Immune and complement signatures predict the treatment response to ultrasound-assisted thrombolysis in acute pulmonary embolism
D Draxler, J Brodard, A K Blaser, H Ho, K Chalkou, C B Keragala, D Heg, J A Kremer Hovinga, R L Medcalf, A Angelillo-Scherrer, S StorteckyAbstract
Background
In acute pulmonary embolism (PE), inflammation and complement activation contribute to thrombosis, pulmonary hypertension, and adverse outcomes. Ultrasound-assisted catheter-directed thrombolysis (USAT) promotes fibrinolysis via plasmin generation, which may simultaneously activate and resolve inflammatory and complement pathways.
Purpose
To characterize the immune and complement response during USAT in acute PE, assess its relationship with fibrinolysis, and identify biomarkers predicting treatment efficacy.
Methods
Patients with intermediate-high and high-risk PE undergoing USAT with recombinant tissue-type plasminogen activator were studied. Plasma samples were collected before, during (6 h), and after treatment (24 h). Cytokine/chemokine profiles and complement components (C3a, C4a, C5a, sC5b-9, Ba, Bb, factor H, factor I) were quantified. Fibrinolytic activity was assessed using thromboelastometry and plasmin-related markers. Immune and complement markers were correlated with fibrinolysis and pulmonary-arterial hemodynamic improvement.
Results
USAT induced a dynamic biphasic immune response, with early Th1/Th17 activation (↑IFNγ, MMP-10) followed by regulatory and reparative signaling (↑IL-4, FLT3L, LAP TGF-β1). In parallel, complement activation decreased during treatment, with reductions in C3a and terminal pathway components. Plasmin activity correlated positively with regulatory complement factors (factor H) and negatively with Ba, Bb, C5a, and sC5b-9, suggesting suppression of complement activation during effective thrombolysis. Cytokines (IL-2, MCP-3, STAMBP, 4E-BP1, LAP TGF-β1) and complement markers (C5a↓, Ba↑) predicted greater reductions in pulmonary arterial pressure. Pre-treatment chemokines and growth factors (MCP-3, CXCL1, FGF5, HGF, DNER) were associated with improved hemodynamic response.
Conclusions
USAT orchestrates coordinated immune and fibrinolytic responses in acute PE. Early inflammatory activation transitions to regulatory and reparative signaling, while complement activation is downregulated despite plasmin generation. These pathways are linked to hemodynamic improvement, suggesting that immune and complement biomarkers may help predict and monitor treatment response to USAT.Summary figureFor image description, please refer to the figure legend and surrounding text.