Roles of tissue plasminogen activator in chronic subdural hematoma, independent of the fibrinolytic system

Inflammation and angiogenesis are critical processes contributing to the progression of chronic subdural hematoma (CSDH). Tissue plasminogen activator (tPA), which is highly abundant in CSDH effusion, has been implicated not only in hematoma liquefaction but also in progressive hematoma enlargement. Notably, tPA expression has also been reported in intracranial neoplasms, where it contributes to the development of peritumoral edema, suggesting roles beyond fibrinolysis. We therefore hypothesized that tPA exerts non-fibrinolytic effects in the pathophysiology of CSDH. Twenty CSDH fluid specimens and eight outer membrane samples were analyzed. The concentrations of tPA and matrix metalloproteinase-9 (MMP-9) were markedly higher in CSDH fluid than in cerebrospinal fluid. Immunoblotting confirmed the presence of low-density lipoprotein receptor-related protein-1 (LRP-1), phosphorylated Mek (p-Mek), Mek, phosphorylated Erk (p-Erk), Erk, MMP-9, caspase-3, and cleaved caspase-3 in the outer membrane. Immunohistochemical analyses revealed that LRP-1, p-Erk, Erk, and MMP-9 were predominantly localized to vascular endothelial cells, whereas LRP-1, caspase-3, and cleaved caspase-3 were mainly expressed in fibroblasts within the outer membrane. Moreover, exposure of fibroblasts to CSDH effusion significantly attenuated staurosporine-induced cleaved caspase-3 expression in vitro. Collectively, these findings suggest that elevated tPA in CSDH effusion is associated with activation of LRP-1-dependent Mek-Erk signaling and increased MMP-9 expression, and may also be linked to anti-apoptotic responses in fibroblasts. These pathology-associated signaling features extend beyond the classical fibrinolytic role of tPA and may have therapeutic implications for refractory CSDH, warranting further functional and interventional studies.