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Published on: March 9, 2018
Indications that the Antimycotic Drug Amphotericin B Enhances the Impact of Platelets on Aspergillus
Günter Rambach1,2, Bianca Striednig1, Magdalena Neurauter1
1Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
Abstract:
Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant in vivo. The stimulating effect was corroborated by a broad spectrum of platelet activation parameters, including degranulation, aggregation, budding of microparticles, morphological changes, and enhanced adherence to fungal hyphae. Comparison between the deoxycholate and the liposomal formulation excluded the possibility that the liposomal part of L-Amb is responsible for these effects, as no difference was visible. The induction of platelet activation and alteration by L-AmB resulted in the activation of other parts of innate immunity, such as stimulation of the complement cascade and interaction with granulocytes. These mechanisms might substantially fuel the antifungal immune reaction in invasive mycoses. On the other hand, thrombosis and excessive inflammatory processes might occur via these mechanisms. Furthermore, the viability of L-AmB-activated platelets was consequently decreased, a process that might contribute to thrombocytopenia in patients.
Insights
Amphotericin B (AmB) activates platelets, crucial immune cells, within minutes. This interaction enhances antifungal immunity but may also risk thrombosis and thrombocytopenia in patients.
Area of Science:
- Immunology
- Pharmacology
- Hematology
Background:
- Invasive fungal infections are rising, especially during COVID-19, posing risks to immunocompromised individuals.
- Platelets possess antimicrobial functions and are vital in host defense against fungi like Aspergillus and mucormycetes.
- Evaluating drug interactions with platelets is critical for optimizing antifungal therapies.
Purpose of the Study:
- To investigate the effects of Amphotericin B (AmB), a key antifungal drug, on platelet activation.
- To compare the impact of deoxycholate (AmB-D) and liposomal (L-AmB) formulations of Amphotericin B on platelets.
- To explore the downstream consequences of AmB-induced platelet activation on innate immunity and potential adverse effects.
Main Methods:
- Platelet activation assays measuring degranulation, aggregation, microparticle formation, morphology, and adherence.
- In vitro exposure of platelets to clinically relevant concentrations of AmB-D and L-AmB.
- Assessment of complement cascade activation and granulocyte interaction post-platelet stimulation.
- Evaluation of platelet viability following AmB exposure.
Main Results:
- Amphotericin B rapidly and potently activates platelets at concentrations found in patients.
- Platelet activation by AmB involves degranulation, aggregation, microparticle release, and enhanced fungal adherence.
- Both AmB-D and L-AmB formulations induce similar platelet activation, indicating the drug itself is responsible.
- L-AmB-induced platelet activation triggers complement and granulocyte responses, potentially amplifying antifungal immunity.
- AmB treatment reduces platelet viability, suggesting a mechanism for thrombocytopenia.
Conclusions:
- Amphotericin B significantly activates platelets, contributing to innate immune responses against fungal infections.
- Platelet activation by AmB may promote thrombosis and inflammation.
- AmB-induced platelet activation and subsequent decrease in viability could explain thrombocytopenia in patients undergoing treatment.
- These findings highlight a complex interplay between antifungal therapy, platelets, and innate immunity.
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