# Bleeding on Direct Oral Anticoagulants: Identification of Genetic Risk Factors and a Polygenic Predictive Score in Patients with Atrial Fibrillation

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $78,550

## Abstract

PROJECT SUMMARY/ABSTRACT
Atrial fibrillation (AF) is the most common cardiac arrhythmia and the leading cause of ischemic stroke.
Anticoagulants reduce the risk of stroke in AF patients by about two-thirds, but the main safety concern of this
long-term oral therapy is the risk of fatal or life-threatening bleeding. Warfarin was once the leading oral
anticoagulant in patients with AF, but it is being replaced by Direct Oral Anticoagulants (DOACs). Although AF
patients bleed less with DOACs than warfarin, bleeding is still a major problem varying from ~2% to ~40%.
Clinical factors predisposing to bleeding are well-known, but they do not fully explain bleeding risk. The best
clinical prediction model still does not explain 32% of bleeding events on DOACs. Unlike warfarin, which is
monitored by international normalized ratio (INR), there is no routinely used measure for clinical monitoring of
DOACs. Therefore, there is a critical need to better understand the risk factors for bleeding from DOACs. Since
drug responses are highly heritable, the central hypothesis of this research is that genetics can help explain
bleeding risk in AF patients on DOACs. Therefore, the overall goal of this research is to identify genetic variants
associated with bleeding risk from DOACs. Previous candidate gene studies associated genetic variants with
changes in plasma concentration of DOACs, which may increase bleeding risk in AF patients. However, there
are only a few candidate gene studies assessing bleeding as an outcome with very small sample sizes (typically
n <400) and inconclusive results. Therefore, the objective of Aim 1 is to overcome those limitations by performing
candidate gene association analysis of a large clinical & genomic dataset with bleeding outcomes (n=2,470 AF
patients on DOACs in the Michigan Genomics Initiative [MGI]). Another limitation of the previous studies was the
reliance on the candidate gene approach, which can miss unsuspected genes. A genome-wide association study
(GWAS) could discover novel variants associated with the risk of bleeding from DOACs and enable the derivation
of the first polygenic score for predicting this risk, which are the objective of Aim 2. Both approaches will be
carried out to compensate for the limitations of each method. The overall approach is to analyze an existing
clinical & genomic dataset (MGI), which integrates whole genome array data (post quality control & imputation)
and complete access to electronic medical records (EMR). The primary outcome is a composite of major and
clinically relevant non-major (CRNM) bleeding. The secondary outcomes are major and clinically relevant non-
major bleeding. This research is feasible by leveraging an existing dataset, the expertise of all sponsors,
resources at the University of Michigan, and established methods. Also, this research is highly relevant because
it addresses an important clinical knowledge gap by determining the association of genetic variants with bleedin...

## Key facts

- **NIH application ID:** 10536789
- **Project number:** 1F32HL162231-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Alessandra Menezes Campos Staffico
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,550
- **Award type:** 1
- **Project period:** 2022-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536789

## Citation

> US National Institutes of Health, RePORTER application 10536789, Bleeding on Direct Oral Anticoagulants: Identification of Genetic Risk Factors and a Polygenic Predictive Score in Patients with Atrial Fibrillation (1F32HL162231-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10536789. Licensed CC0.

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