Clinical trial NCT06944275: Characterising the Loss of Haemostasis in Haemorrhagic Fever With Renal Syndrome
Official title: Characterising the Loss of Haemostasis in Haemorrhagic Fever With Renal Syndrome
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Haemorrhagic Fever With Renal Syndrome
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Institute of microbiology and immunology, Slovenia
First posted: 2025-04-25
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients will be recruited from the University Medical Centre Ljubljana. Suspected cases of HFRS will be identified based on a clinical case definition of presence of fever and one of the following: acute kidney injury (AKI), thrombocytopenia, bleeding, or epidemiological risk. Cases will be confirmed for inclusion in the study following laboratory confirmation of hantavirus infection using serological methods for antibody detection or reverse transcription polymerase chain reaction (RT-PCR) to detect hantavirus genetic material in the blood.

Brief summary: Hantaviruses are globally distributed viruses that cause haemorrhagic fever with renal syndrome (HFRS) in Europe, a disease characterised by acute kidney failure and, in some cases, significant bleeding complications. The mechanisms underlying clotting abnormalities in HFRS remain poorly understood. This study aims to investigate the pathological mechanisms of clotting dysfunction in hospitalised HFRS patients, assess the impact of different hantavirus types on disease severity, and evaluate the accuracy of a severity scoring system developed in China for predicting mortality in European patients.

Hospitalised patients with laboratory-confirmed HFRS will be prospectively recruited from University Medical Centre Ljubljana, Slovenia. Blood samples will be analysed for routine laboratory markers, thromboelastography (TEG) will assess real-time clotting function, and transcriptomic analysis will identify hantavirus strains and gene expression patterns linked to disease severity. Patients will be stratified into haemorrhagic and non-haemorrhagic groups, with statistical analyses comparing clinical and laboratory parameters to identify predictors of bleeding risk. Findings from this study may contribute to improved risk stratification and potential therapeutic targets for HFRS.

Detailed description: Hantaviruses are globally distributed viruses that are transmitted to humans through the inhalation of viral particles found in the urine and faeces of infected rodents. In Europe, hantaviruses cause haemorrhagic fever with renal syndrome (HFRS), a disease characterised by acute kidney failure and, in some cases, significant bleeding complications. Despite advances in understanding HFRS, the mechanisms underlying these bleeding abnormalities remain poorly understood. Several hypotheses suggest that hantaviruses may interfere with the function of blood clotting factors, but definitive evidence is lacking.

Slovenia, a country in southern Europe, has one of the highest incidences of HFRS relative to its population, with recent years seeing large outbreaks. Discussions with leading hantavirus experts in Slovenia have highlighted the urgent need for further research, particularly to understand why some patients with HFRS develop severe bleeding complications. Currently, no licensed treatments exist for HFRS, raising concerns about future outbreaks, which are expected to become more frequent due to climate change. By investigating the mechanisms leading to clotting dysfunction, this study aims to identify potential targets for future therapeutic interventions.

This study will explore the pathological mechanisms driving clotting abnormalities and bleeding in hospitalised patients with HFRS. Additionally, it will assess whether different hantavirus types influence disease severity and haemorrhagic complications and evaluate the applicability of a severity scoring system-originally developed for HFRS cases in China-in predicting outcomes among Slovenian patients.

Patients with laboratory-confirmed HFRS will be prospectively recruited from University Medical Centre Ljubljana, Slovenia. Blood samples will be collected at multiple time points during their illness and tested for standard laboratory markers, including clotting factors, blood cell counts, kidney function, and liver function. Additionally, thromboelastography (TEG) will be performed to assess real-time clotting dynamics, providing a more detailed evaluation of clotting abnormalities.

An additional blood sample will undergo transcriptomic analysis using nanopore sequencing. This will identify the specific hantavirus strain in each patient and analyse gene expression patterns associated with disease severity and bleeding risk. Patients will also be assigned a severity score based on their clinical presentation, laboratory results, and symptoms, using a scoring system developed in China to predict HFRS-related mortality. This study will evaluate the reliability of this scoring system in a European cohort.

To better understand the factors contributing to bleeding in HFRS, patients will be categorised into two groups: those with haemorrhagic manifestations and those without. Statistical analyses will compare laboratory and clinical findings between these groups, aiming to identify key predictors of bleeding complications. The findings from this research may help inform future therapeutic strategies for HFRS.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18 or older, including pregnant women
* Laboratory-confirmed HFRS (serology and/or RT-PCR)
* Willing and able to provide informed consent

Exclusion Criteria:

* Patients under 18 years of age
* Co-infections with other pathogens
* Pre-existing coagulation disorders
* Use of anticoagulant medication
* Inability or refusal to provide consent

Primary outcomes:
measure: Change in Reaction Time (R) on thromboelastography from admission to follow-up (3-7 days), assessing clot initiation and its association with haemostatic dysfunction in HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in K-Time (K) on thromboelastography from admission to follow-up (3-7 days), evaluating clot kinetics and fibrin polymerisation in relation to haemostatic abnormalities in HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in Alpha Angle (α-Angle) on thromboelastography from admission to follow-up (3-7 days), reflecting fibrin build-up and clot formation rate in patients with HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in Maximum Amplitude (MA) on thromboelastography from admission to follow-up (3-7 days), assessing overall clot strength and platelet contribution to clot stability in HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in Lysis 30 (LY30) on thromboelastography from admission to follow-up (3-7 days), measuring fibrinolysis and clot breakdown in relation to bleeding risk in HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in Percentage Inhibition (% Inhibition) on thromboelastography from admission to follow-up (3-7 days), evaluating the effect of antithrombotic pathways on clot formation in HFRS.
timeFrame: Baseline and 3-7 days later
measure: Change in Percentage Aggregation (% Aggregation) on thromboelastography from admission to follow-up (3-7 days), assessing platelet function and its role in haemostatic dysfunction in HFRS.
timeFrame: Baseline and 3-7 days later
Secondary outcomes:
measure: Change in platelet count over the course of illness, assessing thrombocytopenia and its role in haemostatic dysfunction in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in prothrombin time (PT) over the course of illness, evaluating coagulation factor activity and clotting dysfunction in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in activated partial thromboplastin time (APTT) over the course of illness, assessing abnormalities in the intrinsic clotting pathway in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in fibrinogen levels over the course of illness, investigating fibrinogen consumption and clot formation abnormalities in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in D-dimer levels over the course of illness, evaluating fibrinolysis and its association with haemorrhagic complications in HFRS
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in aspartate aminotransferase (AST) over the course of illness, assessing liver involvement and potential contributions to haemostatic dysfunction in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in alanine aminotransferase (ALT) over the course of illness, evaluating liver injury and its association with disease severity in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in haemoglobin levels over the course of illness, assessing anaemia and its potential link to bleeding severity in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in white cell count (WCC) over the course of illness, evaluating immune response and its association with disease severity in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in blood film findings over the course of illness, identifying morphological changes in blood cells associated with HFRS severity.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in creatinine levels over the course of illness, evaluating renal impairment and disease progression in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Change in urea levels over the course of illness, assessing kidney dysfunction and its relationship to HFRS severity.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Day of illness at hospital presentation, assessing timing of medical intervention in relation to disease progression.
timeFrame: Baseline (at admission)
measure: Frequency of symptoms at presentation and throughout hospitalisation, characterising the clinical course and severity of HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Maximum level of clinical care required during hospitalisation, assessing disease severity and need for intensive care in HFRS patients.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Survival outcome, evaluating overall mortality and predictors of fatal HFRS cases.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Frequency of blood product use during hospitalisation, assessing transfusion requirements as a marker of haemorrhagic severity in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Frequency of acute renal replacement therapy use during hospitalisation, evaluating the need for dialysis as an indicator of severe renal dysfunction in HFRS.
timeFrame: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days
measure: Viral RNA genomic analysis and its association with disease severity and haemostatic dysfunction
timeFrame: Baseline (at admission)
measure: Host RNA genomic analysis and its association with disease severity and haemostatic dysfunction
timeFrame: Baseline (at admission)
measure: Validation of a severity score for predicting risk of death from HFRS in European patients
timeFrame: Baseline (at admission)
Other outcomes:
Locations:
Study officials:
References:
citation: Hu H, Zhan J, Chen W, Yang Y, Jiang H, Zheng X, Li J, Hu F, Yu D, Li J, Yang X, Zhang Y, Wang X, Bi Z, Liang Y, Shen H, Du H, Lian J. Development and validation of a novel death risk stratification scale in patients with hemorrhagic fever with renal syndrome: a 14-year ambispective cohort study. Clin Microbiol Infect. 2024 Mar;30(3):387-394. doi: 10.1016/j.cmi.2023.11.003. Epub 2023 Nov 11.