Abstract
Platelets are central to normal hemostasis and must be tightly controlled to prevent thrombosis. However, drug treatments that also affect platelets could lead to unwanted side effects on hemostasis or thrombosis. In this study, the effect of auranofin on platelets was tested. Auranofin, a gold-based thioredoxin reductase (TRXR) inhibitor, has been previously used in arthritis. Recently, auranofin and other inhibitors of the thioredoxin system have been proposed as novel anti-cancer therapies. TRXR is an important part of the antioxidant defenses in many cells that maintain intracellular proteins in their reduced state.TRXR activity in platelets could be completely inhibited by auranofin. Auranofin-treated platelets showed several features of cell death, including the inability to aggregate in response to thrombin, leakage of cytosolic lactate dehydrogenase, and surface exposure of procoagulant phosphatidylserine. Auranofin increased platelet reactive oxygen species production and intracellular calcium concentration. DTT, a sulfydyl reducing agent, and BAPTA-AM, which chelates intracellular calcium, prevented auranofin-induced phosphatidylserine exposure. These data suggest that TRXR is an important part of the platelet antioxidant defense. TRXR inhibition by auranofin triggers oxidative stress and disrupts intracellular calcium homeostasis, leading to platelet necrosis. The use of auranofin or other TRXR inhibitors could therefore lead to unwanted side effects.
Highlights
Platelets are central to normal hemostasis following vascular injury
Whilst platelet procoagulant activity is important for normal hemostasis, it is involved in the pathogenesis of arterial thrombosis on ruptured atherosclerotic plaques [7]
Lactate dehydrogenase (LDH) release was determined as a marker of loss of plasma membrane integrity
Summary
Platelets rapidly adhere to sites of vascular damage and aggregate to form a multicellular plug [1]. A fraction of adherent, activated platelets undergo a necrosis-like cell death process triggered by intracellular calcium overload, mitochondrial dysfunction, and increased reactive oxygen species (ROS), resulting in surface exposure of phosphatidylserine (PS) [2,3,4,5]. Whilst platelet procoagulant activity is important for normal hemostasis, it is involved in the pathogenesis of arterial thrombosis on ruptured atherosclerotic plaques [7]. For this reason, platelet intracellular calcium concentration and ROS must be tightly regulated to prevent inappropriate coagulation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
