Effects of combination therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation

Iba, Toshiaki; Hagiwara, Akiyoshi; Saitoh, Daizoh; Anan, Hideaki; Ueki, Yutaka; Sato, Koichi; Gando, Satoshi

doi:10.1186/s13613-017-0332-z

Cited by 24 publications

(29 citation statements)

References 30 publications

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“…In addition, we could not conduct a detailed analysis of respiratory function due to the limitations of the DPC database. Iba et al reported a significant improvement in 28-day mortality following AT + TM combination therapy in patients with sepsis-associated DIC 7 . Although our study was characterized by substantially longer observation periods and more subject hospitals, the differences between our findings and those of Iba et al 7 underscore the need for further research to explore the merits of AT + TM combination therapy.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of combined antithrombin and thrombomodulin therapy on in-hospital mortality in mechanically ventilated septic patients with disseminated intravascular coagulation

Umegaki

Kunisawa

Nishimoto

et al. 2020

Sci Rep

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Septic patients can develop disseminated intravascular coagulation (DIC), which is characterized by systemic blood coagulation and an increased risk of life-threatening haemorrhage. Although antithrombin (AT) and thrombomodulin (TM) combination anticoagulant therapy is frequently used to treat septic patients with DIC in Japan, its effectiveness in improving patient outcomes remains unclear. In this large-scale multicentre retrospective study of adult septic patients with DIC treated at Japanese hospitals between February 2010 and March 2016, we compared in-hospital mortality between AT monotherapy and AT + TM combination therapy. We performed logistic regression analysis with in-hospital mortality as the dependent variable and anticoagulant therapy as the main independent variable of interest. Covariates included patient demographics, disease severity, and body surface area. The AT group and AT + TM group comprised 1,017 patients from 352 hospitals and 1,205 patients from 349 hospitals, respectively. AT + TM combination therapy was not significantly associated with lower mortality when compared with AT monotherapy (odds ratio: 0.97, 95% confidence interval: 0.78-1.21; P = 0.81). AT + TM combination therapy was also not superior to AT monotherapy in reducing mechanical ventilation or hospitalization durations. Despite its widespread use for treating sepsis with DIC, AT + TM combination therapy is not more effective in improving prognoses than the simpler AT monotherapy. Sepsis can lead to disseminated intravascular coagulation (DIC), which is a serious condition characterized by widespread coagulation throughout a patient's bloodstream 1,2. The rapid depletion of blood coagulation factors in these patients increases the risk of potentially fatal haemorrhage. In Japan, this condition was responsible for 10,318 deaths per 100,000 population in 2018, which was comparable to the mortality rates of oesophageal tumours and malignant lymphomas 3. Antithrombin (AT) and thrombomodulin (TM) are frequently administered together as anticoagulant therapy to treat septic patients with DIC in Japan. In a meta-analysis of sepsis-induced DIC, Yatabe et al. reported that AT use is a key factor in DIC resolution 4. A phase III trial conducted between 2000 and 2005 found that TM was not significantly associated with improvements in 28-day mortality when compared with heparin, but that its use significantly improved DIC 5. Similarly, the multinational, multicentre SCARLET randomized clinical trial reported that TM use in patients with sepsis-associated coagulopathy was not significantly associated with reduced mortality 6. In Japan, a multicentre post-marketing survey conducted between 2014 and 2016 showed that approximately half of 510 sepsis-associated DIC patients were treated with AT + TM combination therapy despite the lack of evidence to support its use 7. However, little is known about the effectiveness of AT + TM combination

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Section: Discussionmentioning

confidence: 99%

Effectiveness of combined antithrombin and thrombomodulin therapy on in-hospital mortality in mechanically ventilated septic patients with disseminated intravascular coagulation

Umegaki

Kunisawa

Nishimoto

et al. 2020

Sci Rep

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“…Recently, the efficacy of anticoagulant therapy using rTM has been demonstrated for infection-induced DIC (1-4), with some reports describing the efficacy of combination therapy with rTM and AT (8). In Japan, DIC treatments using AT and/or rTM are common for patients with sepsis-induced DIC.…”

Section: Discussionmentioning

confidence: 99%

“…The efficacy of antithrombin (AT) for DIC has also previously been reported (5,6), and treatment with rTM and AT recently played an important role in anticoagulant therapy for infection-related DIC in Japan (7). More recently, combination therapy with rTM and AT has been shown to be effective for DIC (8).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Combined Thrombomodulin and Antithrombin in Anticoagulant Therapy for Acute Cholangitis-induced Disseminated Intravascular Coagulation

et al. 2019

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Objective The efficacy and safety of concomitant use of antithrombin (AT) with recombinant human soluble thrombomodulin (rTM) for acute cholangitis-induced disseminated intravascular coagulation (AC-induced DIC) remains unclear. This study was conducted to investigate the efficacy of AT combined with rTM as anticoagulant therapy for AC-induced DIC. Methods One hundred patients with AC-induced DIC received anticoagulant therapy using rTM from April 2010 to December 2017. Of the 83 patients treated with rTM immediately after the diagnosis of DIC, excluding those who had not undergone biliary drainage or who had malignancies or a serum AT III level >70%, 56 patients were studied. Outcomes and adverse events (AEs) were retrospectively compared between the 16 patients treated with rTM alone (rTM group) and the 40 patients treated with rTM and AT (rTM+AT group). Results Patients' background characteristics did not differ markedly, except for a significantly higher serum D-dimer level in the rTM group than in the rTM+AT group (p=0.038). The DIC resolution rates on day 9 were 100% and 95.1% in the rTM and rTM+AT groups, respectively (p=0.909). The mean DIC scores were significantly lower in the rTM group than in the rTM+AT group on days 3 (p=0.012), 5 (p<0.001), 7 (p=0.033), and 9 (p=0.007). The incidence of AEs was 6.3% and 10.0% (p=0.941), and the in-hospital mortality rates was 0% and 5.0% (p=0.909) in the rTM and rTM+AT groups, respectively. Conclusion The concomitant use of AT with anticoagulant therapy using rTM for AC-induced DIC may not help improve the treatment outcome.

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“…A large multinational phase III clinical trial was recently completed and the results scheduled for presentation at the end of 2018 (NCT01598831). The co‐administration of recombinant soluble thrombomodulin with antithrombin was associated with reduced mortality among patients with sepsis‐induced DIC without increasing the risk of bleeding (Iba et al , ). However, the use of recombinant soluble thrombomodulin is currently restricted to Japan.…”

Section: Further Considerations For Treatment Of Haemostasis In Sepsismentioning

confidence: 99%

How we manage haemostasis during sepsis

Scully

Levi

2019

Br J Haematol

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Summary Sepsis may be associated with activation of the coagulation system and, in its most severe form, may result in disseminated intravascular coagulation (DIC). Initially, there is thrombosis primarily affecting small and medium sized vessels and contributing to organ dysfunction, but continued activation results in consumption of coagulation factors. This results in prolongation of global coagulation parameters. Often thrombocytopenia is the initial feature in sepsis, which may be followed by prolongation of global coagulation assays, and in severe cases, associated with hypofibrinogenaemia, with overactivation of the fibrinolytic path. The end result is a bleeding phenotype. Scoring systems can be used to help identify patients at risk of DIC and aid in confirming a diagnosis of DIC utilising routine laboratory parameters. Discussion includes medical and blood product support of haemostasis, from thrombotic to bleeding states, in relation to sepsis trigger.

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Effects of combination therapy using antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation

Cited by 24 publications

References 30 publications

Effectiveness of combined antithrombin and thrombomodulin therapy on in-hospital mortality in mechanically ventilated septic patients with disseminated intravascular coagulation

Effectiveness of combined antithrombin and thrombomodulin therapy on in-hospital mortality in mechanically ventilated septic patients with disseminated intravascular coagulation

Efficacy of Combined Thrombomodulin and Antithrombin in Anticoagulant Therapy for Acute Cholangitis-induced Disseminated Intravascular Coagulation

How we manage haemostasis during sepsis

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