Plasminogen activator inhibitor‐1 augments damage by impairing fibrinolysis after traumatic brain injury

Abstract

Objective Plasminogen activator inhibitor‐1 (PAI‐1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI‐1 mediates post‐traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI‐1 attenuating clot formation and lesion expansion after brain trauma. Methods We evaluated PAI‐1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI‐1 with PAI‐039 and stimulation by tranexamic acid, and we confirmed our results in PAI‐1–deficient animals. Results PAI‐1 mRNA was time‐dependently upregulated, with a 305‐fold peak 12 hours after CCI, which effectively counteracted the 2‐ to 3‐fold increase in cerebral tissue‐type/urokinase plasminogen activator expression. PAI‐039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post‐traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI‐1–deficient mice, the therapeutic effect of PAI‐039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. Interpretation This study identifies impaired fibrinolysis as a critical process in post‐traumatic secondary brain damage and suggests that PAI‐1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667–680

Neutrophils mediate early cerebral cortical hypoperfusion in a murine model of subarachnoid haemorrhage

“…RNA was isolated from the left hemispheres of brain samples using a Qiagen-RNeasy Plus Universal kit (Qiagen, Hilden, Germany) and reverse-transcribed into cDNA with QuantiTect Reverse Transcription Kit (Qiagen) according to the manufacturer’s instructions. The mRNA quantification by real-time quantitative polymerase chain reaction (qPCR) was performed as described 30,34–36 . Briefly, the cDNA of each sample was amplified using a real-time Lightcycler 480 PCR System (Roche).…”

Temporal Changes in Fibrinolysis following Injury

“…A recent mouse traumatic brain injury (TBI) model demonstrated high PAI-1 production at 12 hours from injury. 67 This elevated PAI-1 is believed to cause secondary brain injury. It was demonstrated that the inhibition of PAI-1 resulted in smaller brain lesions compared with control, whereas TXA made brain contusion larger.…”

“…It was demonstrated that the inhibition of PAI-1 resulted in smaller brain lesions compared with control, whereas TXA made brain contusion larger. 67 Ongoing investigation on injury-specific (TBI vs. non-TBI polytrauma and mixed TBI polytrauma) generation of PAI-1 in acquired fibrinolysis shutdown following trauma warrant future investigation and assessment if the magnitude of PAI-1 generation can predict adverse outcomes. Fig.…”

The abnormalities of coagulation and fibrinolysis in acute lung injury caused by gas explosion

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“…Another key focus of the present study, a natural inhibitor of tissue factor, 33 TFPI was also elevated in the alveolar lavage fluid in our rats model, however, TFPI levels did not rise and persist like TF, and thus do not effectively block the function and do not inhibit the hypercoagulable state in the alveoli. Moreover, PAI‐1 is known to enhance clot formation after injury and mediate post‐traumatic coagulopathy 19 . In ALI, elevated levels of PAI‐1 are a hallmark of fibrinolysis inhibition.…”