Inherited Genetic Variants Associated With Bleeding on Common Anticoagulant

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A group of gene mutations seen only in African-Americans and people of African ancestry may contribute to an increased risk of serious bleeding while taking warfarin, a common anticoagulant drug, according to a Northwestern Medicine study published in the Journal of the American Medical Association.

These bleeding events are mostly unpredictable with current clinical tools, but incorporating testing for these genetic variants into diagnostic guidelines could make warfarin safer in the future, said Minoli Perera, PharmD, PhD, associate professor of Pharmacology and senior author of the study.

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“These mutations could be included in the risk-benefit calculations every physician makes with a patient,” said Perera, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Center for Pharmacogenomics.

Warfarin is an old but effective anticoagulation drug used to alleviate blood clots in a variety of conditions. The risk of severe bleeding is well known, so clinicians tailor doses to keep patients’ anticoagulant levels in a moderate range, according to the study.

However, during a previous investigation, Perera noticed a larger than expected number of African-American patients on warfarin experiencing clinically significant bleeds — bleeds that put these patients in the hospital.

“They were bleeding when this drug would have been thought to be therapeutic or only slightly elevated,” Perera said. “A physician wouldn’t be clinically suspicious of these levels of anticoagulation.”

This inspired the current study; a genome-wide analysis of 215 patients in which 31 patients who, while raising no alarms with their anticoagulant levels, experienced serious bleeding while taking warfarin.

The analysis revealed four single-nucleotide polymorphisms (SNPs) that were associated with a higher risk of warfarin bleeding among these otherwise normal patients. These four mutations are inherited together in the same chunk of DNA on chromosome six, and are found only in people with African ancestry.

Perera and her colleagues then added the presence of these mutations to a pre-existing survey used to determine the risk of bleeding, finding the addition boosted the predictive power of the survey from about 67 percent to 78 percent.

“This shows the SNP is adding information that the scoring system cannot capture,” Perera said. “If it didn’t improve predictive power, it would mean the effect of the SNPs are already captured by the factors already known.”

While not enough is known about these mutations to immediately incorporate them into clinical testing, they might have value in a future where a patient’s genomic data is more readily available, Perera said.

“I envision that one day we’ll all have our genomes in our medical record, and a physician will discover their patient who needs anticoagulation has this SNP,” Perera said. “It might mean that you’re more vigilant with their anticoagulant levels, or maybe you think about other less intense ways to anticoagulate them.”

In addition, Perera is interested in the mechanisms by which these mutations confer susceptibility to bleeding on warfarin. Preliminary analysis in the study showed this gene was highly expressed in endothelial cells, which line the blood vessels and may be involved in clotting.

“These endothelial cells are interacting with blood and platelets,” Perera said. “When there’s a break in the blood vessel, these cells are what the clots form on — maybe if you don’t express that gene, the platelets don’t bind to the break.”

Other authors include Perera laboratory members Tanima De, PhD, postdoctoral fellow and first author of the study, and Cristina Alarcon, PhD, laboratory manager, in addition to collaborators at the University of Illinois and the University of Florida.

The study was funded by National Heart, Lung, and Blood Institute (NHBLI) grants K23 HL089808-01A2, R21 HL106097 and R01MD009217, National Institutes of Health National Institute of General Medical Sciences grant K23GM112014 and American Heart Association Midwest Affiliate grant 10GRNT3750024.