Genetic Variants Increase Risk of Intracerebral Hemorrhage in Patients on Warfarin

Christopher D. Anderson, MD, MMSc Neurocritical Care | Acute Stroke Center for Human Genetic Research Massachusetts General Hospital Harvard Medical School Broad Institute of Harvard and Interview with:
Christopher D. Anderson, MD, MMSc
Neurocritical Care | Acute Stroke
Center for Human Genetic Research
Massachusetts General Hospital
Harvard Medical School
Broad Institute of Harvard and MIT

Medical Research: What are the main findings of the study?

Dr. Anderson: Previous studies have linked Apolipoprotein E (APOE) epsilon variants with spontaneous intracerebral hemorrhage (ICH) particularly in the lobar (cortical and subcortical) regions of the brain, but it was not known whether this association would extend to warfarin-related ICH, or whether the risk of intracerebral hemorrhage on warfarin would be multiplicatively compounded by APOE epsilon allele status.  Our results demonstrate that APOE e2 and e4 variants are associated with more than a two-fold risk of lobar ICH for patients on warfarin, in comparison to warfarin-exposed individuals without ICH.  This observed association was strongest when analyzing subjects with definite or probable Cerebral Amyloid Angiopathy (CAA), as defined by the Boston Criteria.  No association between APOE e2 or e4 and non-lobar ICH was identified following our replication phase.  Furthermore, we did not detect an interaction between APOE status and warfarin status in ICH subjects using a case-only design.

Medical Research: Were any of the findings unexpected?

Dr. Anderson: Overall, the observed results support the notion that the vasculopathic small vessel changes that lead to intracerebral hemorrhage are influenced by similar genetic factors regardless of whether or not a patient is on warfarin.  The fact that we did not observe an interaction between APOE epsilon allele status and warfarin exposure may be surprising to some, but given our sample size we cannot definitively exclude the possibility that a supra-additive interaction exists.

Medical Research: What should clinicians and patients take away from your report?

Dr. Anderson: Our results suggest that APOE e2 and e4, genetic variants that are implicated in the pathogenesis of Cerebral Amyloid Angiopathy, influence the risk of warfarin-related ICH in the lobar regions of the brain.  We have found that the use of APOE genotypes improves our ability to differentiate ICH subjects from warfarin-exposed individuals who have not suffered an ICH.  These findings are preliminary, but could inform future studies to help identify patients who are at the greatest risk of ICH on anticoagulation.  Certainly, at this point, there is no evidence to support APOE genetic testing to inform decision-making around the use of warfarin in patients for whom that medication is indicated.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Anderson: In the future, APOE genotypes and diagnostic criteria for CAA may help to identify patients at greater risk for ICH on warfarin.  Because our study used a hospital-based case-control study design, our observations would need to be supported by similar results in a prospective framework before an interventional strategy could be supported.  However, these results may eventually lead to new strategies in “precision medicine” to guide decision-making in patients being considered for warfarin anticoagulation.


APOE ε variants increase risk of warfarin-related intracerebral hemorrhage

Falcone GJ1, Radmanesh F1, Brouwers HB1, Battey TW1, Devan WJ1, Valant V1, Raffeld MR1, Chitsike LP1, Ayres AM1, Schwab K1, Goldstein JN1, Viswanathan A1, Greenberg SM1, Selim M1, Meschia JF1, Brown DL1, Worrall BB1, Silliman SL1, Tirschwell DL1, Flaherty ML1, Martini SR1, Deka R1, Biffi A1, Kraft P1, Woo D1, Rosand J1, Anderson CD2; On Behalf of the International Stroke Genetics Consortium.
2014 Aug 22. pii: 10.1212/WNL.0000000000000816. [Epub ahead of print