A novel assay for hyperfibrinolysis in trauma

About This Grant

Abstract Trauma is the 4th leading cause of death in the United States, and the leading cause in Americans aged 1 to 46 years. Uncontrolled bleeding accounts for more deaths than any other contributing cause. The acquired coagulopathy of trauma is frequently of rapid onset and has a complex pathophysiology that includes fibrinolytic activation, sometimes profound, which is recognized to contribute to hemorrhagic outcomes. The CRASH-2 study demonstrated that the antifibrinolytic agent tranexamic acid (TXA) reduces risk of death from bleeding, but only when administered within the first 3 hours. However, TXA administration does not invariably suppress endogenous fibrinolytic activation completely, and there remain some questions about the optimal dose. Furthermore, the recommendation in favor of universal administration of TXA to all trauma subjects is controversial. Some Centers selectively administer TXA only to those with evidence of hyperfibrinolysis on whole blood viscoelastic testing (VET). The specific parameters used as a measure of hyperfibrinolysis in VET have been criticized for their slow output (45-60 minutes) and insensitivity to less profound degrees of fibrinolytic activation that are also associated with poor clinical bleeding outcomes. The current R33 application will advance the development of an in- house assay for fibrinolytic activation that can be performed in 5 minutes on plasma. We have termed this assay the ‘Fibrinolytic Activation Screening Test’, or ‘FAST’. The FAST assay is not inhibited by TXA, nor by therapeutic levels of commonly used anticoagulants, thereby allowing a snapshot of fibrinolytic activation on a wide variety of patients. Our first Specific Aim is to complete the characterization of pre-analytic and analytic variables in the FAST assay. The second Specific Aim is to clinically validate the FAST assay in retrospective and prospective trauma cohorts. We expect that successful completion of these Aims will result in a validated diagnostic approach to detect fibrinolytic activation in trauma. The knowledge gained from this assay can be used to guide the care of patients with trauma, not only encouraging more widespread use of TXA, but also sequentially tracking fibrinolytic activation to suggest when additional dosing of TXA or other anti-fibrinolytic interventions might be indicated. The assay is also amenable to an even more rapid version as a point-of-care whole blood platform in the next phase of development.