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Mechanisms and Modifiers of Bleeding

Sponsor: Scientific Committee on Hemostasis
Program: Scientific Program
Hematology Disease Topics & Pathways:
Bleeding Disorders, Hemophilia, Bleeding and Clotting, Diseases, Biological Processes, inflammation, integrative -omics
Monday, December 7, 2020: 8:55 AM-9:00 AM

Description:
Coagulation is a dynamic process. In its normal setting, it involves a pro-coagulant pathway that results in the development of a fibrin clot that is balanced by mechanisms that limit the extent of the clot to the site of injury. This complex highly regulated system involves interactions between the vessel wall, platelets, and coagulation factors among others. Disruption to this balance may result in either bleeding or thrombosis. Over the last decade great strides have been made in understanding mechanisms and modifiers of this system. This session will present recent developments across diverse fields that continue to push the envelope on our knowledge and understanding of the mechanisms and modifiers of bleeding.

Dr. Mitchell Cohen will discuss the drivers and mechanisms of acute traumatic coagulopathy. Specifically, he will describe the clinical and biologic picture of coagulation and inflammatory perturbations after severe injury and shock. In addition, Dr. Cohen will address translational approaches to the study of these topics and future research.

Dr. Valerie O’Donnell will discuss the interaction of the phospholipid membrane surface of platelets and white blood cells with coagulation factors, specifically the generation and action of enzymatically-oxidized phospholipids formed by lipoxygenases. Her lab has shown that these lipids regulate coagulation during development of abdominal aortic aneurysms (AAA) in mice, and that they are found in human AAA lesions. Extensive in vitro studies have defined the mechanisms of action of these lipids, showing that they enhance the ability of phosphatidylserine to support coagulation.

Dr. Karin Leiderman will discuss a mathematical and computational approach to studying variability in bleeding patterns among individuals with hemophilia A. Uncertainty and sensitivity analysis were recently performed on a mathematical model of flow-mediated coagulation to identify parameters most likely to enhance thrombin generation in the context of FVIII deficiency. Results from those computational studies identified low-normal FV (50%) as the strongest modifier, with additional thrombin enhancement when combined with high‐normal prothrombin (150%). Partial FV inhibition (60% activity) augmented thrombin generation in FVIII‐inhibited or FVIII‐deficient plasma in CAT and boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies; these effects were amplified by high‐normal prothrombin levels in both experimental models. Dr. Leiderman will highlight how the mathematical model was used to predict a biochemical mechanism underlying the modified thrombin response.

Chair:
Shannon Meeks, MD, Emory University
Disclosures:
Meeks: Sanofi: Membership on an entity's Board of Directors or advisory committees; octapharma: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy; Spark: Consultancy; Pfizer: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees.
Coagulation is a dynamic process. In its normal setting, it involves a pro-coagulant pathway that results in the development of a fibrin clot that is balanced by mechanisms that limit the extent of the clot to the site of injury. This complex highly regulated system involves interactions between the vessel wall, platelets, and coagulation factors among others. Disruption to this balance may result in either bleeding or thrombosis. Over the last decade great strides have been made in understanding mechanisms and modifiers of this system. This session will present recent developments across diverse fields that continue to push the envelope on our knowledge and understanding of the mechanisms and modifiers of bleeding.

Dr. Mitchell Cohen will discuss the drivers and mechanisms of acute traumatic coagulopathy. Specifically, he will describe the clinical and biologic picture of coagulation and inflammatory perturbations after severe injury and shock. In addition, Dr. Cohen will address translational approaches to the study of these topics and future research.

Dr. Valerie O’Donnell will discuss the interaction of the phospholipid membrane surface of platelets and white blood cells with coagulation factors, specifically the generation and action of enzymatically-oxidized phospholipids formed by lipoxygenases. Her lab has shown that these lipids regulate coagulation during development of abdominal aortic aneurysms (AAA) in mice, and that they are found in human AAA lesions. Extensive in vitro studies have defined the mechanisms of action of these lipids, showing that they enhance the ability of phosphatidylserine to support coagulation.

Dr. Karin Leiderman will discuss a mathematical and computational approach to studying variability in bleeding patterns among individuals with hemophilia A. Uncertainty and sensitivity analysis were recently performed on a mathematical model of flow-mediated coagulation to identify parameters most likely to enhance thrombin generation in the context of FVIII deficiency. Results from those computational studies identified low-normal FV (50%) as the strongest modifier, with additional thrombin enhancement when combined with high‐normal prothrombin (150%). Partial FV inhibition (60% activity) augmented thrombin generation in FVIII‐inhibited or FVIII‐deficient plasma in CAT and boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies; these effects were amplified by high‐normal prothrombin levels in both experimental models. Dr. Leiderman will highlight how the mathematical model was used to predict a biochemical mechanism underlying the modified thrombin response.

Mitchell J. Cohen

University of Colorado, Denver, CO

Valerie O'Donnell

Cardiff University, Cardiff, United Kingdom

Karin Leiderman, PhD

Colorado School of Mines, Arvada, CO

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