A Thrombomodulin Alfa Effective for Treatment of Sepsis-Associated Disseminated Intravascular Coagulation
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Abstract
Disseminated intravascular coagulation is a serious complication of sepsis that leads to severe organ dysfunction and high mortality, thus early and effective treatment is essential. While thrombomodulin alfa is known as an effective therapeutic agent for disseminated intravascular coagulation, its optimal plasma level has yet to be established. The present two-phase investigation was conducted to evaluate the relationship between plasma concentration of thrombomodulin alfa and both therapeutic efficacy and safety in patients with sepsis-induced disseminated intravascular coagulation, in order to clarify the optimal concentration. For the first phase, patients were divided into high- and low-concentration groups based on a plasma trough cutoff level of 600 ng/mL, then treatment efficacy and bleeding-related adverse events were compared. For the second phase, receiver operating characteristic curve analysis was performed to determine the cutoff value for plasma trough concentration that significantly affected clinical outcomes. Treatment efficacy was higher with concentrations ≥600 ng/mL, without an increase in bleeding complications. Furthermore, receiver operating characteristic analysis identified a cutoff value of 1010 ng/mL, with the 90-day survival rate significantly higher at that concentration (91.7% vs. 63.4%, p = 0.017), while safety was maintained. The present findings suggest that for treatment of sepsis-induced disseminated intravascular coagulation, adjustment of thrombomodulin alfa dose to maintain a plasma trough concentration of at least 1010 ng/mL provides an effective and safe therapeutic strategy.
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References
2. Gando S, Saitoh D, Ogura H, et al. Disseminated intravascular coagulation (DIC) diagnosed based on the Japanese Association for Acute Medicine criteria is a dependent continuum to overt DIC in patients with sepsis. Thromb Res. 2009; 123: 715-718.
3. Eguchi Y, Gando S, Ishikura H, et al. Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation. J Intensive Care. 2014; 2: 30.
4. Gando S, Shiraishi A, Yamakawa K, et al. Role of disseminated intravascular coagulation in severe sepsis. Thromb Res. 2019; 178: 182-188.
5. Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters HMGB1: a novel anti-inflammatory mechanism. J Clin Invest. 2005; 115: 1267–1274.
6. Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin in disseminated intravascular coagulation: a phase III, randomized, double-blind trial. Crit Care Med. 2007; 35: 657–662.
7. Yamakawa K, Aihara M, Ogura H, et al. Recombinant human soluble thrombomodulin in sepsis: a systematic review and meta-analysis. Crit Care. 2015; 19: 543.
8. Japanese Society on Thrombosis and Hemostasis. Disseminated intravascular coagulation management guidelines 2024. Jpn J Thromb Hemost. 2025; 36: 68-156.
9. Vincent JL, Francois B, Zabolotskikh I, et al. SCARLET trial: recombinant thrombomodulin in sepsis-associated coagulopathy. N Engl J Med. 2019; 380: 617–628.
10. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: International Guidelines 2021. Intensive Care Med. 2021; 47: 1181–1247.
11. Singer M, Deutschman CS, Seymour CW, et al. The Third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016; 315: 801-810.
12. Gando S, Iba T, Eguchi Y, et al. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006; 34: 625-631.
13. Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med. 1985; 13: 818-829.
14. Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the working group on sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996; 22: 707-710.
15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31-41.
16. Recomodulin® Inj, 12800 package insert. Available at: https://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/100898_3339401D1027_1_15 [In Japanese]. (accessed August 29, 2025).
17. Imaura M, Tsumori M, Nagase S, et al. Therapeutic and adverse effects of thrombomodulin alfa to treat sepsis-induced disseminated intravascular coagulation. Shock. 2020; 54: 50-55.
18. Imaura M, Katagiri F, Nagase S, et al. Optimal plasma concentration of thrombomodulin alfa to treat sepsis-induced disseminated intravascular coagulation. Shock. 2023; 60: 221-226.
19. Mouksassi MS, Marier JF, Bax L, et al. Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment. Clin Pharmacol Drug Dev. 2015; 4: 210-217.
20. Mohri M, Sugimoto E, Sata M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation--a comparison with other anticoagulants. Thromb Haemost. 1999; 82: 1687-1693.
21. Yamakawa K, Ogura H, Fujimi S, et al. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis. Intensive Care Med. 2013; 39: 644-652.
22. Tawara S, Sakai T, Matsuzaki O. Anti-inflammatory and anti-fibrinolytic effects of thrombomodulin alfa through carboxypeptidase B2 in the presence of thrombin. Thromb Res. 2016; 147: 72-79.
23. Sakata Y, Curriden S, Lawrence D, et al. Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity. Proc Natl Acad Sci USA. 1985; 82: 1121-1125.
24. Macias WL, Yan SB, Williams MD, et al. New insights into the protein C pathway: potential implications for the biological activities of drotrecogin alfa (activated). Crit Care. 2005; 9 (Suppl 4): S38-S45.
25. Toltl LJ, Beaudin S, Liaw PS. Activated protein C up-regulates IL-10 and inhibits tissue factor in blood monocytes. J Immunol. 2008; 181: 2165-2173.
26. Shi CS, Shi GY, Hsiao HM, et al. Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood. 2008; 112: 3661-3670.
27. Abeyama K, Stern DM, Ito Y, et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest. 2005; 115: 1267-1274.
28. Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nat Med. 2009; 15: 1318-1321.
29. Esmon CT, Taylor Jr FB, Snow TR. Inflammation and coagulation: linked processes potentially regulated through a common pathway mediated by protein C. Thromb Haemost. 1991; 66: 160-165.
30. Information to overview of application materials of thrombomodulin alfa 2025. https://www.info.pmda.go.jp/go/interview/1/100898_3339401D1027_1_018_1F.pdf [In Japanese]. (accessed August 29, 2025).
31. Mohri M, Sugimoto E, Sata M, et al. The inhibitory effect of recombinant human soluble thrombomodulin on initiation and extension of coagulation--a comparison with other anticoagulants. Thromb Haemost. 1999; 82: 1687-1693.