Fibrinolysis Resistance in Infection and Trauma

Recruiting

• Conditions: Sepsis and Septic Shock; Trauma

• Registration Number: NCT06680180
• Lead Sponsor: Anders Aneman

Brief Summary

Blood coagulation disorders are often seen in critically ill patients e.g. with severe infection or following extensive injury, that can lead to life threatening events as a result of excessive blood clot formation leading to organ failure. This study aims to use Viscoelastic Testing (VET) technology to detect patients at risk of excessive blood blot formation at the bedside, test new blood coagulation drugs, and guide life-saving use of blood modifying treatments.

Detailed Description

In healthy individuals blood coagulates (clots) to minimise blood loss then, as part of the process of wound repair, blood clots are broken down in a process called fibrinolysis which involves two key proteins: tissue plasminogen activator (tPA) and plasminogen. In severe infection (sepsis) or following extensive injury (trauma), fibrinolysis abnormalities commonly develop, which include reduced fibrinolysis activity (fibrinolysis resistance) resulting in extensive clot formation and frequently leading to organ failure and death. Currently, the cause of fibrinolysis resistance in sepsis and trauma are unknown and clinical trials to address coagulopathies in sepsis have failed, likely due to inadequate disease phenotyping.

The viscoelastic testing (VET) technology ClotPro® has been used to identify fibrinolysis resistance in 55% of critically ill patients (COVID and non-COVID with acute respiratory failure) and through novel adaptation of the technology, determined that this is likely driven by reduced tPA and/or plasminogen activity. Furthermore, it has been used to detect in real time the impact of a 24 hr tPA infusion on fibrinolysis in a patient. Thus, this preliminary work has demonstrated the feasibility of a personalised treatment approach to fibrinolysis resistance management that can guide life-saving use of fibrinolysis enhancers to overcome resistance in an individualised basis that is likely to increase therapeutic efficacy and safety.

This project aims to scientifically validate the aforementioned preliminary work, increase our knowledge on the mechanisms of reduced fibrinolysis enzyme activity in severe infection and injury, discover potential treatment options, and progress these findings towards translation. The results of this project will drive future clinical trials of repurposed or novel therapies guided by VET to deliver a personalised dose to critically ill patients who demonstrate fibrinolysis resistance, which in conjunction with rapid detection, is anticipated to significantly improve patient outcomes.

Study Timeline

• Study Start: 2024-06-01
• Study First Submitted: 2024-10-09
• Status Verified: 2024-11
• Study First Submitted QC: 2024-11-06
• Last Update Submitted: 2024-11-06
• Study First Posted: 2024-11-08
• Last Update Posted: 2024-11-08
• Primary Completion: 2025-12-31
• Study Completion: 2026-06-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

• Admission to ICU, needing at least one organ supportand principally for the management of clinically suspected Sepsis or Septic shock according to Spesis-3 criteria (including SARS-COV-2)
• Expected to remain in ICU and survive beyond the day after tomorrow

Sepsis

Exclusion Criteria

• On oral anticoagulant/antiplatelet therapy
• Not for full, active ICU support
• Death is deemed inevitable within 24 hrs

Trauma Inclusion Criteria:

• Trauma is the principal diagnosis on ICU admission
• Expected to remain in ICU and survive beyond the day after tomorrow
• Receiving respiratory support at the time of ICU admission - high-flow nasal prongs, non-invasive or invasive ventilation
• Already received, or considered at risk of needing a blood product transfusion within 24 hrs of injury

Trauma Exclusion Criteria:

• Nursing home resident
• Unsurvivable head injury
• Not for full, active ICU support
• Death is deemed inevitable within 24 hrs

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
VET testing and analysis	From admission to ICU and at 24 hours, 48 hours, 5 days, 7 days, 10 days, and 15 days post ICU admission	VET testing in whole blood will determine the kinetics and contribution of: i) both plasma and platelets to clot formation following the addition of tissue factor.; ii) plasma clot formation only by adding tissue factor and platelet inhibitors. iii) tPA-induced fibrinolysis by adding tissue factor and tPA.; The following test parameters will be used for analytical purposes: clotting time, clot amplitude at 10 min, maximum clot firmness, lysis time, maximum lysis. The platelet contribution to the clot will be calculated by subtracting (ii) from (i). An additional blood sample will be collected at the time of VET analysis for processing and storage for subsequent fibrinolysis protein analysis.
Laboratory evaluation of fibrinolytic profile	From admission to ICU and at 24 hours, 48 hours, 5 days, 7 days, 10 days, and 15 days post ICU admission	We will evaluate the temporal changes in key fibrinolytic markers (i.e. plasminogen, antiplasmin, PAI-1 activity) and also changes in overall fibrinolytic capacity of patient plasma (i.e. how responsive plasma is to generate plasmin ex vivo) in relation to the VET testing.; Commercial ELISAs will be used to determine plasminogen, alpha2 antiplasmin levels, PAI-1 and tPA activity; A novel tPA inducible plasmin-antiplasmin test will be used to evaluate plasmin generation; amidolytic assay will be used to determine plasmin activity.

Trial Locations

Locations (4)

The Canberra hospital (ICU); 🇦🇺 Canberra, Australian Capital Territory, Australia

Liverpool Hospital (ICU); 🇦🇺 Liverpool, New South Wales, Australia

Macquarie University Hospital (ICU); 🇦🇺 Macquarie, New South Wales, Australia

Royal North Shore Hospital (ICU); 🇦🇺 St Leonards, New South Wales, Australia