Combination effect of antithrombin and recombinant human soluble thrombomodulin in a lipopolysaccharide induced rat sepsis model

Abstract

IntroductionRecombinant human soluble thrombomodulin (rhsTM) is newly developed for the treatment of DIC. The purpose of this study was to evaluate the efficacy of the concomitant administration of rhsTM and antithrombin (AT).MethodsIn the first series, rats were treated with either 62.5, 125, 250 or 500 IU/kg (n = 6, each) of AT or 0.125, 0.25, 0.5 or 1.0 mg/kg (n = 6, each) of rhsTM followed by lipopolysaccharide (LPS) injection. 8 h later, the fibrinogen level was examined. In the second series, TM group was pretreated with 0.25 mg/kg of rhsTM, AT group was pretreated with 125 IU/kg of AT, AT/TM group was pretreated with both AT and rhsTM, and control group was pretreated with saline (n = 7, each). The platelet count, fibrinogen, ALT, LDH and high-mobility group box 1 (HMGB1) levels were measured. In addition, histologic changes in liver were examined. In the third series, survival was calculated up to 24 h.ResultsBoth AT and rhsTM produced a linear dose-response with regard to the fibrinogen level, with 125 IU/kg of AT and 0.25 mg/kg of rhsTM producing equivalent effects. The combined administration of AT and rhsTM significantly reduced the decrease in the platelet count and the fibrinogen level (P < 0.05, 0.01, respectively). The elevations in ALT and LDH were significantly suppressed in all treatment groups. The HMGB1 level and the histologic changes tended to indicate damage reduction. Survival was significantly better only in AT/TM group (P < 0.01).ConclusionsThe coadministration of AT and rhsTM might be effective for the treatment of severe sepsis.

Recombinant human soluble thrombomodulin administration improves sepsis-induced disseminated intravascular coagulation and mortality: a retrospective cohort study

“…Although rhTM improves fibrinogen levels in animal studies [12,13], fibrinogen levels were normal in all patients in the present study. Therefore, fibrinogen levels showed no significant differences between the control and treatment groups.…”

Clinical Features and Treatment Outcomes of Six Patients with Disseminated Intravascular Coagulation Resulting from Acute Promyelocytic Leukemia and Treated with Recombinant Human Soluble Thrombomodulin at a Single Institution

“…This pathway halts further thrombin formation by the TF expressed on APL cells and by the CP-producing APL cells (10). The antiinflammatory effect results from the ability of rTM to suppress the production of high-mobility group box 1 (HMGB 1), which is the key cytokine involved in the induction of sepsis (17).…”

Effects of Recombinant Human Soluble Thrombomodulin Treatment for Disseminated Intravascular Coagulation at a Single Institution -An Analysis of 62 Cases Caused by Infectious Diseases and 30 Cases Caused by Hematological Diseases

“…Consequently, the inactivation of factors VIIIa and Va by APC under protein S results in the cessation of further thrombin formation (5). Second, this anti-inflammatory effect is a result of the suppression by rTM of the production of the high-morbidity group box, which is the key cytokine involved in sepsis (14). Moreover, TM may exert cytoprotective effects on endothelial cells via the upregulation of extracellular signalregulated kinase/myeloid leukemia cell-1 signaling (15).…”