Age-related differences in the survival benefit of the administration of antithrombin, recombinant human thrombomodulin, or their combination in sepsis

Wada, Takeshi; Kabata, Daijiro; Abe, Toshikazu; Ogura, Hiroshi; Shiraishi, Atsushi; Saitoh, Daizoh; Kushimoto, Shigeki; Fujishima, Seitaro; Mayumi, Toshihiko; Hifumi, Toru; Shiino, Yasukazu; Nakada, Taka‐aki; Tarui, Takehiko; Otomo, Yasuhiro; Okamoto, Kohji; Umemura, Yutaka; Kotani, Joji; Sakamoto, Yuichiro; Sasaki, Junichi; Shiraishi, Shin‐ichiro; Takuma, Kiyotsugu; Tsuruta, Ryosuke; Hagiwara, Akiyoshi; Masuno, Tomohiko; Takeyama, Naoshi; Yamashita, Norio; Ikeda, Hiroto; Ueyama, Masashi; Fujimi, Satoshi; Gando, Satoshi

doi:10.1038/s41598-022-13346-3

Cited by 7 publications

(8 citation statements)

References 44 publications

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“…However, these results do not indicate that antithrombin administration in trauma patients has no therapeutic efficacy. The importance of correctly identifying an optimal patient population with sepsis that can benefit from anticoagulant therapy has been repeatedly reported (40)(41)(42)(43); consequently, we suggest that for trauma patients it is necessary to clarify the type of bleeding (simple type hemorrhage or oozing type hemorrhage), the type of coagulation changes (DIC or not), and when antithrombin should be administered (acute phase or sub-acute phase) to effectively identify target patients that can benefit from antithrombin administration. The results of this study provide important evidence that forms the basis for undertaking randomized controlled trials to test the efficacy of antithrombin correction in trauma-induced DIC.…”

Section: Discussionmentioning

confidence: 97%

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

et al. 2022

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IntroductionTrauma activates the innate immune system to modulate hemostasis and minimize the damage caused by physiological bodily responses, including the activation of coagulation. Sufficiently severe trauma overwhelms physiological responses and elicits the systemic inflammatory response syndrome, which leads to the onset of disseminated intravascular coagulation (DIC), characterized by dysregulated inflammatory coagulofibrinolytic responses. Impaired anticoagulant mechanisms, including antithrombin, constitutes the pathology of DIC, while the dynamics of antithrombin and relevance to outcomes in trauma-induced coagulopathy have not been fully elucidated. This study investigated the associations of antithrombin activity with DIC onset and outcomes in severely injured patients.MethodsThis retrospective sub-analysis of a multicenter, prospective study included patients with an injury severity score ≥16. We characterized trauma patients with low antithrombin activity (antithrombin <80% on hospital arrival, n = 75) in comparison with those who had normal antithrombin activity (antithrombin ≥80%, n = 200). Global markers of coagulation and fibrinolysis, molecular biomarkers for thrombin generation (soluble fibrin [SF]), and markers of anticoagulation (antithrombin) were evaluated to confirm the associations of antithrombin with DIC development and outcomes, including in-hospital mortality and the multiple organ dysfunction syndrome (MODS).ResultsPatients with low antithrombin activity had higher prevalence of shock, transfusion requirements, and in-hospital mortality. Higher DIC scores and more severe organ dysfunction were observed in the low AT group compared to that in the normal AT group. Antithrombin activity on arrival at the hospital was an independent predictor of the development of DIC in trauma patients, and levels of SF increased with lower antithrombin values (antithrombin activity > 85%). Antithrombin activity at 3 h showed good predictive performance for in-hospital mortality, and a multivariable Cox proportional-hazard regression model with a cross-product term between the antithrombin and DIC showed that the in-hospital mortality in patients with DIC increased with decreased antithrombin activity. A multivariable logistic regression model showed that the odds for the development of MODS in patients with DIC increased with lower antithrombin values.ConclusionDecreased antithrombin activity in trauma-induced coagulopathy is associated with poor outcomes through worsening of DIC.

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Section: Discussionmentioning

confidence: 97%

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

et al. 2022

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“…In addition, this study was unable to evaluate the duration and dosage of anticoagulant agents. Third, the efficacy of anticoagulant therapy might not have been evaluated correctly because we did not exclude patients with prescribed anticoagulants as with our previous studies [ 8 , 37 , 39 ]. However, sensitivity analysis of a cohort of patients with a PT-INR value ≤ 2.2 to exclude the effect of patients with an extremely high PT-INR (possibly due to the prescribed anticoagulants) confirmed the robustness of the results regarding the interaction between anticoagulant therapy and in-hospital mortality.…”

Section: Discussionmentioning

confidence: 99%

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study

Wada

Kabata²,

Abe³

et al. 2023

j intensive care

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Background The development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of “high disease severity” in addition to “sepsis with DIC” has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize “severe” sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy. Methods This retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination. Results In total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy. Conclusions The combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis. Trial registration: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

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“…In addition, this study was unable to evaluate the duration and dosage of anticoagulant agents. Third, the e cacy of anticoagulant therapy might not have been evaluated correctly because we did not exclude patients with prescribed anticoagulants as with our previous study [8,15,43]. However, sensitivity analysis of a cohort of patients with a PT-INR value ≤ 2.2 to exclude the effect of patients with an extremely high PT-INR (possibly due to the prescribed anticoagulants), con rmed the robustness of the results regarding the interaction between anticoagulant therapy and in-hospital mortality.…”

Section: Discussionmentioning

confidence: 99%

Identification of Patient Population Benefiting from Anticoagulant Therapy for Sepsis-Related Coagulopathy Based on the Disseminated Intravascular Coagulation Diagnostic Criteria: A Retrospective Database Study

Wada

Kabata²,

Abe

et al. 2022

SSRN Journal

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Age-related differences in the survival benefit of the administration of antithrombin, recombinant human thrombomodulin, or their combination in sepsis

Cited by 7 publications

References 44 publications

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

Association of antithrombin with development of trauma-induced disseminated intravascular coagulation and outcomes

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study

Identification of Patient Population Benefiting from Anticoagulant Therapy for Sepsis-Related Coagulopathy Based on the Disseminated Intravascular Coagulation Diagnostic Criteria: A Retrospective Database Study

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