Conventional and Pro-Inflammatory Pathways of Fibrinolytic Activation in Non-Traumatic Hyperfibrinolysis

Johannes Zipperle; Bernhard Ziegler; Herbert Schöchl; Wolfgang Voelckel; Peter Dungel; Janne Cadamuro; Marcin Osuchowski; Christoph J Schlimp; Daniel Oberladstätter

doi:10.3390/jcm11247305

Conventional and Pro-Inflammatory Pathways of Fibrinolytic Activation in Non-Traumatic Hyperfibrinolysis

J Clin Med. 2022 Dec 9;11(24):7305. doi: 10.3390/jcm11247305.

Authors

Affiliations

¹ Ludwig Boltzmann Institute for Traumatology, The Research Center in Cooperation with AUVA, 1200 Vienna, Austria.
² Department of Anaesthesiology, Perioperative Medicine and General Intensive Care Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.
³ AUVA Trauma Centre Salzburg, Department of Anaesthesiology and Intensive Care Medicine, Academic Teaching Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria.
⁴ Department of Laboratory Medicine, University Hospital SALK, 5020 Salzburg, Austria.
⁵ AUVA Trauma Centre Linz, Department of Anaesthesiology and Intensive Care Medicine, 4010 Linz, Austria.

Abstract

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC pathway also plays a role in inflammatory responses such as neutrophil extracellular trap formation (NETosis), which might contribute to lysis through cleavage of fibrin by neutrophil elastases. We investigated whether the APC and the plasminogen pathway were general drivers of HF, even in the absence of a traumatic incident. Additionally, we were interested in inflammatory activation such as the presence of NETs as potential contributing factors to HF. A total of 41 patients with OHCA were assigned to a HF and a non-HF group based on maximum lysis (ML) in thromboelastometry. Thrombin-antithrombin (TAT)-complex, soluble thrombomodulin (sTM), APC-PC inhibitor complex, t-PA, PAI-1, t-PA-PAI-1 complex, plasmin-antiplasmin (PAP), d-dimers, neutrophil elastase, histonylated DNA (hDNA) fragments, and interleukin-6 were assessed via immunoassays in the HF group vs. non-HF. APC-PC inhibitor complex is significantly higher in HF patients. Antigen levels of t-PA and PAI-1 do not differ between groups. However, t-PA activity is significantly higher and t-PA-PAI-1 complex significantly lower in the HF group. Consistent with these results, PAP and d-dimers are significantly elevated in HF. HDNA fragments and neutrophil elastase are not elevated in HF patients, but show a high level of correlation, suggesting NETosis occurs in OHCA as part of inflammatory activation and cellular decay. Just as in trauma, hypoperfusion, the activation of protein C, and the initiation of the plasminogen pathway of fibrinolysis manifest themselves in the HF of cardiac arrest. Despite features of NETosis being detectable in OHCA patients, early pro-inflammatory responses do not appear be associated with HF in cardiac arrest.

Keywords: activated protein C; cardiac arrest; hyperfibrinolysis; inflammation; ischemia; neutrophil extracellular traps; reperfusion; thromboelastometry; viscoelastic tests.

Grants and funding

This research was funded by institutional funds and, in part, by the Austrian Science Fund (FWF) [project number P-35425]. For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.