staphylococcus aureus, a type of
Gram-positive bacterium. It is probably that other pathogens such as Gram-positive bacteria
might cause death through mechanisms distinct from that of Gram-negative bacteria.
Peptidoglycan, a cell-wall component of Gram-positive bacteria, can cause DIC and impair
survival in primates by activating both extrinsic and intrinsic coagulation pathways, which
might not be targeted by heparin. We speculate that the discrepancy between the previous
clinical trials of heparin might be due to the difference in infected pathogens. Thus,
stratification of patients based on the type of invading pathogens might improve the
therapeutic efficiency of heparin in sepsis, and this merits future investigations.
Phase:
Phase 3
Details
Lead Sponsor:
The Third Xiangya Hospital of Central South University