Multi-level thromboinflammatory activation after TAVR: systemic, cellular, and platelet transcriptomic changes

Backround

Transcatheter aortic valve replacement (TAVR) induces a thromboinflammatory response characterized by hypercoagulability and dynamic platelet alterations. The integrated mechanisms underlying these changes remain incompletely defined.

Purpose

To comprehensively characterize periprocedural hemostatic and inflammatory changes after TAVR across systemic, cellular, and transcriptomic levels.

Methods

In this prospective single-center study, patients undergoing TAVR were enrolled between September 2022 and July 2024. Blood samples were obtained on the day of the procedure (T0; prior to valve implantation) and at hospital discharge (T1; median 3.5 days, IQR 2–4 days). At both time points, soluble biomarkers were assessed by routine laboratory testing, cellular phenotype by flow cytometry (FACS), and isolated platelets underwent RNA sequencing.

Results

Soluble biomarkers were assessed in 102 consecutive TAVR patients, with FACS and transcriptomic analysis in a sub-cohort of 32. TAVR induced a pronounced systemic increase in markers of coagulation and inflammation. The most relevant changes were observed for D-dimers (medianΔ 0.67 mg/L [IQRΔ 0.44–1.07]; p = 0.001), von Willebrand factor activity (medianΔ 87% p < 0.0001), fibrinogen (medianΔ 125 mg/dL; p < 0.0001), Il-6 (medianΔ 19.70 ng/l [IQRΔ 10.80–35.25]; p < 0.0001 and Troponin T medianΔ 43.20 ng/l;p < 0.0001, consistent with acute coagulation and inflammatory activation with myocardial injury.

At cellular level, platelet count declined (medianΔ −27 × 10³/µL [−54.5 to −5.5]; p < 0.0001), accompanied by reduced GPIIb/IIIa (ΔgeoMFI −275 a.u.; p < 0.0001) and CD62P expression (ΔgeoMFI −98 a.u.; p =0.003), and increased platelet–neutrophil aggregates (CD42a+CD15+, ΔgeoMFI 377.0 a.u. p = 0.036), reflecting platelet phenotypic alteration and enhanced platelet–immune interaction.

At the transcriptomic level, RNA sequencing identified 188 upregulated and 508 downregulated differentially expressed transcripts.Gene set enrichment analysis demonstrated upregulation of platelet activation, aggregation, and hemostasis pathways. Over-representation analysis confirmed enrichment of platelet activation–associated genes, including DMTN, FCER1G, MMRN1, SELP, and FUNDC2.

Conclusion

TAVR induces a coordinated thromboinflammatory response across systemic, cellular, and transcriptomic levels, characterized by systemic coagulation and inflammatory activation, platelet phenotypic alterations, and transcriptional enrichment of platelet activation pathways. Together, these findings provide mechanistic insight into the acute thromboinflammatory milieu associated with the procedure.Periprocedural changes of systemic parametersFor image description, please refer to the figure legend and surrounding text.Periprocedural changes of cell based markersFor image description, please refer to the figure legend and surrounding text.