Endothelial Permeability and Hemostasis in Septic Shock
Open accessAbstract
Background We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality. Methods This was a prospective study of biomarkers of endothelial cell permeability (vascular endothelial growth factor [VEGF], soluble fms-like tyrosine kinase 1 [sFLT-1], angiopoietin 2 [Ang-2]) and biomarkers of hemostasis (von Willebrand factor [vWF], thrombomodulin [TM], tissue plasminogen activator [tPA] in 605 of the 1,341 ProCESS participants in a derivation cohort and 305 participants in a validation cohort. Analyses assessed (1) the impact of varying resuscitation strategies on biomarker profiles and (2) the association of endothelial biomarkers with 60-day in-hospital mortality. The study was conducted in 31 US EDs in adult patients with septic shock. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, at 6 h, and at 24 h. Results There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts, respectively. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang-2 and sFLT-1) and hemostasis (vWF, TM, tPA) biomarkers were higher and VEGF levels were lower in nonsurvivors (P < .05 for all). At baseline, sFLT-1 had the highest point estimate for mortality discrimination (derivation area under the curve [AUC], 0.74; validation, 0.70), similar to lactate (AUC, 0.74) and Sequential Organ Failure Assessment score (AUC, 0.73). In an analysis including all time points and adjusted for age, presence of cancer, and Charlson comorbidity score, the adjusted AUC for sFLT-1 was 0.80. Conclusions We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did find that elevated levels of endothelial cell biomarkers of permeability and hemostasis were associated with increased mortality. Trial registry ClinicalTrials.gov; No.: NCT00510835 and NCT00793442; URL: www.clinicaltrials.gov.
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Inflammation increases capillary permeability.
“Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin.”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [35]
The introductory passage (section labelled “CONCLUSIONS:”; page unavailable) identifies inflammation and vascular permeability as features of sepsis and links endothelial markers to permeability. It does not establish that inflammation itself increases capillary permeability, so the causal claim is stronger than the passage supports. (LLM, conf=0.76)
Experimental — accuracy not yet measuredIn infection mild to severe, serum albumin concentration decreases, vascular permeability increases, absolute synthesis increases, half-life decreases, total mass decreases, distribution volume increases, and VEGF increases.
“Infection mild to severe | ↓ to ↓↓↓ | ↑ to ↑↑↑ | ↑ to ↑↑↑ | ↓ to ↓↓↓ | ↓ to ↓↓↓ | ↑ to ↑↑↑a | ↑35 | Inflammatory course unpredictable due to bacterial interference”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [35]
The introductory passage (section labeled CONCLUSIONS; page unavailable) links endothelial permeability and VEGF to sepsis, supporting only the claim’s broad vascular component. The paper does not report the claimed changes in albumin concentration, synthesis, half-life, mass, or distribution volume across mild-to-severe infection. Its Discussion reports discordant VEGF findings, and its own study associates lower VEGF with higher mortality, so it does not establish a general VEGF increase. (LLM, conf=0.85)
Experimental — accuracy not yet measuredVEGF expression and increased vascular permeability occur in infection, trauma, during fetal and postnatal growth, preparing for lactation, cancer, protein-losing enteropathy, and nephrotic syndrome.
“VEGF expression and increased vascular permeability occur in infection,14, 35 trauma,15, 16, 36 during fetal and postnatal growth,29, 37, 38, 39 preparing for lactation,39, 40 cancer,41, 42 protein‐losing enteropathy,43 and nephrotic syndrome44, 45 (Table 1).”
From Hypoalbuminemia: Pathogenesis and Clinical Significance (2019) · cites this paper as [35]
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- Authors
- Hou, P. C., Filbin, M. R., Wang, H., Ngo, L., Huang, D. T., Aird, W. C., Yealy, D. M., Angus, D. C., Kellum, J. A., & Shapiro, N. I.
- Affiliations
- Brigham and Women's Hospital (US)
- Massachusetts General Hospital (US)
- University of Alabama at Birmingham (US)
- University of Pittsburgh (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Shapiro, Nathan I.
- ORCID
- Venue
- Chest
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 152
- Issue
- 1
- Pages
- 22-31
- ISSN
- 0012-3692 (ISSN-L)
- PMC
- PMC5577354
- OpenAlex
- W2575911653
- Cited by
- 97
- References
- 32
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 8 · 2022: 11 · 2021: 20 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 2
- FWCI
- 7.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- CHEST Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM076659)
- National Institute on Aging (L30 AG022931)
- National Heart, Lung, and Blood Institute (R01HL091757, RO1 HL091757)
- National Institute of General Medical Sciences (P50GM076659, HL091757, GM076659)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- septic shock, endothelial permeability, hemostasis, soluble fms-like tyrosine kinase-1, angiopoietin-2, vascular endothelial growth factor, von Willebrand factor, thrombomodulin, tissue plasminogen activator, mortality prediction, ProCESS trial, sepsis biomarkers, lactate, SOFA score, emergency department
- MeSH terms
- Aged, Female, Hemostasis, Humans, Male, Middle Aged, Permeability, Tissue Plasminogen Activator, Resuscitation, Shock, Septic, Statistics as Topic, von Willebrand Factor, Biomarkers, Hospital Mortality, Thrombomodulin, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor A, Angiopoietin-2, Endothelial Cells
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