Characterising the Loss of Haemostasis in Haemorrhagic Fever With Renal Syndrome

Обзор

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.

Подробное описание

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.

Вмешательства

• Процедура Blood draw for thromboelastography - admission
  Two blood samples will be collected at admission for thromboelastography using the TEG 6s platform (Haemonetics®). One sample will be collected in a citrated blood tube for global haemostasis assessment, and one sample will be collected in a heparinised tube for platelet function analysis.
• Процедура Blood draw for thromboelastography - follow-up
  Two blood samples will be collected 3 - 7 days after initial thromboelastography for follow-up analysis using the TEG 6s platform (Haemonetics®). One sample will be collected in a citrated blood tube for global haemostasis assessment, and one sample will be collected in a heparinised tube for platelet function analysis.
• Процедура Blood draw for transcriptomic analysis
  One blood sample will be collected at admission for transcriptomic analysis. Blood sample will be collected into a PAXgene® RNA tube and analysed using nanopore sequencing to characterise the viral and host transcriptome.
• Другое Data collection - clinical/demographic/epidemiological data
  Routine clinical/demographic/epidemiological data will be collected at admission and throughout hospitalisation. This will relate to clinical presentation (day of illness at presentation, presenting symptoms); demographics and epidemiology (age, gender, site of infection); clinical course during hospitalisation (maximum level of care, dialysis use, blood product use, survival outcome).
• Другое Data collection - routine laboratory parameters
  Data on routine laboratory parameters will be collected throughout hospitalisation. These will relate to laboratory clotting parameters (platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer); liver function tests (aspartate aminotransferase, alanine aminotransferase); laboratory haematology parameters (haemoglobin, white cell count, blood film); laboratory biochemistry parameters (urea, creatinine); viral load.
• Другое Severity score calculation
  A severity score will be assigned to each patient based on clinical and laboratory data at admission according to a pre-defined scoring system.

Первичные конечные точки

• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]
• 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. [Срок оценки: Baseline and 3-7 days later]

Вторичные конечные точки (12)

• Change in platelet count over the course of illness, assessing thrombocytopenia and its role in haemostatic dysfunction in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in prothrombin time (PT) over the course of illness, evaluating coagulation factor activity and clotting dysfunction in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in activated partial thromboplastin time (APTT) over the course of illness, assessing abnormalities in the intrinsic clotting pathway in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in fibrinogen levels over the course of illness, investigating fibrinogen consumption and clot formation abnormalities in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in D-dimer levels over the course of illness, evaluating fibrinolysis and its association with haemorrhagic complications in HFRS [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in aspartate aminotransferase (AST) over the course of illness, assessing liver involvement and potential contributions to haemostatic dysfunction in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in alanine aminotransferase (ALT) over the course of illness, evaluating liver injury and its association with disease severity in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in haemoglobin levels over the course of illness, assessing anaemia and its potential link to bleeding severity in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in white cell count (WCC) over the course of illness, evaluating immune response and its association with disease severity in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in blood film findings over the course of illness, identifying morphological changes in blood cells associated with HFRS severity. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in creatinine levels over the course of illness, evaluating renal impairment and disease progression in HFRS. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]
• Change in urea levels over the course of illness, assessing kidney dysfunction and its relationship to HFRS severity. [Срок оценки: Baseline (day 1) and daily thereafter through hospitalisation, up to 21 days]

Критерии участия

Критерии включения

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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

• 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. PMID 37952580

Идентификаторы

NCT: NCT06944275 · 25-011

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗