Fibrinolysis Resistance in Infection and Trauma (FORTITUDE)

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.

Study Overview

• Status: Recruiting
• Conditions: Trauma; Sepsis and Septic Shock
• Intervention / Treatment: Diagnostic test: Viscoelastometric assessment of fibrinolysis

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 Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Anders Aneman, MD, PhD, EDIC, FCICM; Phone Number: +61427915693; Email: anders.aneman@health.nsw.gov.au
• Study Contact Backup: Name: Lucy Coupland, Nurs Cert, BSci (hons), PhD; Phone Number: +61419723330; Email: lucy.coupland@health.nsw.gov.au

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Recruiting
      • The Canberra hospital (ICU)
      • Contact: Philip Crispin, MBBS(Hons), FRACP, FRCPA; Phone Number: + 61251240000; Email: philip.crispin@act.gov.au
      • Contact: Sean W Chan; Phone Number: + 61251240000; Email: seanweng.chan@act.gov.au
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Recruiting
      • Liverpool Hospital (ICU)
      • Contact: Lucy Coupland, Nurs Cert, BSci (hons), PhD; Phone Number: + 61419723330; Email: lucy.coupland@health.nsw.gov.au
      • Contact: Eurwin Suryana, BMedSci (hons), PhD; Phone Number: + 61415148742; Email: eurwin.suryana@health.nsw.gov.au
    • Macquarie, New South Wales, Australia, 2109
      • Recruiting
      • Macquarie University Hospital (ICU)
      • Contact: Anders Aneman, MD, PhD, EDIC, FCICM; Phone Number: + 61427915693; Email: anders.aneman@health.nsw.gov.au
    • St Leonards, New South Wales, Australia, 2065
      • Recruiting
      • Royal North Shore Hospital (ICU)
      • Contact: Pierre Janin; Phone Number: + 61299267111; Email: pierre.janin@health.nsw.gov.au

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients who are admitted to an ICU

Description

Sepsis/Septic shock 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 Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sepsis/Septic shock; According to Sepsis-3 definitions (including SARS CoV-2 as pathogen); expected to remain in ICU and survive beyond the day after tomorrow and for full, active ICU treatment; arterial and secure venous access established or imminent as part of standard care; not on oral anticoagulant/antiplatelet therapy.	Diagnostic test: Viscoelastometric assessment of fibrinolysis; Viscoelastometric assessment of whole blood fibrinolysis using supplemental tissue plasminogen activator (tPA) and other agents ex vivo to influence fibrinolysis capacity.
Severe Trauma; Admitted via the Emergency Department resuscitation bay requiring trauma team response; deemed at risk of significant blood loss and where transfusion of blood products i considered in the ED during the acute phase of the resuscitation by a senior clinician; expected to remain in ICH and survive beyond the day after tomorrow and for full, active ICU treatment; Not on oral anticoagulant/antiplatelet therapy. A clinical based inclusion approach is the most pragmatic means of patient selection and can be objectively supported by routine blood tests demonstrating poor oxygen supply to the organs. Exclusion criteria: unsurvivable head injury.	Diagnostic test: Viscoelastometric assessment of fibrinolysis; Viscoelastometric assessment of whole blood fibrinolysis using supplemental tissue plasminogen activator (tPA) and other agents ex vivo to influence fibrinolysis capacity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VET testing and analysis	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.	From admission to ICU and at 24 hours, 48 hours, 5 days, 7 days, 10 days, and 15 days post ICU admission
Laboratory evaluation of fibrinolytic profile	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.	From admission to ICU and at 24 hours, 48 hours, 5 days, 7 days, 10 days, and 15 days post ICU admission

Collaborators and Investigators

• Sponsor: Anders Aneman
• Collaborators: Royal North Shore Hospital; Macquarie University, Australia; The Canberra Hospital; Liverpool Hospital, South Western Sydney Local Health District

Publications and helpful links

General Publications

• Coupland LA, Rabbolini DJ, Schoenecker JG, Crispin PJ, Miller JJ, Ghent T, Medcalf RL, Aneman AE. Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study. Crit Care. 2023 Feb 10;27(1):55. doi: 10.1186/s13054-023-04329-5.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: October 9, 2024
• First Submitted That Met QC Criteria: November 6, 2024
• First Posted (Estimated): November 8, 2024

Study Record Updates

• Last Update Posted (Estimated): November 8, 2024
• Last Update Submitted That Met QC Criteria: November 6, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Sepsis; Trauma; Tissue Plasminogen Activator; Plasminogen; Fibrinolytic Agents; Fibrin Modulating Agents; Viscoelastic testing (VET)
• Additional Relevant MeSH Terms: Wounds and Injuries
• Other Study ID Numbers: 2022/ETH02122

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No