# The role of soluble thrombomodulin (sTM) in risk stratification of hemorrhagic fever with renal syndrome and prognostic assessment

## TL;DR

This study shows that soluble thrombomodulin (sTM) can predict disease severity and survival in patients with hemorrhagic fever with renal syndrome (HFRS), offering a new biomarker for early risk assessment.

## Contribution

The study demonstrates that sTM is a novel and effective biomarker for risk stratification and prognosis in HFRS patients.

## Key findings

- sTM levels increase stepwise with HFRS severity, peaking in critical cases.
- sTM levels in non-survivors were twice as high as in survivors.
- A cut-off sTM value of 49.98 TU/mL predicted mortality with 81.36% sensitivity and 100% specificity.

## Abstract

The increase in vascular permeability and bleeding caused by systemic endothelial damage is the most basic pathological change of hemorrhagic fever with renal syndrome(HFRS) caused by Hantavirus, but there is a lack of early biomarkers to detect the severity and prognosis of HFRS. Soluble thrombomodulin (sTM) is a sensitive marker of endothelial damage. In this study we investigated the role of sTM in the evaluation of the severity and prognosis of HFRS patients.

A retrospective analysis was conducted on 51 patients with HFRS treated in the Infectious Diseases Department of the Second Affiliated Hospital of Air Force Medical University from January 2023 to January 2024. We compared the changes of sTM among patients with HFRS in different phases and subtypes, and analyzed the correlation between sTM and related laboratory diagnostic indicators. Additionally, we evaluated the differences of sTM and related laboratory diagnostic indicators between survivors and non-survivors, and assessed the predictive ability of sTM for the mortality risk of HFRS patients based on the ROC curve, and determined the cut-off value of sTM.

In the HFRS phases, sTM increased during the febrile phase, reached its peak during the hypotensive phase, and decreased during the oliguria-dipuria phase. In the HFRS subtypes, there was no difference between the mild and moderate subtypes (P > 0.05), while in the moderate, severe, and critical subtypes, it showed a “stepwise” increase (P < 0.05), with the greatest jump being from “severe” to “critical” (P < 0.0001). Linear regression analysis revealed a strong positive correlation between sTM and SOFA scores (R² = 0.6076, P < 0.0001). The level of sTM in the non-survivor group (62.25 (54.60, 81.98) TU/mL) was significantly higher than that in the survivor group (28.10 (21.40, 44.15) TU/mL). The ROC curve indicated that the AUC of sTM was 0.9317, which had a high predictive value for the mortality risk of HFRS patients and was second only to SOFA (0.9309), and the combined AUC could reach 0.9492. When the cut-off of sTM was 49.98 TU/mL, the sensitivity and specificity were 81.36% and 100%. In addition, the Kaplan-Meiers survival analysis showed that when sTM ≥ 49.8 TU/mL, the 28-day mortality rate of HFRS patients was higher (P < 0.01).

sTM serves as a valuable biomarker for risk stratification and prognosis evaluation in HFRS.

Hantavirus is the causative agent of hemorrhagic fever with renal syndrome (HFRS), a disease characterized by the increased permeability and bleeding of tiny blood vessels. Early detection of this vascular damage is challenging, yet it plays a decisive role in determining which patients will progress to a critical condition. We investigated whether a natural blood protein, sTM- a biomarker that endothelial cells release as a silent alarm upon injury-could serve as an early warning indicator for HFRS. In a study involving 51 HFRS patients, we observed that sTM levels increase in a stepwise manner in accordance with the severity of the disease. Specifically, the more severe the symptoms, such as shock and kidney failure, the higher the sTM levels. Notably, sTM levels in patients who ultimately succumbed to the disease were twice as high as those in survivors. A simple blood test measuring sTM upon patient admission was able to identify severe cases with 91% accuracy. A normalized sTM value above 49.80 was the most predictive of a poor prognosis. Given that sTM is a stable biomarker and can be easily quantified using routine hospital analyzers, it has the potential to be immediately implemented for the triage of HFRS patients.