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By Lynn Malec, MD, MSc, and Janice Staber, MD

From the stock market to politics, keeping gains and losses straight these days can be confusing. Scientific gains and losses can be equally overwhelming. Thankfully, in Monday’s Scientific Spotlight Session on Redox Biology in Thrombosis, the pathways involved in electron losses and gains and their effect on platelet biology were highlighted by two thought leaders.

Reactive oxygen species (ROS), a type of unstable molecule, are a natural byproduct of aerobic metabolism involved in endogenous signaling. A buildup of ROS is associated with oxidative stress and is implicated in disease states, including atherosclerosis, diabetes, neurodegeneration, and aging. ROS and redox biology have received significant attention in vascular biology; however, there has previously been little focus on ROS production by, and influences on, platelet function. Co-Chair Craig Morrell, DVM, PhD, explored the intersection of platelets and thrombosis through investigating the role of ROS in platelet function. Dr. Morrell and co-chair, Karen Vanhoorelbeke, PhD, provided attendees with new data regarding the complicated interplay between ROS, platelets, and various disease states.

Dr. Morrell opened the session, discussing the intersection of platelets and thrombosis. During his lecture titled Oxidative Signaling in Platelets, he focused on the mechanisms of platelet signaling in response to ROS, both endogenous and exogenous, noting that extracellular ROS can contribute to platelet hyper-reactivity in disease states. He highlighted the role of ERK5, a typical MAP kinase and redox/ROS sensor in endothelial cells, and its downstream effects on platelet activation. He raised the question as to whether ERK5, given its function, could be a target to inhibit platelet activation seen in patients with acute myocardial infarction. He highlighted his work investigating this question by using an ERK5–/– mouse model. These mice have less post–myocardial infarction cardiac fibrosis and more “containment” of the cardiac injury compared to wild-type mice. Regarding other ischemic vascular pathologies, he discussed how the presence of ROS changes in the platelet proteome, and linked these findings to peripheral artery disease.

Dr. Vanhoorelbeke became interested in studying von Willebrand factor (vWF) and ADAMTS13 shortly after the cleaving protease was discovered. Her insightful studies have deepened our knowledge of thrombotic thrombocytopenic purpura (TTP), including the development of TTP animal models for both the congenital and acquired forms, and the investigation of new therapies for TTP treatment. Following Dr. Morrell’s lecture, Dr. Vanhoorelbeke presented two topics covering TTP: N-acetylcysteine [NAC] in Thrombotic Thrombocytopenic Purpura, and ADAMTS13 Conformation and Autoantibodies in TTP. She began with a review of the novel therapeutics that are either approved or under development for the treatment of TTP, including recombinant ADAMTS13 and inhibitors of vWF-GP1b interaction. Dr. Vanhoorelbeke discussed pre- clinical models of TTP treated with NAC. Through a series of experiments, she demonstrated that NAC reduces the size and activity of vWF in vivo by reducing disulfide bonds linking vWF monomers, thereby decreasing ultra-large vWF multimers. Subsequently, the role of NAC was reviewed as it relates to treating patients with TTP, noting there are both responsive and nonresponsive patients when this therapy is added to the standard backbone of plasma exchange and immunosuppression, and that a clinical trial of this therapy is underway.

Dr. Vanhoorelbeke also discussed novel data regarding the role of anti-ADAMTS13 autoantibodies in immune-mediated TTP. She identified an antibody recognizing a cryptic epitope in the spacer domain of ADAMTS13 and subsequently developed an immunoassay to detect open and closed ADAMTS13. She demonstrated that open ADAMTS13 is likely a novel biomarker for subclinical disease in TTP and can be a surrogate marker for the presence of anti-ADAMTS13 autoantibodies. After these talks, attendees undoubtedly had a better appreciation for the importance of studying gains and losses in thrombotic biology and the interface of redox biology in platelets and thrombosis.

Dr. Malec and Dr. Staber indicated no relevant conflicts of interest.

 

 

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