Impact of the Y285C Prothrombin Variant on Coagulation and Hemostasis, and Investigations into Treatment

Grants and Contracts Details

Description

Impact of the Y285C prothrombin variant on coagulation and hemostasis, and investigations into treatment Abstract A patient with a familial history of moderate-to-severe, life-threatening bleeding presented to the Versiti Blood Research Institute in Milwaukee. While the cause of the bleeding is unknown, genetic sequencing revealed a novel mutation in the gene for prothrombin (Y285C), the precursor protein to thrombin, which segregates with the bleeding phenotype. Thrombin is the enzyme that converts soluble fibrinogen into an insoluble fibrin clot. Due to its position in the protein, we hypothesize that the Y285C mutation alters the activation of thrombin and results in the accumulation of an anticoagulant enzyme known as meizothrombin. The goals of this project are to: (1) determine the effect of the Y285C mutation on the structure, activation, and function of prothrombin and on coagulation and fibrin clot formation ex vivo; (2) assess the impact of the mutation in ex vivo models of human hemostasis and in vivo models of murine hemostasis (performed by collaborator Shawn Jobe, MD, Michigan State University); and (3) investigate the effect of current and novel hemostatic treatments ex vivo and in vivo as potential agents to promote clot formation and prevent hemorrhage. Scope of Our Work The work in Aim 1 will be performed here. This includes the expression and purification of recombinant prothrombin containing the mutation, biochemical analyses of prothrombin activation and function, and computer modeling of prothrombin structure. We will also provide protein to Dr. Jobe for use in Aim 2, and will use our biochemical models to assess potential therapeutic agents (Aim 3).
StatusFinished
Effective start/end date3/1/222/28/23

Funding

  • Versiti Blood Research Institute Foundation: $63,500.00

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