Fibrinolysis Resistance in Infection and Trauma (FORTITUDE)

Anders Aneman

Status: Enrolling

Conditions: Sepsis and Septic Shock; Trauma

Treatments: Diagnostic Test: Viscoelastometric assessment of fibrinolysis

Study type: Observational

Funder types: Other

Identifiers

NCT06680180

2022/ETH02122

Details and patient eligibility

About

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.

Full 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.

Enrollment: 150 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

150 participants in 2 patient groups

Sepsis/Septic shock

Description:

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.

Treatment:

Diagnostic Test: Viscoelastometric assessment of fibrinolysis

Severe Trauma

Description:

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.

Treatment:

Diagnostic Test: Viscoelastometric assessment of fibrinolysis