Warfarin-associated hemorrhage and cerebral amyloid angiopathy
Abstract
BACKGROUND: Intracerebral hemorrhage (ICH) is the most feared complication of warfarin therapy. The pathogenesis of this often-fatal complication remains obscure. Cerebral amyloid angiopathy (CAA) is a major cause of spontaneous lobar hemorrhage in the elderly and is associated with specific alleles of the APOE gene. OBJECTIVE: To assess the role of CAA in warfarin-associated ICH. METHODS: Clinical characteristics and APOE genotype were compared between 41 patients with warfarin-related ICH (from a cohort of 59 consecutive patients aged > or = 65 years with supratentorial ICH on warfarin) and 66 randomly selected individuals aged > or = 65 years without ICH taking warfarin. In addition, all neuropathologic specimens from ICH patients were reviewed for the presence and severity of CAA. RESULTS: Hemorrhages tended to be in the lobar regions of the brain, and most (76%) occurred with an international normalized ratio of < or = 3.0. The APOE epsilon2 allele was overrepresented among patients with warfarin-associated lobar hemorrhage (allele frequency 0.13 versus 0.04 in control subjects; p = 0.031). After controlling for other variables associated with ICH, carriers of the epsilon2 allele had an OR of 3.8 (95% CI, 1.0 to 14.6) for lobar ICH. CAA was pathologically diagnosed as the cause of lobar hemorrhage in 7 of 11 patients with available tissue samples. CONCLUSIONS: CAA is an important cause of warfarin-associated lobar ICH in the elderly. Although diagnosis of CAA before hemorrhage is not yet possible, these data offer hope that future patients at high risk for hemorrhage may be identified before initiation of warfarin therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028 · see citing works
Risk Factors for Stroke and Efficacy of Antithrombotic Therapy in Atrial Fibrillation
(1994) · Archives of Internal Medicine · doi:10.1001/archinte.1994.00420130036007 · Cited by 2,066 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Hemorrhagic Complications of Anticoagulant Treatment
Levine, M. N., Raskob, G. E., Landefeld, S., & Kearon, C. (2001) · CHEST Journal · doi:10.1378/chest.119.1_suppl.108s · Cited by 1,129 · see citing works
Cerebral amyloid angiopathy. A critical review.
Vinters, H. V. (1987) · Stroke · doi:10.1161/01.str.18.2.311 · Cited by 1,070 · see citing works
Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin
Hylek, E. M., & Singer, D. E. (1994) · Annals of Internal Medicine · doi:10.7326/0003-4819-120-11-199406010-00001 · Cited by 915 · see citing works
Self-citationLandefeld, C. S., & Goldman, O. L. (1989) · The American Journal of Medicine · doi:10.1016/s0002-9343(89)80689-8 · Cited by 777 · see citing works
Oral Anticoagulants and Intracranial Hemorrhage
Hart, R. G., Boop, B. S., & Anderson, D. C. (1995) · Stroke · doi:10.1161/01.str.26.8.1471 · Cited by 545 · see citing works
Apolipoprotein E ϵ4 and cerebral hemorrhage associated with amyloid angiopathy
Greenberg, S. M., Rebeck, G. W., Vonsattel, J. P., Gómez‐Isla, T., & Hyman, B. T. (1995) · Annals of Neurology · doi:10.1002/ana.410380219 · Cited by 540 · see citing works
Self-citationApolipoprotein E Genotype and the Risk of Recurrent Lobar Intracerebral Hemorrhage
O’Donnell, H. C., Rosand, J. M., Knudsen, K. A., Furie, K. L., Segal, A. Z., Chiu, R. I., Ikeda, D., & Greenberg, S. M. (2000) · New England Journal of Medicine · doi:10.1056/nejm200001273420403 · Cited by 499 · see citing works
Self-citationFranke, C., Koehler, P., Gorter, J., Kappelle, L., Rinkel, G., Tjeerdsma, H., van Gijn, J., Dammers, J., Straatman, H., ten Houten, R., et al. (1997) · Annals of Neurology · doi:10.1002/ana.410420606 · Cited by 477 · see citing works
Bleeding During Antithrombotic Therapy in Patients With Atrial Fibrillation
(1996) · Archives of Internal Medicine · doi:10.1001/archinte.156.4.409 · Cited by 435 · see citing works
Premkumar, D. R., Cohen, D., Hedera, P., Friedland, R. P., & Kalaria, R. N. (1996) · Europe PMC (PubMed Central) · Cited by 345 · see citing works
Diagnosis of Cerebral Amyloid Angiopathy: Sensitivity and Specificity of Cortical Biopsy
Greenberg, S. M., & Vonsattel, J.-P. G. (1997) · Stroke · doi:10.1161/01.str.28.7.1418 · Cited by 312 · see citing works
Self-citationMajor bleeding during anticoagulation after cerebral ischemia
Gorter, J. W., (SPIRIT), F. T. S. P. I. R. I. T., & Groups, E. A. F. T. (. S. (1999) · Neurology · doi:10.1212/wnl.53.6.1319 · Cited by 307 · see citing works
ApoE genotype and survival from intracerebral haemorrhage
Alberts, M., Graffagnino, C., McClenny, C., DeLong, D. M., Strittmatter, W. J., Saunders, A. M., & Roses, A. D. (1995) · The Lancet · doi:10.1016/s0140-6736(95)91411-0 · Cited by 287 · see citing works
High frequency of apolipoprotein E ϵ2 Allele in hemorrhage due to cerebral amyloid angiopathy
Nicoll, J. A. R., Burnett, C., Love, S., Graham, D. I., Dewar, D., Ironside, J. W., Stewart, J., & Vinters, H. V. (1997) · Annals of Neurology · doi:10.1002/ana.410410607 · Cited by 284 · see citing works
Bleeding During Antithrombotic Therapy in Patients With Atrial Fibrillation
(1996) · Archives of Internal Medicine · doi:10.1001/archinte.1996.00440040081009 · Cited by 283 · see citing works
Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy
Greenberg, S. M., Vonsattel, J.-P. G., Segal, A. Z., Chiu, R. I., Clatworthy, A. E., Liao, A., Hyman, B. T., & Rebeck, G. W. (1998) · Neurology · doi:10.1212/wnl.50.4.961 · Cited by 267 · see citing works
Self-citationClinicopathologic Studies of Primary Cerebral Amyloid Angiopathy
Okazaki, H., Reagan, T. J., & Campbell, R. J. (1979) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(25)18993-3 · Cited by 259 · see citing works
Contrast sonography for detection of vesicoureteral reflux
Kaneko, K., Kuwatsuru, R., Fukuda, Y., Yamataka, A., Yabuta, K., Katayama, H., & Miyano, T. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92123-7 · Cited by 222 · see citing works
Atrial fibrillation and stroke. Three new studies, three remaining questions
Albers, G. W. (1994) · Archives of Internal Medicine · doi:10.1001/archinte.154.13.1443 · Cited by 182 · see citing works
MRI detection of new hemorrhages: Potential marker of progression in cerebral amyloid angiopathy
Greenberg, S. M., O’Donnell, H. C., Schaefer, P. W., & Kraft, E. (1999) · Neurology · doi:10.1212/wnl.53.5.1135 · Cited by 177 · see citing works
Self-citationRådberg, J., Olsson, J. E., & Rådberg, C. (1991) · Stroke · doi:10.1161/01.str.22.5.571 · Cited by 171 · see citing works
McCarron, M. O., Nicoll, J. A. R., Stewart, J., Ironside, J. W., Mann, D. M. A., Love, S., Graham, D. I., & Dewar, D. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199907000-00005 · Cited by 160 · see citing works
Atrial Fibrillation and Stroke
Albers, G. W. (1994) · Archives of Internal Medicine · doi:10.1001/archinte.1994.00420130030006 · Cited by 145 · see citing works
Gustafsson, C., Asplund, K., Britton, M., Norrving, B. G., Olsson, B. S., & Marké, L.-Å. (1992) · BMJ · doi:10.1136/bmj.305.6867.1457 · Cited by 129 · see citing works
The Apolipoprotein E ε4 Allele and Outcome in Cerebrovascular Disease
McCarron, M. O., Muir, K. W., Weir, C. J., Dyker, A. G., Bone, I., Nicoll, J. A. R., & Lees, K. R. (1998) · Stroke · doi:10.1161/01.str.29.9.1882 · Cited by 125 · see citing works
Sloan, M. A., Price, T. R., Petito, C. K., Randall, A. M. Y., Solomon, R. E., Terrin, M. L., Gore, J. M., Collen, D., Kleiman, N. S., Feit, F., et al. (1995) · Neurology · doi:10.1212/wnl.45.4.649 · Cited by 122 · see citing works
Hemorrhagic Complications of Anticoagulant Treatment
Levine, M., Raskob, G. E., Landefeld, S., & Kearon, C. (1998) · CHEST Journal · doi:10.1378/chest.114.5_supplement.511s · Cited by 117 · see citing works
McCarron, M. O., Nicoll, J. A. R., Ironside, J. W., Love, S., Alberts, M. J., & Bone, I. (1999) · Stroke · doi:10.1161/01.str.30.8.1643 · Cited by 92 · see citing works
McCarron, M. O., & Nicoll, J. A. R. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00286-9 · Cited by 88 · see citing works
Greenberg, S. M., & Edgar, M. A. (1996) · New England Journal of Medicine · doi:10.1056/nejm199607183350308 · Cited by 44 · see citing works
Self-citationMelo, T. P. E., Bogousslavsky, J., Regli, F., et al. (2008) · European Neurology · doi:10.1159/000116890 · Cited by 19 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet . 1994; 343: 687–691.
Cited by
Sorted by citations
Qureshi, A. I., Mendelow, A. D., & Hanley, D. F. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60371-8 · Cited by 1,526 · see citing works
Broderick, J., Connolly, S., Feldmann, E., Hanley, D., Kase, C., Krieger, D., Mayberg, M., Morgenstern, L., Ogilvy, C. S., Vespa, P., et al. (2007) · Stroke · doi:10.1161/strokeaha.107.183689 · Cited by 1,125 · see citing works
Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria
Knudsen, K. A., Rosand, J., Karluk, D., & Greenberg, S. M. (2001) · Neurology · doi:10.1212/wnl.56.4.537 · Cited by 1,015 · see citing works
Self-citationCharidimou, A., Gang, Q., & Werring, D. J. (2012) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2011-301308 · Cited by 611 · see citing works
Cerebral Amyloid Angiopathy: Emerging Concepts
Yamada, M. (2015) · Journal of Stroke · doi:10.5853/jos.2015.17.1.17 · Cited by 367 · see citing works
Jeerakathil, T., Wolf, P. A., Beiser, A., Hald, J. K., Au, R., Kase, C. S., Massaro, J. M., & DeCarli, C. (2004) · Stroke · doi:10.1161/01.str.0000131809.35202.1b · Cited by 319 · see citing works
Atrial Fibrillation and Stroke: Concepts and Controversies
Hart, R. G., & Halperin, J. L. (2001) · Stroke · doi:10.1161/01.str.32.3.803 · Cited by 318 · see citing works
Sporadic cerebral amyloid angiopathy: pathology, clinical implications, and possible pathomechanisms
Attems, J. (2005) · Acta Neuropathologica · doi:10.1007/s00401-005-1074-9 · Cited by 238 · see citing works
Hanley, J. P. (2004) · Journal of Clinical Pathology · doi:10.1136/jcp.2003.008904 · Cited by 215 · see citing works
Cerebrovascular pathology in Down syndrome and Alzheimer disease
Head, E., Phelan, M. J., Doran, E., Kim, R. C., Poon, W. W., Schmitt, F. A., & Lott, I. T. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0499-4 · Cited by 105 · see citing works
(2012) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-385883-2.00006-0 · Cited by 84 · see citing works
Prevalence of cortical superficial siderosis in patients with cognitive impairment
Wollenweber, F. A., Buerger, K., Mueller, C., Ertl-Wagner, B., Malik, R., Dichgans, M., Linn, J., & Opherk, C. (2014) · Journal of Neurology · doi:10.1007/s00415-013-7181-y · Cited by 53 · see citing works
- Authors
- Rosand, J., Hylek, E. M., O’Donnell, H. C., & Greenberg, S. M.
- Affiliations
- Harvard University (US)
- Venue
- Neurology
- Published
- 2000-10-10
- Volume
- 55
- Issue
- 7
- Pages
- 947-951
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W2068808615
- Semantic Scholar
- aa2602637f6ce47da9897c0b3e4686a4da80e931
- Cited by
- 309
- References
- 36
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 9 · 2019: 6 · 2018: 13 · 2017: 12 · 2016: 14 · 2015: 12 · 2014: 21 · 2013: 17 · 2012: 12
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Chinese Academy of Agricultural Sciences
- National Institute on Aging (AG00725)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Neurology › Intracranial Aneurysms: Treatment and Complications
- Keywords
- warfarin, intracerebral hemorrhage, cerebral amyloid angiopathy, APOE ε2 allele, lobar hemorrhage, elderly patients, international normalized ratio, hemorrhagic stroke risk, neuropathology
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Apolipoproteins E, Cerebral Hemorrhage, Female, Genotype, Humans, Male, Prospective Studies, Warfarin, Cerebral Amyloid Angiopathy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
