RESUMEN
BACKGROUND: Paclitaxel is one of the most widely used anti-cancer drugs, but numerous case reports of thrombotic events in the cancer patients using paclitaxel raise concern over its pro-thrombotic risk. MATERIALS AND METHODS: We investigated whether paclitaxel can elicit pro-thrombotic properties in red blood cells (RBCs) through phosphatidylserine (PS) exposure and microvesicle (MV) release. RESULTS: In freshly isolated human RBCs, paclitaxel induced thrombin generation through PS exposure and MV release, whereas either coagulation factors or platelets were unaffected. Paclitaxel-induced PS exposure in RBC was mediated by scramblase activation which was induced by calcium-independent protein kinase C (PKC)ζ activation. Paclitaxel also increased RBC-endothelial cell adhesion and RBC aggregate formation which can also contribute to thrombosis. Indeed, intravenous administration of paclitaxel to rats induced PS exposure and PKCζ activation in RBCs in vivo which ultimately promoted venous thrombus formation. CONCLUSION: These results demonstrated that paclitaxel may elicit pro-thrombotic properties in RBCs through PS exposure and MV release, which can ultimately promote thrombus formation.
Asunto(s)
Antineoplásicos/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Eritrocitos/fisiología , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Trombosis/prevención & control , Adolescente , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Micropartículas Derivadas de Células/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Paclitaxel/efectos adversos , Paclitaxel/uso terapéutico , Fosfatidilserinas/metabolismo , Proteínas de Transferencia de Fosfolípidos/metabolismo , Ratas , Ratas Sprague-Dawley , Trombina/metabolismo , Trombosis/etiología , Adulto JovenRESUMEN
Thrombotic risk associated with chemotherapy including doxorubicin (DOX) has been frequently reported; yet, the exact mechanism is not fully understood. Here, we report that DOX can induce procoagulant activity in platelets, an important contributor to thrombus formation. In human platelets, DOX increased phosphatidylserine (PS) exposure and PS-bearing microparticle (MP) generation. Consistently, DOX-treated platelets and generated MPs induced thrombin generation, a representative marker for procoagulant activity. DOX-induced PS exposure appeared to be from intracellular Ca²âº increase and ATP depletion, which resulted in the activation of scramblase and inhibition of flippase. Along with this, apoptosis was induced by DOX as determined by the dissipation of mitochondrial membrane potential (Δψ), cytochrome c release, Bax translocation, and caspase-3 activation. A Ca²âº chelator ethylene glycol tetraacetic acid, caspase inhibitor Q-VD-OPh, and antioxidants (vitamin C and trolox) can attenuate DOX-induced PS exposure and procoagulant activity significantly, suggesting that Ca²âº, apoptosis, and reactive oxygen species (ROS) were involved in DOX-enhanced procoagulant activity. Importantly, rat in vivo thrombosis model demonstrated that DOX could manifest prothrombotic effects through the mediation of platelet procoagulant activity, which was accompanied by increased PS exposure and Δψ dissipation in platelets.
Asunto(s)
Antibióticos Antineoplásicos/efectos adversos , Plaquetas/efectos de los fármacos , Doxorrubicina/efectos adversos , Agregación Plaquetaria/efectos de los fármacos , Trombosis/inducido químicamente , Adolescente , Adulto , Animales , Antibióticos Antineoplásicos/uso terapéutico , Plaquetas/citología , Plaquetas/metabolismo , Caspasa 3/metabolismo , Células Cultivadas , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Doxorrubicina/uso terapéutico , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Microscopía Confocal , Activación Plaquetaria/efectos de los fármacos , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Trombosis/sangre , Factores de Tiempo , Adulto Joven , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Anemia is probably one of the most well-known toxic effects of lead. Previously, lead-induced anemia was considered to be from the inhibition of δ-aminolevulinic acid dehydratase participating in the heme biosynthesis. However, little is known whether lead could affect the destruction of erythrocyte, another important factor for anemia. In the present study, we demonstrated that lead could accelerate the splenic sequestration of erythrocytes through phosphatidylserine (PS) exposure and subsequently increased erythrophagocytosis. In freshly isolated human erythrocytes, Pb(2+)- induced PS exposure at relatively low concentrations (â¼0.1 µM) by inhibiting flippase, a key aminophospholipid translocase for the maintenance of PS asymmetry and adenosine triphosphate depletion appeared to underlie this phenomenon. Abnormal shape changes of erythrocytes and microvesicle generation and other triggers for the erythrophagocytosis were also observed in the Pb(2+)-exposed erythrocytes. In vitro data showed that human macrophage indeed recognized and phagocytosis PS-exposed erythrocytes. In good accordance with these in vitro results, the oral administration of Pb(2+) increased PS exposure on erythrocytes in rat in vivo. In addition, reduction of hematocrit and hemoglobin and increased spleen weight were observed along with enhanced splenic sequestration of erythrocytes in the rats exposed to Pb(2+) subchronically for 4 weeks through drinking water. In conclusion, these results suggest that Pb(2+)-induced anemia may be explained at least in part by increased PS exposure on erythrocytes, erythrophagocytosis, and splenic sequestration.