Effect of recombinant tissue-type plasminogen activator on peripheral blood mononuclear cells of patients with alteplase-associated angioedema

Background and objectives: Recombinant tissue-type plasminogen activator (R-tPA) is a thrombolytic agent used to treat acute ischemic stroke (IS). A rare but serious adverse effect of R-tPA is angioedema, which is characterized by plasma extravasation and increased release of vasoactive factors such as bradykinin, vascular endothelial growth factor A (VEGF-A), CXCL8, angiopoietin-1 (ANGPT-1), and ANGPT-2. Objective: To investigate whether R-tPA modulates immune cell activity differently in IS patients with and without angioedema, focusing on the release of vasoactive mediators from human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were isolated from 7 healthy controls (HCs), 7 IS patients without angioedema, and 7 IS patients who developed angioedema during R-tPA treatment (ISAE). The production and/or release of CXCL8, VEGF-A, ANGPT-1, and ANGPT-2 following ex vivo stimulation with R-tPA was measured. Plasma levels of these mediators were also assessed in ISAE patients during both angioedema attacks and remission. Results: R-tPA inhibited the spontaneous release of VEGF-A, ANGPT-1, and ANGPT-2 from the PBMCs of HCs and IS patients. In contrast, a significant increase in the release of these mediators after stimulation with R-tPA was observed in PBMCs from ISAE patients. Plasma concentrations of all 4 mediators were higher during angioedema attacks than in remission, with a statistically significant elevation recorded for ANGPT-2. Conclusions: These preliminary data suggest that R-tPA-related angioedema may result from abnormal immune cell activation, leading to increased release of vasoactive mediators. This immune dysregulation may contribute to the pathophysiology of angioedema in susceptible IS patients treated with R-tPA.