Cerebral Microbleeds and Macrobleeds: Should They Influence Our Recommendations for Antithrombotic Therapies?

Intracerebral hemorrhage (ICH, or macrobleeds) and cerebral microbleeds—smaller foci of hemosiderin deposits commonly detected by magnetic resonance imaging of older adults with or without ICH—are both associated with an increased risk of future ICH. These hemorrhagic pathologies also share risk factors with ischemic thromboembolic conditions that may require antithrombotic therapy, requiring specialists in cardiology, internal medicine, and neurology to weigh the benefits vs hemorrhagic risks of antithrombotics in individual patients. This paper will review recent advances in our understanding of hemorrhage prone cerebrovascular pathologies with a particular emphasis on use of these markers in decision making for antithrombotic use.

[1]  B. Hyman,et al.  Association of apolipoprotein E epsilon2 and vasculopathy in cerebral amyloid angiopathy. , 1998, Neurology.

[2]  Ale Algra,et al.  Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis , 2010, The Lancet Neurology.

[3]  A. Hofman,et al.  Cerebral microbleeds are associated with worse cognitive function: The Rotterdam Scan Study , 2011, Alzheimer's & Dementia.

[4]  J. Mohr A randomized trial of unruptured brain arteriovenous malformations (ARUBA). , 2008, Acta neurochirurgica. Supplement.

[5]  S. Greenberg,et al.  Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria , 2003, Current atherosclerosis reports.

[6]  D. Singer,et al.  Can Patients Be Anticoagulated After Intracerebral Hemorrhage?: A Decision Analysis , 2003, Stroke.

[7]  Matthew P. Frosch,et al.  Detection of isolated cerebrovascular β‐amyloid with pittsburgh compound B , 2008, Annals of neurology.

[8]  S. Greenberg,et al.  White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage , 2004, Neurology.

[9]  J. Menzin,et al.  The economic burden of intracerebral hemorrhage: evidence from managed care. , 2006, Managed care interface.

[10]  Eric E. Smith,et al.  Clinical diagnosis of cerebral amyloid angiopathy: Validation of the Boston Criteria , 2003, Current atherosclerosis reports.

[11]  S. Greenberg,et al.  Patient-Specific Decision-Making for Warfarin Therapy in Nonvalvular Atrial Fibrillation: How Will Screening With Genetics and Imaging Help? , 2008, Stroke.

[12]  E. Connolly,et al.  Management of Ruptured Brain Arteriovenous Malformations , 2012, Current Atherosclerosis Reports.

[13]  S. Juvela,et al.  Risk factors for spontaneous intracerebral hemorrhage. , 1995, Stroke.

[14]  D. Singer,et al.  The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. , 2004, Archives of internal medicine.

[15]  P. Neužil,et al.  Left Atrial Appendage Closure With the Watchman Device in Patients With a Contraindication for Oral Anticoagulation , 2013 .

[16]  N. Deshpande Apixaban versus warfarin in patients with atrial fibrillation , 2012 .

[17]  G. Breithardt,et al.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. , 2011, The New England journal of medicine.

[18]  A. Massumi,et al.  Initial experience with a novel percutaneous left atrial appendage exclusion device in patients with atrial fibrillation, increased stroke risk, and contraindications to anticoagulation. , 2013, The American journal of cardiology.

[19]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[20]  Y. H. Kim,et al.  Cerebral microbleeds are regionally associated with intracerebral hemorrhage , 2004, Neurology.

[21]  L Goldman,et al.  Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. , 1989, The American journal of medicine.

[22]  D. Atar,et al.  Apixaban versus warfarin in patients with atrial fibrillation. , 2011, The New England journal of medicine.

[23]  S. Greenberg,et al.  Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage , 2004, Neurology.

[24]  Eric E. Smith,et al.  MRI Markers of Small Vessel Disease in Lobar and Deep Hemispheric Intracerebral Hemorrhage , 2010, Stroke.

[25]  Eric E. Smith,et al.  Antiplatelet use after intracerebral hemorrhage , 2006, Neurology.

[26]  Eric E. Smith,et al.  Hemorrhage Burden Predicts Recurrent Intracerebral Hemorrhage After Lobar Hemorrhage , 2004, Stroke.

[27]  A. Verma,et al.  Imaging of Amyloid Burden and Distribution in Cerebral Amyloid Angiopathy , 2008 .

[28]  Keith A. Johnson,et al.  Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy , 2012, Neurology.

[29]  Eric E. Smith,et al.  Impaired visual evoked flow velocity response in cerebral amyloid angiopathy , 2008, Neurology.

[30]  E. Benjamin,et al.  Stroke Prevention in Atrial Fibrillation in Older Adults: Existing Knowledge Gaps and Areas for Innovation: A Summary of an American Federation for Aging Research Seminar , 2013, Journal of the American Geriatrics Society.

[31]  Istvan Csapo,et al.  Spatial Distribution of White-Matter Hyperintensities in Alzheimer Disease, Cerebral Amyloid Angiopathy, and Healthy Aging , 2008, Stroke.

[32]  S. Greenberg,et al.  Warfarin-associated hemorrhage and cerebral amyloid angiopathy , 2000, Neurology.

[33]  C. Brayne,et al.  Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review , 2009, BMC neurology.

[34]  H. Chiou,et al.  Alzheimer disease and risk of stroke , 2013, Neurology.

[35]  M. Woodward,et al.  Effects of Perindopril-Based Lowering of Blood Pressure on Intracerebral Hemorrhage Related to Amyloid Angiopathy: The PROGRESS Trial , 2010, Stroke.

[36]  D. Nichols,et al.  Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment , 2003, The Lancet.

[37]  S. Yusuf,et al.  Dabigatran versus warfarin in patients with atrial fibrillation. , 2009, The New England journal of medicine.

[38]  J. McNeil,et al.  Risk factors for cerebral hemorrhage in the era of well-controlled hypertension. Melbourne Risk Factor Study (MERFS) Group. , 1996, Stroke.

[39]  M. van Buchem,et al.  Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy , 2010, Neurology.

[40]  J. Gorter,et al.  Major bleeding during anticoagulation after cerebral ischemia , 1999, Neurology.

[41]  Bradley T. Hyman,et al.  Apolipoprotein E ε4 Is Associated With the Presence and Earlier Onset of Hemorrhage in Cerebral Amyloid Angiopathy , 1996 .

[42]  S. Greenberg,et al.  Management of intracerebral hemorrhage , 2008, Current atherosclerosis reports.

[43]  Keith A. Johnson,et al.  Cerebral amyloid angiopathy burden associated with leukoaraiosis: A positron emission tomography/magnetic resonance imaging study , 2013, Annals of neurology.

[44]  C. Sudlow,et al.  Antithrombotic Drug Use, Cerebral Microbleeds, and Intracerebral Hemorrhage: A Systematic Review of Published and Unpublished Studies , 2010, Stroke.

[45]  J. Broderick,et al.  The increasing incidence of anticoagulant-associated intracerebral hemorrhage , 2007, Neurology.

[46]  Daniel B Hier,et al.  Clinical discriminators of lobar and deep hemorrhages , 1991, Neurology.

[47]  Eric E. Smith,et al.  Leukoaraiosis is associated with warfarin-related hemorrhage following ischemic stroke , 2002, Neurology.

[48]  Aad van der Lugt,et al.  Prevalence and Risk Factors of Cerebral Microbleeds: An Update of the Rotterdam Scan Study , 2010, Stroke.

[49]  Steven Warach,et al.  Cerebral Microbleeds : A Field Guide to their Detection and Interpretation , 2012 .

[50]  K. Furie,et al.  Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. , 2000, The New England journal of medicine.

[51]  K. Jellinger,et al.  The impact of cerebrovascular lesions in Alzheimer disease , 2003, Journal of Neurology.

[52]  Eric E. Smith,et al.  Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy , 2010, Neurology.

[53]  M. Graber,et al.  Rivaroxaban vs. warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. , 2012, American family physician.

[54]  S. Leurgans,et al.  Cerebral amyloid angiopathy pathology and cognitive domains in older persons , 2011, Annals of neurology.

[55]  A. Dávalos,et al.  Predictors of good outcome in medium to large spontaneous supratentorial intracerebral haemorrhages , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[56]  M. Aguilar,et al.  Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation , 2007, Annals of Internal Medicine.

[57]  J. Baron,et al.  Spectrum of Transient Focal Neurological Episodes in Cerebral Amyloid Angiopathy: Multicentre Magnetic Resonance Imaging Cohort Study and Meta-Analysis , 2012, Stroke.

[58]  E. Szczerba [Summary of the article: Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011; 365: 1557-1559]. , 2012, Kardiologia polska.

[59]  Rebecca A Betensky,et al.  Microbleeds Versus Macrobleeds: Evidence for Distinct Entities , 2009, Stroke.

[60]  X. Estivill,et al.  Variants at APOE influence risk of deep and lobar intracerebral hemorrhage , 2010, Annals of neurology.

[61]  S. Greenberg,et al.  Association of apolipoprotein E ϵ2 and vasculopathy in cerebral amyloid angiopathy , 1998, Neurology.

[62]  Egill Rostrup,et al.  The spatial distribution of age-related white matter changes as a function of vascular risk factors—Results from the LADIS study , 2012, NeuroImage.

[63]  Wi-Sun Ryu,et al.  Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage , 2009, Neurology.

[64]  D. Atar,et al.  Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. , 2014, European heart journal.

[65]  B T Hyman,et al.  Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. , 1996, Stroke.

[66]  M. Dichgans,et al.  Superficial siderosis is a warning sign for future intracranial hemorrhage , 2012, Journal of Neurology.

[67]  Y. W. Chen,et al.  Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy , 2006, Neurology.

[68]  P. Coutinho,et al.  Superficial Siderosis and Anticoagulation Therapy: Different Presentations, Different Outcomes , 2012, Case reports in neurological medicine.

[69]  Andrew Dumas,et al.  Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy , 2012, Annals of neurology.

[70]  R. Du,et al.  Natural history of cerebral arteriovenous malformations: a meta-analysis. , 2013, Journal of neurosurgery.

[71]  H. Leung,et al.  Risk vs benefit of anti-thrombotic therapy in ischaemic stroke patients with cerebral microbleeds , 2008, Journal of Neurology.

[72]  S. Finklestein,et al.  Petechial hemorrhages accompanying lobar hemorrhage , 1996, Neurology.

[73]  Petr Neuzil,et al.  Left atrial appendage closure with the Watchman device in patients with a contraindication for oral anticoagulation: the ASAP study (ASA Plavix Feasibility Study With Watchman Left Atrial Appendage Closure Technology). , 2013, Journal of the American College of Cardiology.

[74]  M. Gürol Cerebral Amyloid Angiopathy , 2009 .

[75]  Mark D. Huffman,et al.  Heart disease and stroke statistics--2013 update: a report from the American Heart Association. , 2013, Circulation.