Dataset Information

Recombinant human thrombomodulin for pneumonia-induced severe ARDS complicated by DIC in children: a preliminary study.

ABSTRACT:

Purpose

Recombinant human soluble thrombomodulin (rTM) has been used to treat disseminated intravascular coagulation (DIC). Recent studies have shown the efficacy of rTM through its anti-inflammatory effects for treatment of adults with acute respiratory distress syndrome (ARDS). However, the safety and efficacy of rTM in children with severe ARDS complicated by DIC have not been reported. In this preliminary study, we reported the feasibility of using rTM for the treatment of pneumonia-induced severe ARDS complicated by DIC in children.

Methods

Six children (age: median 10 months old) with pneumonia-induced severe ARDS complicated by DIC were enrolled in this preliminary study. rTM (380 U/kg) was administered for a maximum of 6 days, in addition to conventional therapies after diagnosis of severe ARDS complicated by DIC. After administration of rTM, we measured changes in the plasma TM concentration and evaluated the clinical course, status of DIC and ARDS, and other laboratory findings, including levels of cytokines, chemokines, and biomarkers.

Results

In all six children, the plasma concentration of TM increased and DIC scores decreased after administration of rTM. Four of the six children recovered from the severe ARDS complicated by DIC after treatment, and were discharged from the hospital with no complications. In survived children, levels of soluble receptors for advanced glycation end products, interleukin-6, interleukin-8 and monocyte chemotactic protein-1 decreased after administration of rTM compared to those before rTM.

Conclusions

The rTM administration is feasible as an adjunctive therapeutic strategy for children over 2 months with pneumonia-induced severe ARDS complicated by DIC.

SUBMITTER: Hirata N

PROVIDER: S-EPMC8278185 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionRecent studies have shown that histones, the chief protein component of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and act as major mediators of the death of an organism. This study was designed to elucidate the cellular and molecular basis of histone-induced lethality and to assess the protective effects of recombinant thrombomodulin (rTM). rTM has been approved for the treatment of disseminated intravascular coagulation (DIC) in Japan, and is currently undergoing a phase III clinical trial in the United States.MethodsHistone H3 levels in plasma of healthy volunteers and patients with sepsis and DIC were measured using enzyme-linked immunosorbent assay. Male C57BL/6 mice were injected intravenously with purified histones, and pathological examinations were performed. The protective effects of rTM against histone toxicity were analyzed both in vitro and in mice.ResultsHistone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. These levels were higher in non-survivors than in survivors. Extracellular histones triggered platelet aggregation, leading to thrombotic occlusion of pulmonary capillaries and subsequent right-sided heart failure in mice. These mice displayed symptoms of DIC, including thrombocytopenia, prolonged prothrombin time, decreased fibrinogen, fibrin deposition in capillaries, and bleeding. Platelet depletion protected mice from histone-induced death in the first 30 minutes, suggesting that vessel occlusion by platelet-rich thrombi might be responsible for death during the early phase. Furthermore, rTM bound to extracellular histones, suppressed histone-induced platelet aggregation, thrombotic occlusion of pulmonary capillaries, and dilatation of the right ventricle, and rescued mice from lethal thromboembolism.ConclusionsExtracellular histones cause massive thromboembolism associated with consumptive coagulopathy, which is diagnostically indistinguishable from DIC. rTM binds to histones and neutralizes the prothrombotic action of histones. This may contribute to the effectiveness of rTM against DIC.