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Coagulation Phenotypes in Sepsis and Effects of Recombinant Human Thrombomodulin: An Analysis of Three Multicenter Observational Studies
Daisuke Kudo
Tohoku University Graduate School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8213-5176
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Keywords
anticoagulants, disseminated intravascular coagulation, machine learning, phenotype, precision medicine, thrombomodulin
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Reviewer #4 agreed
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Reviewer #2 agreed
On 13 Jan, 2021
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Invitations sent on 07 Jan, 2021
Reviewer #1 agreed
On 07 Jan, 2021
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On 05 Jan, 2021
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This preprint is under consideration at Critical Care. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Coagulation Phenotypes in Sepsis and Effects of Recombinant Human Thrombomodulin: An Analysis of Three Multicenter Observational Studies
Daisuke Kudo
Tohoku University Graduate School of Medicine
Corresponding Author
ORCiD: https://orcid.org/0000-0001-8213-5176
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 11 Jan, 2021
No community comments so far
Reviewer #4 agreed
On 21 Jan, 2021
Reviewer #3 agreed
On 21 Jan, 2021
Review #1 received
Received 20 Jan, 2021
Reviewer #2 agreed
On 13 Jan, 2021
Reviewers invited
Invitations sent on 07 Jan, 2021
Reviewer #1 agreed
On 07 Jan, 2021
Editor assigned
On 05 Jan, 2021
Editor invited
On 05 Jan, 2021
Submission checks complete
On 05 Jan, 2021
First submitted
On 03 Jan, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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