Impaired megakaryopoiesis due to aberrant macrophage polarization via BTK/Rap1/NF-κB pathway in sepsis-induced thrombocytopenia.

Summary

This preclinical study connects macrophage BTK activation to impaired megakaryopoiesis in sepsis-induced thrombocytopenia. Pharmacologic BTK inhibition (BGB-3111) restored megakaryocyte and platelet production in mice via a Rap1/NF-κB–dependent effect on macrophage polarization.

Key Findings

• SIT patients and septic mice exhibited increased pro-inflammatory macrophages and elevated macrophage p-BTK, correlating inversely with platelet counts.
• BTK inhibitor BGB-3111 increased megakaryocyte and platelet production in SIT mice.
• Macrophage depletion and coculture experiments confirmed macrophages as key mediators of platelet recovery upon BTK inhibition.
• Single-cell RNA-seq implicated Rap1 signaling linking macrophages to megakaryopoiesis under BTK influence.
• BTK inhibition reduced pro-inflammatory macrophage polarization via Rap1/NF-κB.

Clinical Implications

Supports testing BTK inhibitors (e.g., zanubrutinib) in septic patients with severe thrombocytopenia, with careful safety monitoring given infection risks. Platelet count recovery could be mediated by modulating macrophage polarization rather than direct thrombopoiesis.

Limitations

• Preclinical models; no human interventional data
• Potential off-target and infection risks of BTK inhibitors in sepsis not assessed

Future Directions

Conduct early-phase clinical trials of BTK inhibition in sepsis-induced thrombocytopenia, validate Rap1/NF-κB signaling biomarkers, and define patient selection criteria (e.g., high p-BTK macrophage signature).