Daily Sepsis Research Analysis
Three impactful sepsis studies span mechanistic biology and clinical prognostication. A Blood paper identifies STK10 as a kinase controlling platelet activation and thromboinflammation, improving survival in murine sepsis and showing activation in septic patients. Clinically, antithrombin supplementation responses in sepsis-associated DIC and pediatric platelet count trajectories both refine risk stratification and support individualized care.
Summary
Three impactful sepsis studies span mechanistic biology and clinical prognostication. A Blood paper identifies STK10 as a kinase controlling platelet activation and thromboinflammation, improving survival in murine sepsis and showing activation in septic patients. Clinically, antithrombin supplementation responses in sepsis-associated DIC and pediatric platelet count trajectories both refine risk stratification and support individualized care.
Research Themes
- Platelet-driven thromboinflammation and kinase signaling in sepsis
- Precision dosing and monitoring in sepsis-associated DIC
- Dynamic hematologic trajectories as prognostic tools in pediatric sepsis
Selected Articles
1. STK10 regulates platelet function in arterial thrombosis and thromboinflammation.
This mechanistic study shows that STK10 is a key kinase in platelets, directly phosphorylating ILK (Ser343) to regulate multiple activation endpoints. Platelet STK10 deletion dampened thromboinflammation and improved survival in murine sepsis, with STK10/ILK activation also elevated in septic patients.
Impact: Identifies a previously unrecognized platelet kinase pathway linking to sepsis survival and thromboinflammation, offering a tractable therapeutic target. Integrates phosphoproteomics, protein interaction, enzymology, in vivo models, and patient data.
Clinical Implications: Suggests STK10-ILK signaling as a target to modulate platelet-driven thromboinflammation in sepsis and cardiovascular disease; motivates development of selective STK10 inhibitors or pathway modulators.
Key Findings
- STK10 is expressed in human/mouse platelets; its deletion impairs hemostasis and arterial thrombosis.
- STK10 directly phosphorylates ILK at Ser343; ILK phosphorylation decreases with STK10 deletion.
- Deletion of platelet STK10 reduces aggregation, alpha-granule release, αIIbβ3 activation, procoagulant activity, spreading, and clot retraction.
- STK10 deletion attenuates platelet–neutrophil interactions and NETs, ameliorates thromboinflammation, and improves survival in murine sepsis; STK10/ILK activation increases in sepsis patients.
Methodological Strengths
- Megakaryocyte/platelet-specific knockout mice with in vivo functional outcomes
- Integrated phosphoproteomics, IP–MS, in vitro kinase assays, and human patient corroboration
Limitations
- Preclinical study without pharmacologic STK10 inhibition data or clinical intervention
- Potential off-target or compensatory pathways not fully delineated
Future Directions: Develop selective STK10 inhibitors; evaluate safety/efficacy in thromboinflammatory models; biomarker studies to stratify patients by platelet STK10/ILK activation.
Serine-threonine kinase 10 (STK10) is a member of Ste20 family of serine/threonine kinases and regulates lymphocyte adhesion. Quantitative phosphoproteomic assay showed increased STK10 phosphorylation in activated platelet. However, its role in platelet function remains unclear. In our study, we investigated the expression and role of STK10 in platelet function. We first showed STK10 expression in human and mouse platelets. By establishing megakaryocyte/platelet-specific STK10 knockout mice, we found that deletion of platelet STK10 impaired hemostasis and arterial thrombosis. Consistently, platelet aggregation, a-granule release, aIIbb3 activation, procoagulant activity, spreading and clot retraction were all reduced after deletion of STK10. Quantitative phosphoproteomic assays revealed several dysregulated phosphoproteins, which were enriched in platelet activation and focal adhesion. By using immunoprecipitation coupled to mass spectrometry and protein phosphorylation profiles screening approaches, we identified that STK10 interacts with integrin-linked protein kinase (ILK) and deletion of STK10 significantly reduced ILK phosphorylation (Ser343). Following in vitro phosphorylation assay demonstrated that STK10 directly phosphorylated ILK at Ser343. Additionally, inhibition of calcium, PKC or PI3K inhibited STK10 phosphorylation in activated platelets. Moreover, deletion of platelet STK10 reduced platelet-neutrophil interactions, neutrophil accumulation and neutrophil extracellular traps formation, ameliorated thromboinflammation, as well as increased the survival of sepsis mice. Furthermore, an increase of the activation of platelet STK10 and ILK was observed in sepsis mice and patients. In conclusion, our study identifies a novel regulatory role of STK10 in platelet function, arterial thrombosis and thromboinflammation, implying that it might be a potential target for the treatment of thrombotic or cardiovascular diseases.
2. Factors influencing antithrombin activity following supplementation in sepsis-associated disseminated intravascular coagulation.
In a large post-marketing cohort of sepsis-associated DIC, antithrombin activity rose by a mean 0.99% per IU/kg by day 1, but increases were blunted in patients with SOFA ≥13 or high FDP. A per-unit activity increase ≥1%/IU/kg correlated with improved 28-day survival without increasing bleeding risk, supporting individualized dosing strategies.
Impact: Clarifies determinants of pharmacodynamic response to antithrombin and links response magnitude to survival, informing precision dosing in sepsis-associated DIC.
Clinical Implications: Consider illness severity (SOFA) and fibrinolytic activity (FDP) when targeting antithrombin activity increases; aim for ≥1%/IU/kg rise where feasible; weight-based dosing alone may be insufficient.
Key Findings
- Median antithrombin activity increased from 49% to 74% on day 1; mean change 0.99% per IU/kg.
- SOFA ≥13 and FDP ≥25 μg/mL were associated with smaller activity increases after supplementation.
- Achieving ≥1% per IU/kg activity increase was associated with improved 28-day survival (RR 0.72; p=0.004), with no increase in bleeding risk.
Methodological Strengths
- Large sample size with real-world post-marketing surveillance data (n=1,524)
- Appropriate multivariable modeling and survival analysis (logistic regression, Kaplan–Meier)
Limitations
- Retrospective observational design with potential residual confounding
- Lack of randomized dosing strategies and limited granularity on bleeding definitions
Future Directions: Prospective trials to test individualized antithrombin dosing algorithms targeting activity rise thresholds; pharmacokinetic/pharmacodynamic modeling across severity strata.
BACKGROUND: Antithrombin, a key regulator of the coagulation cascade, is often decreased in patients with sepsis-associated disseminated intravascular coagulation (DIC). Antithrombin is commonly supplemented when activity levels fall to 70% or below in Japan. While there is considerable interindividual variability in antithrombin activity following treatment, the factors contributing to this variability remain unclear. This study aims to identify the determinants of post-treatment antithrombin activity levels and to investigate the potential association between antithrombin activity and bleeding risk. METHODS: We conducted a retrospective analysis using data from the post-marketing surveillance of antithrombin concentrate in patients with sepsis-associated DIC. Changes in antithrombin activity were calculated as: (Day 1 activity - baseline activity [%]) divided by the daily dose (international units [IU] per kilogram of body weight). Logistic regression analysis was employed to identify factors associated with changes in antithrombin activity following supplementation and factors related to bleeding risk. Additionally, Kaplan-Meier survival curves were used to examine the relationship between antithrombin activity and 28-day survival outcomes. RESULTS: A total of 1,524 patients were included in the analysis. The median baseline antithrombin activity was 49%, which increased to 74% on day 1 post-treatment. The mean change in antithrombin activity was 0.99% /IU/kg and followed a normal distribution. The SOFA score ≥ 13 (p = 0.035) and FDP score ≥ 3 (≥ 25μg/mL), part of the JAAM DIC score, (p = 0.016) were significantly associated with lower antithrombin activity increase. Patients achieving ≥ 1% /IU/kg increase showed a higher 28-day survival rate (relative risk: 0.72, p = 0.004). No significant association was found between antithrombin doses or activity changes and bleeding risk. CONCLUSION: A higher SOFA score and FDP level were associated with a smaller increase in post-treatment antithrombin activity. There was no clear association between antithrombin doses and bleeding risk. The present study suggests the necessity of individualized dosing beyond weight-based regimens.
3. Platelet Count Trajectory and Survival in Children With Sepsis: Single-Center Retrospective Study in China, 2015-2023.
Using group-based trajectory modeling in 1,010 pediatric sepsis cases, three 7-day platelet count trajectories were identified with strong associations to 28-day mortality. Persistently higher platelet counts conferred the lowest risk, while low trajectories carried a 12.6% mortality; trajectories correlated with fibrinogen, APTT, and lactate.
Impact: Introduces dynamic platelet trajectories as a robust prognostic tool in pediatric sepsis, moving beyond single time-point counts and enabling earlier risk stratification.
Clinical Implications: Serial platelet trajectories over the first week can inform bedside prognostication and may guide monitoring intensity and adjunctive therapies in high-risk pediatric patients.
Key Findings
- Three distinct 7-day platelet count trajectories were identified among 1,010 children with sepsis.
- Overall 28-day mortality was 5.4%: 12.6% in the low-platelet trajectory, 2.2% in high-normal, and 1.2% in persistently high.
- Adjusted Cox models showed reduced 28-day death hazard for high-normal (HR 0.26; p<0.001) and persistently high (HR 0.18; p=0.021) versus low trajectory.
- Age, fibrinogen, APTT, and lactate levels were associated with trajectory membership.
Methodological Strengths
- Large pediatric cohort with systematic trajectory modeling
- Robust multivariable adjustment (Cox models) for confounding factors
Limitations
- Single-center retrospective design limits generalizability
- Observational nature precludes causal inference; potential residual confounding
Future Directions: Prospective multicenter validation of platelet trajectory-based risk models and intervention trials targeting high-risk trajectory groups.
OBJECTIVES: In children with sepsis, thrombocytopenia is linked to poor outcomes, including longer hospital length of stay, increased bleeding risk, and higher mortality. However, the clinical significance of changes in platelet counts over time remain poorly characterized. We have examined dynamic platelet patterns and their association with mortality and patient-illness factors. DESIGN: Single-center retrospective cohort study. SETTING: Hospital pediatrics and PICU at Guangdong Women and Children Hospital, China. PATIENTS: Children with sepsis between January 2015 and December 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Group-based trajectory analysis was used to examine the trend in platelet count during the first 7 days of hospital admission. A regression model was developed to investigate possible associations between patient characteristics with platelet count trajectory. Additionally, a multivariable Cox proportional hazards model, adjusted for age, sex, comorbidities, and site/source of infection, was constructed to evaluate the association between platelet count trajectories and 28-day mortality. Among 1010 children with sepsis, we identified three platelet count trajectories with distinct characteristics. Age, fibrinogen level, activated partial thromboplastin time, and lactic acid were each associated with platelet count trajectories. The overall 28-day mortality for the cohort was 5.4%, varying across groups: 1.2% in group 3 with persistently high platelet count; 2.2% in group 2 with high-normal platelet count; and 12.6% in group 1 with low platelet count. In the multivariable Cox proportional hazards model, compared with group 1, both groups 2 and 3 were independently associated with reduced hazard of death at 28 days (hazard ratio, 0.26; p < 0.001 for group 2 and hazard ratio, 0.18; p = 0.021 for group 3). CONCLUSIONS: We have identified three distinct and clinically relevant platelet count trajectories in children with sepsis, which serve as robust associations with survival in this patient population.