Dysregulated calcium signaling enhances the proinflammatory potential of platelets in sepsis.

Introduction Sepsis is a severe complication due to a dysfunctional host response to infectious pathogens, frequently presenting with thromboembolic events. Platelets are involved in sepsis, although the underlying mechanisms remain unknown. Calcium signaling is essential for the function of platelets and further recruitment of leukocytes. A disruption of the calcium-release activated calcium channels, such as ORAI1 could modify store-operated calcium entry (SOCE) and potentially alter platelet function in sepsis. We hypothesize septic-derived IgG modify calcium regulation in platelets, and may contribute to thromboembolic events in sepsis. Hence, this study aims to unravel how sepsis-derived IgG modulate calcium signaling, platelet phenotypes and responsiveness. Method Whole blood samples were collected from healthy donors and sepsis patients. Platelet intracellular calcium flux was investigated with a multimode microplate reader using the calcium-sensitive dye Fluo-4 AM. Platelet phenotypes were analyzed in flow cytometry by measuring the co-expression of CD62P and Phosphatidylserine (procoagulant status) as well as the platelet responsiveness to agonists by detecting CD63 and CD62P expression levels (after challenge with ADP, TRAP-6, or TRAP-6/Convulxin). Separately, these phenotypes were analyzed on platelet-leukocyte aggregates. Patient platelet ORAI1 protein abundance was determined by western blot. To assess the effect of sepsis, patient plasma or purified IgG fractions were incubated with healthy platelets. Results Platelets from septic patients show enhanced intracellular calcium levels compared to healthy controls. Additionally, calcium flux in sepsis patient platelets reaches a larger increment to peak after stimulation with agonists. The protein abundance of ORAI1 is increased in sepsis platelets compared to healthy control. Conversely, procoagulant platelets were more abundant in sepsis patients. We show that platelets from septic patients form more platelet-leukocyte aggregates with an enhanced fraction of procoagulant platelets. Exposure of septic plasma to healthy platelets increased the intracellular calcium level. Moreover, septic plasma and IgG fraction from patients enhanced healthy platelet reactivity to stimuli increased the procoagulant phenotype. Conclusion These results suggest that platelet disruption reflect a pro-inflammatory phenotype, possibly mediated by enhanced calcium signaling. In detail, this outcome is triggered by septic patient-derived IgG and the procoagulant phenotype alters cell-cell interactions. Further investigations and patient recruitment into our ongoing study are needed to characterize the role of IgG-mediated response in sepsis and elucidate their relevance to disease outcomes and clinical practice. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany