Charidimou, Andreas

McCarron, Mark O.

Nicoll, James A.R.

Frontiers in Neurology

PubMed

Andreas Charidimou

James A. R. Nicoll

Mark O. McCarron

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Thrombolysis-Related Intracerebral Hemorrhage and Cerebral Amyloid Angiopathy: Accumulating Evidence

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OPINION
published: 08 May 2015
doi: 10.3389/fneur.2015.00099
Edited by:
Anders Fogh Christensen,
University Hospital of Copenhagen,
Denmark
Reviewed by:
Martin Ebinger,
Charité – Universitätsmedizin Berlin,
Germany
*Correspondence:
Mark O. McCarron
markmccarron@doctors.org.uk
Specialty section:
This article was submitted to Stroke,
a section of the journal
Frontiers in Neurology
Received: 17 March 2015
Accepted: 23 April 2015
Published: 08 May 2015
Citation:
Charidimou A, Nicoll JAR and
McCarron MO (2015)
Thrombolysis-related intracerebral
hemorrhage and cerebral amyloid
angiopathy: accumulating evidence.
Front. Neurol. 6:99.
doi: 10.3389/fneur.2015.00099
Thrombolysis-related intracerebral
hemorrhage and cerebral amyloid
angiopathy: accumulating evidence
Andreas Charidimou 1, James A. R. Nicoll 2 and Mark O. McCarron 3*
1 Department of Neurology, Massachussetts General Hospital, Boston, MA, USA, 2 Department of Neuropathology, University
of Southampton, Southampton, UK, 3 Department of Neurology, Altnagelvin Hospital, Londonderry, UK
Keywords: cerebral amyloid angiopathy, intracerebral hemorrhage, thrombolysis
Intracerebral hemorrhage (ICH) is the most feared risk of systemic thrombolysis for ST-elevated
myocardial infarction, pulmonary embolism, or acute ischemic stroke. Clinical, radiological, and
pathological evidence suggests that cerebral small vessel disease and, in particular, cerebral amyloid
angiopathy (CAA) may contribute to or in some cases directly underpin thrombolysis-related
intracerebral hemorrhage (TICH) (1). Further developments, particularly in neuroimaging, have
strengthened this hypothesis, hinting at the prospect of identifying biomarkers tomeasure TICH risk
for individual patient groups. Emerging biomarkers for CAA such as lobar cerebral microbleeds (2)
may become increasingly useful for outcome endpoints in clinical trials and patient risk stratification
for TICH (3).
Thrombolysis-related intracerebral hemorrhage is a complex pathophysiological process. For
ischemic stroke patients, a key issue is the location of TICH, i.e., hemorrhage into the area of ischemia
vs. hemorrhage in a remote non-ischemic site (occurring in about 20% of patients with symptomatic
TICH). Classification of TICH has traditionally focused on clinical and radiological features (4),
with less emphasis on whether different mechanisms might be implicated in TICH in remote from
or within the acute infarcted region (5) or whether pathological assessment has occurred.
Coregistered Pittsburgh compound B positron emission tomography (PiB-PET) imaging has
revealed that spontaneous hemorrhage hotspots preferentially occur at locations with increased
amyloid β-protein burden (6). In patients treated with recombinant tissue plasminogen activator
(rt-PA) for acute ischemic stroke, cerebral amyloid β-protein (as detected with PiB-PET) retention
was higher in patients with parenchymal hemorrhage compared to patients without (7). Although
PiB-PET has somewhat poor spatial resolution and cannot reliably resolve parenchymal and cere-
brovascular amyloid β-protein, the finding is probably one of the strongest pieces of radiological
evidence implicating CAA in TICH. Matrix metalloproteinase 9, a zinc-dependent endopeptidase
and a marker of hemorrhagic transformation after ischemic stroke, is released from neutrophil
granules by rt-PA in humans (8). Amyloid β-protein can also release and activate MMP-9 from
mouse endothelial cells (9), suggesting that convergent risk factors may lead to hemorrhage.
Cerebral microbleeds identified on MRI in a lobar distribution are considered a characteristic
hemorrhagic marker of a vasculopathy related to CAA (2). It has slowly emerged that multiple
microbleeds might increase the risk of symptomatic ICH following thrombolysis treatment, a
relationship which increases with increasing numbers of microbleeds (10, 11). In more recent
studies with larger groups of ischemic stroke patients receiving intravenous thrombolysis in both
European and Chinese populations, multiple cerebral microbleeds were more clearly associated
with symptomatic and parenchymal hemorrhage, respectively (12, 13). Future study may provide
insights into potential mechanisms, and meta-analyses may highlight the relative importance of
lobar and non-lobar cerebral microbleeds in stratifying the intracerebral hemorrhagic risk from
thrombolysis.
Frontiers in Neurology | www.frontiersin.org May 2015 | Volume 6 | Article 991
Charidimou et al. Thrombolysis-related intracerebral hemorrhage
In a review in 2004 (1), we identified 10 patients with patho-
logical investigation of TICH, 7 of whom had evidence of CAA.
All of these patients had been treated for acute myocardial
infarction and nine of the patients had multiple hemorrhages in
a lobar distribution. With an increasing emphasis on primary
percutaneous intervention for ST-elevated myocardial infarc-
tion, it may not be surprising that no further TICH cases fol-
lowing thrombolysis for acute myocardial infarction have been
reported. However, although thrombolysis rates have increased
for acute ischemic stroke patients, in an updated systematic lit-
erature search, only two further autopsy TICH cases (multiple
and both hemispheres) have been reported in the stroke litera-
ture, both of whom had CAA (14). The relative lack of human
pathological studies compared to neuroimaging studies ham-
pers further developments in this area. A pathological register
attached to a clinical register would enhance our understanding
of TICH, particularly in the older population with acute ischemic
stroke.
The known predictors of clinically significant TICH currently
include age, clinical stroke severity, high blood pressure, hyper-
glycemia, early CT ischemic changes, large baseline diffusion
lesion volume, leukoaraiosis, and cerebral microbleeds on MRI;
the evidence for a role of CAA in TICH continues to accumulate.
Author Contributions
AC conceived the idea and reviewed the literature and drafts of
the paper. JN contributed to the writing, analyzed the literature,
and reviewed drafts of the paper. MM wrote the first draft and
reviewed drafts of the paper.
References
1. McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and thrombolysis-
related intracerebral haemorrhage. Lancet Neurol (2004) 3:484–92. doi:10.1016/
S1474-4422(04)00825-7
2. Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC. Cere-
bral microbleeds: a review of clinical, genetic, and neuroimaging associations.
Front Neurol (2014) 4:205. doi:10.3389/fneur.2013.00205
3. Greenberg SM, Salman RA, Biessels GJ, van BuchemM, Cordonnier C, Lee JM,
et al. Outcomemarkers for clinical trials in cerebral amyloid angiopathy. Lancet
Neurol (2014) 13:419–28. doi:10.1016/S1474-4422(14)70003-1
4. Sussman ES, Connolly ES Jr. Hemorrhagic transformation: a review of the rate
of hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol
(2013) 4:69. doi:10.3389/fneur.2013.00069
5. Mazya MV, Ahmed N, Ford GA, Hobolm C, Mikulik R, Nunes AP, et al.
Remote or extraischemic intracerebral hemorrhage-an uncommon complica-
tion of stroke thrombolysis: results from the safe implementation of treatments
in stroke-international stroke thrombolysis register. Stroke (2014) 45:1657–63.
doi:10.1161/STROKEAHA.114.004923
6. Gurol ME, Dierksen G, Betensky R, Gidicsin C, Halpin A, Becker A, et al.
Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid
angiopathy. Neurology (2012) 79:320–6. doi:10.1212/WNL.0b013e31826043a9
7. Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, O’Keefe G, et al. Cerebral
beta-amyloid detected by Pittsburgh compound B positron emission topogra-
phy predisposes to recombinant tissue plasminogen activator-related hemor-
rhage. Ann Neurol (2010) 68:959–62. doi:10.1002/ana.22072
8. Carbone F, Vuilleumier N, Bertolotto M, Burger F, Galan K, Roversi G. Treat-
ment with recombinant tissue plasminogen activator (r-TPA) induces neu-
trophil degranulation in vitro via defined pathways. Vascul Pharmacol (2015)
64:16–27. doi:10.1016/j.vph.2014.11.007
9. Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, et al. Matrix
metalloproteinase-9 and spontaneous hemorrhage in an animal model of
cerebral amyloid angiopathy. Ann Neurol (2003) 54:379–82. doi:10.1002/ana.
10671
10. Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracra-
nial hemorrhage risk of cerebral microbleeds in acute stroke patients: a sys-
tematic review and meta-analysis. Int J Stroke (2013) 8:348–56. doi:10.1111/j.
1747-4949.2012.00869.x
11. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the risk
of intracerebral haemorrhage after thrombolysis for acute ischaemic stroke:
systematic review and meta-analysis. J Neurol Neurosurg Psychiatry (2013)
84:277–80. doi:10.1136/jnnp-2012-303379
12. Dannenberg S, Scheitz JF, Rozanski M, Erdur H, Brunecker P, Werring
DJ, et al. Number of cerebral microbleeds and risk of intracerebral hemor-
rhage after intravenous thrombolysis. Stroke (2014) 45:2900–5. doi:10.1161/
STROKEAHA.114.006448
13. Yan S, Jin X, Zhang X, Zhang S, Liebeskind DS, Lou M. Extensive cere-
bral microbleeds predict parenchymal haemorrhage and poor outcome after
intravenous thrombolysis. J Neurol Neurosurg Psychiatry (2015). doi:10.1136/
jnnp-2014-309857
14. Mattila OS, Sairanen T, Laakso E, Paetau A, Tanskanen M, Lindsberg PJ.
Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis:
case report and literature review. Neuropathology (2015) 35:70–4. doi:10.1111/
neup.12152
Conflict of Interest Statement: The authors declare that the research was con-
ducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Copyright © 2015 Charidimou, Nicoll and McCarron. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) or licensor are credited and that the original publication in this
journal is cited, in accordance with accepted academic practice. No use, distribution
or reproduction is permitted which does not comply with these terms.
Frontiers in Neurology | www.frontiersin.org May 2015 | Volume 6 | Article 992


Southampton (e-Prints Soton)

OPINIONpublished: 08 May 2015doi: 10.3389/fneur.2015.00099Edited by:Anders Fogh Christensen,University Hospital of Copenhagen,DenmarkReviewed by:Martin Ebinger,Charité – Universitätsmedizin Berlin,Germany*Correspondence:Mark O. McCarronmarkmccarron@doctors.org.ukSpecialty section:This article was submitted to Stroke,a section of the journalFrontiers in NeurologyReceived: 17 March 2015Accepted: 23 April 2015Published: 08 May 2015Citation:Charidimou A, Nicoll JAR andMcCarron MO (2015)Thrombolysis-related intracerebralhemorrhage and cerebral amyloidangiopathy: accumulating evidence.Front. Neurol. 6:99.doi: 10.3389/fneur.2015.00099Thrombolysis-related intracerebralhemorrhage and cerebral amyloidangiopathy: accumulating evidenceAndreas Charidimou 1, James A. R. Nicoll 2 and Mark O. McCarron 3*1 Department of Neurology, Massachussetts General Hospital, Boston, MA, USA, 2 Department of Neuropathology, Universityof Southampton, Southampton, UK, 3 Department of Neurology, Altnagelvin Hospital, Londonderry, UKKeywords: cerebral amyloid angiopathy, intracerebral hemorrhage, thrombolysisIntracerebral hemorrhage (ICH) is the most feared risk of systemic thrombolysis for ST-elevatedmyocardial infarction, pulmonary embolism, or acute ischemic stroke. Clinical, radiological, andpathological evidence suggests that cerebral small vessel disease and, in particular, cerebral amyloidangiopathy (CAA) may contribute to or in some cases directly underpin thrombolysis-relatedintracerebral hemorrhage (TICH) (1). Further developments, particularly in neuroimaging, havestrengthened this hypothesis, hinting at the prospect of identifying biomarkers tomeasure TICH riskfor individual patient groups. Emerging biomarkers for CAA such as lobar cerebral microbleeds (2)may become increasingly useful for outcome endpoints in clinical trials and patient risk stratificationfor TICH (3).Thrombolysis-related intracerebral hemorrhage is a complex pathophysiological process. Forischemic stroke patients, a key issue is the location of TICH, i.e., hemorrhage into the area of ischemiavs. hemorrhage in a remote non-ischemic site (occurring in about 20% of patients with symptomaticTICH). Classification of TICH has traditionally focused on clinical and radiological features (4),with less emphasis on whether different mechanisms might be implicated in TICH in remote fromor within the acute infarcted region (5) or whether pathological assessment has occurred.Coregistered Pittsburgh compound B positron emission tomography (PiB-PET) imaging hasrevealed that spontaneous hemorrhage hotspots preferentially occur at locations with increasedamyloid β-protein burden (6). In patients treated with recombinant tissue plasminogen activator(rt-PA) for acute ischemic stroke, cerebral amyloid β-protein (as detected with PiB-PET) retentionwas higher in patients with parenchymal hemorrhage compared to patients without (7). AlthoughPiB-PET has somewhat poor spatial resolution and cannot reliably resolve parenchymal and cere-brovascular amyloid β-protein, the finding is probably one of the strongest pieces of radiologicalevidence implicating CAA in TICH. Matrix metalloproteinase 9, a zinc-dependent endopeptidaseand a marker of hemorrhagic transformation after ischemic stroke, is released from neutrophilgranules by rt-PA in humans (8). Amyloid β-protein can also release and activate MMP-9 frommouse endothelial cells (9), suggesting that convergent risk factors may lead to hemorrhage.Cerebral microbleeds identified on MRI in a lobar distribution are considered a characteristichemorrhagic marker of a vasculopathy related to CAA (2). It has slowly emerged that multiplemicrobleeds might increase the risk of symptomatic ICH following thrombolysis treatment, arelationship which increases with increasing numbers of microbleeds (10, 11). In more recentstudies with larger groups of ischemic stroke patients receiving intravenous thrombolysis in bothEuropean and Chinese populations, multiple cerebral microbleeds were more clearly associatedwith symptomatic and parenchymal hemorrhage, respectively (12, 13). Future study may provideinsights into potential mechanisms, and meta-analyses may highlight the relative importance oflobar and non-lobar cerebral microbleeds in stratifying the intracerebral hemorrhagic risk fromthrombolysis.Frontiers in Neurology | www.frontiersin.org May 2015 | Volume 6 | Article 991Charidimou et al. Thrombolysis-related intracerebral hemorrhageIn a review in 2004 (1), we identified 10 patients with patho-logical investigation of TICH, 7 of whom had evidence of CAA.All of these patients had been treated for acute myocardialinfarction and nine of the patients had multiple hemorrhages ina lobar distribution. With an increasing emphasis on primarypercutaneous intervention for ST-elevated myocardial infarc-tion, it may not be surprising that no further TICH cases fol-lowing thrombolysis for acute myocardial infarction have beenreported. However, although thrombolysis rates have increasedfor acute ischemic stroke patients, in an updated systematic lit-erature search, only two further autopsy TICH cases (multipleand both hemispheres) have been reported in the stroke litera-ture, both of whom had CAA (14). The relative lack of humanpathological studies compared to neuroimaging studies ham-pers further developments in this area. A pathological registerattached to a clinical register would enhance our understandingof TICH, particularly in the older population with acute ischemicstroke.The known predictors of clinically significant TICH currentlyinclude age, clinical stroke severity, high blood pressure, hyper-glycemia, early CT ischemic changes, large baseline diffusionlesion volume, leukoaraiosis, and cerebral microbleeds on MRI;the evidence for a role of CAA in TICH continues to accumulate.Author ContributionsAC conceived the idea and reviewed the literature and drafts ofthe paper. JN contributed to the writing, analyzed the literature,and reviewed drafts of the paper. MM wrote the first draft andreviewed drafts of the paper.References1. McCarron MO, Nicoll JA. Cerebral amyloid angiopathy and thrombolysis-related intracerebral haemorrhage. Lancet Neurol (2004) 3:484–92. doi:10.1016/S1474-4422(04)00825-72. Yates PA, Villemagne VL, Ellis KA, Desmond PM, Masters CL, Rowe CC. Cere-bral microbleeds: a review of clinical, genetic, and neuroimaging associations.Front Neurol (2014) 4:205. doi:10.3389/fneur.2013.002053. Greenberg SM, Salman RA, Biessels GJ, van BuchemM, Cordonnier C, Lee JM,et al. Outcomemarkers for clinical trials in cerebral amyloid angiopathy. LancetNeurol (2014) 13:419–28. doi:10.1016/S1474-4422(14)70003-14. Sussman ES, Connolly ES Jr. Hemorrhagic transformation: a review of the rateof hemorrhage in the major clinical trials of acute ischemic stroke. Front Neurol(2013) 4:69. doi:10.3389/fneur.2013.000695. Mazya MV, Ahmed N, Ford GA, Hobolm C, Mikulik R, Nunes AP, et al.Remote or extraischemic intracerebral hemorrhage-an uncommon complica-tion of stroke thrombolysis: results from the safe implementation of treatmentsin stroke-international stroke thrombolysis register. Stroke (2014) 45:1657–63.doi:10.1161/STROKEAHA.114.0049236. Gurol ME, Dierksen G, Betensky R, Gidicsin C, Halpin A, Becker A, et al.Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloidangiopathy. Neurology (2012) 79:320–6. doi:10.1212/WNL.0b013e31826043a97. Ly JV, Rowe CC, Villemagne VL, Zavala JA, Ma H, O’Keefe G, et al. Cerebralbeta-amyloid detected by Pittsburgh compound B positron emission topogra-phy predisposes to recombinant tissue plasminogen activator-related hemor-rhage. Ann Neurol (2010) 68:959–62. doi:10.1002/ana.220728. Carbone F, Vuilleumier N, Bertolotto M, Burger F, Galan K, Roversi G. Treat-ment with recombinant tissue plasminogen activator (r-TPA) induces neu-trophil degranulation in vitro via defined pathways. Vascul Pharmacol (2015)64:16–27. doi:10.1016/j.vph.2014.11.0079. Lee JM, Yin KJ, Hsin I, Chen S, Fryer JD, Holtzman DM, et al. Matrixmetalloproteinase-9 and spontaneous hemorrhage in an animal model ofcerebral amyloid angiopathy. Ann Neurol (2003) 54:379–82. doi:10.1002/ana.1067110. Shoamanesh A, Kwok CS, Lim PA, Benavente OR. Postthrombolysis intracra-nial hemorrhage risk of cerebral microbleeds in acute stroke patients: a sys-tematic review and meta-analysis. Int J Stroke (2013) 8:348–56. doi:10.1111/j.1747-4949.2012.00869.x11. Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and the riskof intracerebral haemorrhage after thrombolysis for acute ischaemic stroke:systematic review and meta-analysis. J Neurol Neurosurg Psychiatry (2013)84:277–80. doi:10.1136/jnnp-2012-30337912. Dannenberg S, Scheitz JF, Rozanski M, Erdur H, Brunecker P, WerringDJ, et al. Number of cerebral microbleeds and risk of intracerebral hemor-rhage after intravenous thrombolysis. Stroke (2014) 45:2900–5. doi:10.1161/STROKEAHA.114.00644813. Yan S, Jin X, Zhang X, Zhang S, Liebeskind DS, Lou M. Extensive cere-bral microbleeds predict parenchymal haemorrhage and poor outcome afterintravenous thrombolysis. J Neurol Neurosurg Psychiatry (2015). doi:10.1136/jnnp-2014-30985714. Mattila OS, Sairanen T, Laakso E, Paetau A, Tanskanen M, Lindsberg PJ.Cerebral amyloid angiopathy related hemorrhage after stroke thrombolysis:case report and literature review. Neuropathology (2015) 35:70–4. doi:10.1111/neup.12152Conflict of Interest Statement: The authors declare that the research was con-ducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Copyright © 2015 Charidimou, Nicoll and McCarron. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) or licensor are credited and that the original publication in thisjournal is cited, in accordance with accepted academic practice. No use, distributionor reproduction is permitted which does not comply with these terms.Frontiers in Neurology | www.frontiersin.org May 2015 | Volume 6 | Article 992

Thrombolysis-related intracerebral hemorrhage and cerebral amyloid angiopathy: accumulating evidence

Andreas eCharidimou

James A.R. Nicoll

Mark Owen Mccarron

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Thrombolysis-related intracerebral hemorrhage and cerebral amyloid angiopathy: accumulating evidence

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