micafungin and Hemolysis

The antifungal drug Micafungin is used for the treatment of diverse fungal infections including candidiasis and aspergillosis. Side effects of Micafungin treatment include microangiopathic hemolytic anemia and thrombocytopenia with microvascular thrombosis. The development of thrombosis may be fostered by stimulation of eryptosis, the suicidal death of erythrocytes characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, activated protein kinase C (PKC), casein kinase 1α or p38 kinase and activated caspases. The present study explored, whether Micafungin induces eryptosis.. Flow cytometry was employed to estimate phosphatidylserine abundance at the erythrocyte surface from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, abundance of reactive oxygen species (ROS) from DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. Hemolysis was quantified by measuring haemoglobin concentration in the supernatant.. A 48 hours exposure of human erythrocytes to Micafungin (10 - 25 µg/ml) significantly increased hemolysis and the percentage of annexin-V-binding cells, and significantly decreased forward scatter. Micafungin (25 µg/ml) did not significantly modify Fluo3-fluorescence, DCFDA fluorescence, or ceramide abundance. The effect of Micafungin on annexin-V-binding was not significantly modified by removal of extracellular Ca2+, by PKC inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase 1α inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM).. Micafungin triggers hemolysis and eryptosis with cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane.

Topics: Antifungal Agents; Benzamides; Calcium; Casein Kinase I; Cell Size; Ceramides; Echinocandins; Eryptosis; Erythrocyte Membrane; Erythrocytes; Flow Cytometry; Hemolysis; Humans; Imidazoles; Lipopeptides; Micafungin; Microscopy, Confocal; p38 Mitogen-Activated Protein Kinases; Phosphatidylserines; Protein Kinase C; Pyridines; Reactive Oxygen Species; Staurosporine

Topics: Anemia, Refractory, with Excess of Blasts; Antibodies; Antifungal Agents; Echinocandins; Hematopoietic Stem Cell Transplantation; Hemolysis; Humans; Lipopeptides; Male; Micafungin; Middle Aged

The echinocandins provide an attractive new option for prophylactic and empirical treatment of invasive fungal infections in patients with neutropenia after intensive cytotoxic chemotherapy or hematopoietic stem cell transplantation. We present two patients with hematological diseases who experienced massive intravascular hemolysis followed by renal failure after administration of micafungin. In indirect antiglobulin test, significant agglutination was observed when red blood cells were exposed to the mixture of micafungin and either of the patients' plasma samples, indicating that production of antibodies directed against both micafungin and red blood cell membrane induced hemolysis attack. Micafungin-mediated immune hemolysis represents an uncommon but life-threatening adverse reaction leading to renal failure.

Topics: Antibody Formation; Antifungal Agents; Echinocandins; Erythrocytes; Hemolysis; Humans; Kidney Diseases; Lipopeptides; Male; Micafungin; Middle Aged; Myelodysplastic Syndromes