A new MPI NIH R01 was awarded to Alisa Wolberg, PhD and Karin Leiderman, PhD of University of North Carolina at Chapel Hill School of Medicine, entitled: 鈥淚nterdisciplinary Approach to Elucidate Modifiers of Bleeding Phenotype in Factor XI Deficiency.鈥�
PROJECT SUMMARY Congenital听deficiency听of plasma clotting听factor听(贵)XI听is an autosomal disorder. Whereas some individuals are asymptomatic (non-bleeders), others have excessive听bleeding听after injury, primarily at sites with high fibrinolytic activity (mouth, nose, genitourinary tract) (bleeders). People with similarly reduced FXI听have variable听bleeding听even within families sharing the same FXI听mutation. Clinical assays cannot predict听bleeding听risk in FXI-deficient people, leading to under- or over-treatment to prevent bleeds. Moreover, FXI听inhibition strategies are in clinical trials to reduce thrombosis; however, observations of individuals with congenital FXI听deficiency听suggest these therapies will incur听bleeding听risk in some patients, especially in prophylactic use. Uncovering mechanisms that determine听bleeding听risk in FXI听deficiency听and developing methods to predict听bleeding听will improve treatment for both听bleeding听and thrombosis. Our long-term goals are to characterize mechanisms that promote hemostasis in FXI听deficiency, and translate these findings into clinically-accessible methods to predict听bleeding. Using plasmas from two independent cohorts of well-phenotyped people with FXI听deficiency, we developed and validated specialized plasma assays that differentiate FXI-deficient bleeders from non-bleeders, and discovered that inhibiting the contact pathway in these assays enhances the ability to identify bleeders. We also integrated computational modeling and in vitro assays to uncover synergy between FXIa and tissue听factor听that enhances coagulation. We built on these discoveries with new analyses that revealed plasma proteins whose levels differed significantly between non-bleeders and bleeders, and a novel computational workflow for advancing a prediction model. These findings and advances provide important clues to mechanisms that modify听bleeding听risk in FXI听deficiency, and position us with innovative tools to identify these mechanisms. The objective of this application is to characterize the determinants and functional impact of differently present plasma proteins in non-bleeders and bleeders, and use computational methods to differentiate听bleeding听risk in FXI听deficiency. The central hypothesis of this application is that in FXI听deficiency, differences in plasma composition modify thrombin generation and clot formation, structure, and stability and determine the听bleeding听risk. Specific aims of this application are to: 1) Determine the functional impact and mechanisms differentiating differently present proteins in FXI-deficient non-bleeders and bleeders, 2) Use computational modeling and machine learning to identify predictive features that differentiate FXI-deficient non- bleeders and bleeders, and 3) Use multi-omic methods to define FXI听deficiency听and the听bleeding听phenotype. This proposed research is significant because the experiments will reveal molecular mechanisms that modify hemostatic potential in a predictive functional assay and in individuals with reduced FXI. Successful completion of this work will reveal new biology and lead to novel methods for predicting听bleeding听risk in individuals with congenital FXI听deficiency听and pharmacologically-reduced FXI听for thrombosis prevention.
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