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).
Status | Finished |
---|---|
Effective start/end date | 3/1/22 → 2/28/23 |
Funding
- Versiti Blood Research Institute Foundation: $63,500.00
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