Coagulation Phenotypes in Sepsis and Effects of Recombinant Human Thrombomodulin: An Analysis of Three Multicenter Observational Studies
Background: A recent randomized trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction, suggesting that the effects of thrombomodulin are heterogeneous across sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and 28-day and in-hospital mortality for each phenotype.
Methods: This was a secondary analysis of multicenter registries containing data on adult patients (aged ≥16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicenter registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalized ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in derived clusters using a generalized estimating equation.
Results: Four sepsis phenotypes were derived from 3,694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: −17.8% [95% CI −28.7% to −6.9%]) and in-hospital (adjusted RD: −17.7% [95% CI −27.6 to −7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: −24.9% [95%CI −49.1% to −0.7%]) and in-hospital mortality (RD: −30.9% [95%CI −55.3 to −6.6%]).
Conclusions: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.
Figure 1
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Posted 11 Jan, 2021
On 21 Jan, 2021
On 21 Jan, 2021
Received 20 Jan, 2021
On 13 Jan, 2021
Invitations sent on 07 Jan, 2021
On 07 Jan, 2021
On 05 Jan, 2021
On 05 Jan, 2021
On 05 Jan, 2021
On 03 Jan, 2021
Coagulation Phenotypes in Sepsis and Effects of Recombinant Human Thrombomodulin: An Analysis of Three Multicenter Observational Studies
Posted 11 Jan, 2021
On 21 Jan, 2021
On 21 Jan, 2021
Received 20 Jan, 2021
On 13 Jan, 2021
Invitations sent on 07 Jan, 2021
On 07 Jan, 2021
On 05 Jan, 2021
On 05 Jan, 2021
On 05 Jan, 2021
On 03 Jan, 2021
Background: A recent randomized trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction, suggesting that the effects of thrombomodulin are heterogeneous across sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and 28-day and in-hospital mortality for each phenotype.
Methods: This was a secondary analysis of multicenter registries containing data on adult patients (aged ≥16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicenter registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalized ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in derived clusters using a generalized estimating equation.
Results: Four sepsis phenotypes were derived from 3,694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference [RD]: −17.8% [95% CI −28.7% to −6.9%]) and in-hospital (adjusted RD: −17.7% [95% CI −27.6 to −7.8%]) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: −24.9% [95%CI −49.1% to −0.7%]) and in-hospital mortality (RD: −30.9% [95%CI −55.3 to −6.6%]).
Conclusions: We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.
Figure 1