Oxidative Stress and Thrombosis during Aging: The Roles of Oxidative Stress in RBCs in Venous Thrombosis

Abstract

Mid-life stage adults are at higher risk of developing venous thrombosis (VT)/thromboembolism (VT/E). Aging is characterized by an overproduction of reactive oxygen species (ROS), which could evoke a series of physiological changes involved in thrombosis. Here, we focus on the critical role of ROS within the red blood cell (RBC) in initiating venous thrombosis during aging. Growing evidence has shifted our interest in the role of unjustifiably unvalued RBCs in blood coagulation. RBCs can be a major source of oxidative stress during aging, since RBC redox homeostasis is generally compromised due to the discrepancy between prooxidants and antioxidants. As a result, ROS accumulate within the RBC due to the constant endogenous hemoglobin (Hb) autoxidation and NADPH oxidase activation, and the uptake of extracellular ROS released by other cells in the circulation. The elevated RBC ROS level affects the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability. These changes impair RBC function in hemostasis and thrombosis, favoring a hypercoagulable state through enhanced RBC aggregation, RBC binding to endothelial cells affecting nitric oxide availability, RBC-induced platelet activation consequently modulating their activity, RBC interaction with and activation of coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles, accelerated aging and hemolysis. Thus, RBC oxidative stress during aging typifies an ultimate mechanism in system failure, which can affect major processes involved in the development of venous thrombosis in a variety of ways. The reevaluated concept of the critical role of RBC ROS in the activation of thrombotic events during aging will help identify potential targets for novel strategies to prevent/reduce the risk for VT/E or VT/E recurrences in mid-life stage adults.

The Role of Oxidative Stress in Cardiovascular Aging and Cardiovascular Diseases

“…Up-regulation of ROS-producing enzymes (e.g., NADPH oxidase and myeloperoxidase), along with down-regulation of antioxidant enzymes (e.g., SOD and glutathione peroxidase GPx), occur in the elderly. This imbalance may lead to thrombosis by damaging red blood cell (RBC) shape and function, causing endothelial dysfunction, and triggering platelets and leukocytes, therefore affecting the clotting system [ 374 ]. RBCs can be a major source of oxidative stress in elderly, since RBC redox homeostasis is usually compromised.…”

“…In fact, ROS con easily accumulate within the RBC due to constant autoxidation of endogenous hemoglobin (Hb) and to NADPH oxidase activation. Moreover, RBC in their path uptake extracellular ROS released by other cells in the circulation [ 374 ]. Specifically, ROS affect the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability [ 374 ].…”

“…Moreover, RBC in their path uptake extracellular ROS released by other cells in the circulation [ 374 ]. Specifically, ROS affect the RBC membrane structure and function, causing loss of membrane integrity, and decreased deformability [ 374 ]. This process impairs RBC function in hemostasis and thrombosis, supporting a hypercoagulable state.…”

“…Overall, these changes lead to enhanced RBC aggregation by increased binding to endothelial cells which also affects nitric oxide availability [ 375 ]. Accelerated aging and hemolysis is also a key factor as shown by increased RBC-induced platelet activation, RBC interaction with coagulation factors, increased RBC phosphatidylserine exposure and release of microvesicles [ 374 ].…”

“…In summary, aging and oxidative stress influences greatly RBC deformability, blood rheology, altering blood flow in the circulation [ 376 ]. All the above combined with genetic polymorphisms and mutations can trigger venous prothrombotic events [ 377 ], thus predisposing the elderly to age-related VTE [ 374 ]. In conclusion, a further better understanding of the detailed mechanisms by which aging, and the associated oxidative stress disrupt the coagulation cascade to initiate venous thrombosis would provide new targets for tailored therapies to prevent VTE in the elderly.…”