Inflammation as a pleiotropic regulator of megakaryocyte and platelet hemostatic, immune, and metabolic function

During infectious and noninfectious inflammatory diseases, disruption of the immune-hemostatic balance increases both thrombotic and hemorrhagic risk. We propose that this bidirectional dysregulation reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators, two interconnected regulatory levels that together shape the prothrombotic and hemorrhagic platelet phenotypes observed across inflammatory conditions.

Current evidence supports a two-level framework through which inflammation remodels platelet responses. Upstream, recent studies demonstrate that inflammation remodels thrombopoiesis, megakaryocyte transcriptional programs, and immunometabolism, generating platelets with altered immunothrombotic, thromboinflammatory, and prothrombotic properties. Converging evidence from aging, sepsis, myeloproliferative neoplasms, and rheumatoid arthritis identifies autophagy as a central target of inflammatory signaling linking megakaryocyte and platelet reprogramming to mitochondrial dysfunction and impaired clot contraction. Downstream, inflammatory mediators directly remodel platelet receptor signaling and promote receptor transfer, generating context-dependent platelet functional states that contribute to both thrombotic and hemorrhagic complications.

The platelet phenotype observed across inflammatory diseases reflects the integrated contribution of megakaryocyte reprogramming during thrombopoiesis and direct remodeling of circulating platelets by inflammatory mediators. These two levels of regulation likely operate simultaneously and may amplify each other, yet how they interact to determine platelet functional outcomes in specific inflammatory contexts remains to be determined. Defining these interactions will inform the development of mechanism-based therapeutic strategies that target inflammation-driven platelet dysfunction to reduce thrombotic and hemorrhagic complications across inflammatory diseases.