Transl. Stroke Res.
(2015) 6:257–263
DOI 10.1007/s12975-015-0410-1
REVIEW ARTICLE
The Pathophysiology of Intracerebral Hemorrhage
Formation and Expansion
Frieder Schlunk 1 & Steven M. Greenberg 1
Received: 24 April 2015 / Accepted: 20 May 2015 / Published online: 16 June 2015
# Springer Science+Business Media New York 2015
Abstract Intracerebral hemorrhage is a devastating disease.
Despite its clinical importance, the pathophysiology of intra-
cerebral hemorrhage is not well understood. Hematoma ex-
pansion occurs in a large subset of patients and is a predictor
of poor outcomes. Since hematoma growth provides a poten-
tial opportunity for therapeutic intervention, a thorough under-
standing of its biological mechanisms is of key importance.
After vessel rupture, an initial hematoma forms. Following
this initial phase, accumulating evidence suggests that the
mass effect causes secondary vessel rupture, which contrib-
utes to the hematoma and may trigger an avalanche of further
vessel ruptures. The circumstances under which this occurs
and to what extent secondary hemorrhage contributes to final
hematoma volume remain unknown, however. To address the-
se questions, a translational approach seems most suitable.
Current experimental models include intracranial injections
of collagenase or autologous blood. Each has individual
strengths and weaknesses in its ability to simulate human in-
tracerebral hemorrhage. The ultimate goal for improved un-
derstanding and modeling of the pathophysiology of hemato-
ma expansion is to identify new treatment approaches.
Keywords Intracerebral hemorrhage . Hematoma
expansion . Pathophysiology . Animal models
* Steven M. Greenberg
sgreenberg@mgh.harvard.edu
Frieder Schlunk
fschlunk@gmail.com
1
J. Philip Kistler Stroke Research Center, Department of Neurology,
Massachusetts General Hospital, 175 Cambridge Street,
Boston, MA 02114, USA
Introduction
Intracerebral hemorrhage (ICH) is the deadliest subtype of
stroke with an in-hospital mortality of 40 % [1]. One year after
hemorrhage, 75 % of patients are severely disabled or de-
ceased [2]. To date, no specific therapy has been identified.
Hematoma expansion, which occurs in 30 % of patients dur-
ing hospitalization, has been suggested as a promising target
for treatment [3, 4]. Intensive blood pressure reduction and
rFVIIa have been tested to limit hematoma expansion in re-
cent and ongoing clinical trials with some hints of success
[5–7]; however, the goal of improving outcomes by decreas-
ing hematoma expansion has not been convincingly demon-
strated. A major reason might be our limited knowledge of the
pathophysiology of hematoma expansion. Since we are typi-
cally able to look only at snapshots of specific time points in
medical imaging, it remains difficult to understand the dynam-
ics of the process, highlighting the importance of translational
Bbedside to bench^ approaches. Experimental laboratory
models of ICH each have strengths and limitations in the
reproduction of the assumed sequences of an intracerebral
bleed, from initial vessel rupture to initial hematoma forma-
tion, secondary hematoma growth, and cessation of bleeding
[8, 9].
This review summarizes current knowledge about the path-
ophysiology of primary intracerebral hemorrhage with special
regards to experimental models.
Epidemiology
ICH accounts for 15 % of strokes with about 2 million new
cases worldwide per year [10–13]. The incidence is lower in
high-income countries than in low- and middle-income coun-
tries [14, 15]. With a 1-month mortality rate of 40 %, ICH is
258
the deadliest subtype of stroke [2, 16]. ICH is divided into
primary and secondary. Hypertension and cerebral amyloid
angiopathy (CAA) are the causes of primary ICH, with the
former being the attributable risk factor for approximately
65 % of all cases [11, 17]. Hemorrhages caused by brain
tumors, aneurysms, arteriovenous malformations, cerebral
cavernous malformations, and coagulopathy are classified as
secondary [10, 11]. Although our understanding of the disease
has improved in recent years, no specific therapy exists at
present.
Initial hematoma volume, location of hemorrhage (includ-
ing the presence of intraventricular extension), and hematoma
expansion are predictors of bad outcomes. While initial vol-
ume and location are unchangeable when the patient arrives to
the hospital, hematoma expansion, which occurs in about
30 % of patients during hospitalization, is a potential thera-
peutic target [18–20]. Risk factors for expansion include ini-
tial hematoma volume (with large hematomas more likely to
expand than smaller hemorrhages), anticoagulation, early pre-
sentation after symptom onset, and the CT angiography (CTA)
spot sign [16, 21]. Expansion occurs more frequently in the
first 3 h but can also occur at later time points 6 or more hours
after symptom onset [22, 23]. Hemorrhage growth was shown
in several studies to correlate with poor outcomes. The hazard
ratio of mortality increases by 5 % for every 10 % increase in
ICH volume, and for every milliliter increase in absolute vol-
ume, the patient’s outcome is 7 % more likely to shift to
dependence [16, 23, 24].
Pathophysiology of ICH
Vessel Rupture
Hypertensive intracerebral hemorrhage appears to begin with
the burst of a single vessel, which gives arise to an initial
hematoma [9]. Vessel rupture is a result of chronic hyperten-
sion, which gradually damages vessel walls long before the
event. In this asymptomatic period, chronic hypertension
leads to smooth muscle cell proliferation, smooth muscle cell
necrosis, and finally replacement with collagen, which is
structurally stiff and brittle compared to the normal vessel wall
elements [10, 25–27]. Affected arterioles typically dilate and
form Charcot-Bouchart aneurysms (Fig. 1) [28]. If these thin-
walled Bmicro-balloons^ are exposed to high pressure, as is
the case in deep thalamic, pontine or striatal vessels because of
their downstream proximity to relatively large pial arteries,
they can burst. However, whether ICH occurs in most cases
because of rupture of microaneurysms or weakening of the
vessel wall by arteriosclerosis is still under debate. In an elec-
tron microscopy study of lenticulostriate arteries collected at
surgical evacuation of ICH and at autopsy, severe arterioscle-
rosis was observed in 46 of 48 ruptured arteries [25].
Transl. Stroke Res. (2015) 6:257–263
Fig. 1 Medial hyperplasia in a cerebral arteriole (a) due to reactive
smooth muscle cell proliferation in early hypertension. This stage
represents the compensated phase of arteriolar reaction to sustained
high blood pressure. Collagenization of the tunica media occurs (b) due
to smooth muscle cell death. Collagenization can result in ectasia. The
dilated, collagenized arteriole in b can be considered an early Charcot-
Bouchard aneurysm. Bar=100 μm. (From Sutherland et al. J Clin
Neurosci. 2006 Jun;13(5):511–7)
The magnitude of initial hematoma growth most likely de-
pends on the size of the initially ruptured vessel, the charac-
teristics of the opening in the vessel wall through which blood
can escape, and the capability of the vascular system to stop
the bleeding. Fisher described a focal rupture of an aneurys-
mal dilatation of a small artery with a diameter of 180 μl as the
primary source of a 2×1 cm thalamic bleed. Rupture occurred
during a period of hypertension (pitressin-infusion). Through
a 1-mm opening in the vessel wall, a jet of escaping blood
formed a rounded oblong hemorrhage with its long axis at a
right angle to the bleeding artery [29]. To our knowledge, this
is the only morphological description of the initial bleeding
site of an ICH in the literature.
Vessel rupture in ICH caused by CAA follows a different
pathophysiological sequence. It involves ß-amyloid peptide
(Aβ) deposition in the media of small- and medium-sized
leptomeningeal and cortical vessels surrounding the vascular
smooth muscle cells (SMC) [30–32]. As the disease pro-
gresses, SMC are replaced with Aβ, which can now be found
in all layers of the vessel wall. Microaneurysm formation,
fibrinoid necrosis, and perivascular leakage can be seen
at this stage [33]. Vessel rupture occurs in such weakened
blood vessels resulting in cerebral microbleeds or lobar ICH
[34, 35].
Transl. Stroke Res. (2015) 6:257–263
Initial Hematoma Growth
To determine the speed and the spatial evolution of initial
hematoma growth is difficult, since imaging is usually not
undertaken in the hyperacute phase. However, one would ex-
pect a rather fast expansion rate in the beginning causing sud-
den Bstroke-like^ symptoms when counter pressure from the
surrounding tissue is minimal. A recent report described an
ICH that occurred while the patient was in the MRI scanner
[36]. An 8.8 cc bleed grew over ≤2 min and continued to bleed
to 20.5 cc over the next 10 min. The final hemorrhage volume
was measured at 43.5 cc approximately 1 day later (Fig. 2).
These numbers demonstrate that the greater part of the final
blood volume might be ejected early in the course of a hem-
orrhage, helping to explain why the majority of patients do not
suffer further hematoma enlargement after their baseline CT-
scan [37]. Faster growth in the very early phase of a bleed was
also observed in a recent porcine model of ICH induced by
focused ultrasound and measured by serial MRI at 10 s inter-
vals [38]. The authors identified a primary growth phase of the
hemorrhage with a median duration of 160 s and a volume
expansion rate of 1.5 mm3/s, which was responsible for 85±
15 % of the final volume of hematoma expansion. The first
growing phase was followed by either a secondary stationary
or a secondary growth phase. It is conceivable that the initial
hematoma growth can decrease or stop when counter pressure
of the surrounding tissue, which increases in parallel with
hematoma growth, overcomes the force of the jet of blood
escaping from the primary vessel. Nevertheless, continued
bleeding into the hematoma might still happen and further
expansion might be a result of vessels in the surrounding
finally giving way to the stretch caused by the initial hemato-
ma and rupturing (Fig. 3). The important role of initial hema-
toma growth was supported by a recent study in which ultra-
early hematoma growth, defined as baseline ICH volume
Fig. 2 An 86-year-old man with hyperacute hemorrhage onset and
expansion. Bleeding occurred while the patient was in the MRI scanner.
a A chronic right temporoparietal hemorrhage (dotted arrow) and a new
(since an MRI 2 years prior) right parietal microbleed (solid arrow) are
seen on MRI gradient-recalled echo (GRE) sequence. b Four minutes
later, contrast extravasation is present on the T1-post axial sequence in
the area of the new microbleed. c Ten minutes later, the region of contrast
extravasation has expanded on the T1-post coronal sequence. d A
computed tomography scan 22 h and 22 min after the GRE sequence
demonstrates a large right parietal hyperdense lesion, consistent with
hemorrhage. (From Edlow et al. Neurocrit Care. 2012 Oct;17(2):250–4)
259
c
a b
d
Fig. 3 Illustrative figure of hematoma expansion. a Blood is escaping
from the primary bleeding site (red, solid arrows) and initial hematoma
growth occurs (red, dashed circle). Counter pressure of the surrounding
tissue (black arrows) is yet minimal. b Hemostatic pressure increases in
parallel with hematoma growth. Vessels (represented by blue line) are
stretched by the growing hematoma. The hemostatic pressure of the
surrounding tissue either contributes to cessation of bleeding (solid
circle, c) or the force of bleeding is great enough to rupture adjacent
vessels which results in secondary bleeding (d)
divided by onset-to-imaging time, predicted further hematoma
enlargement [39]. A growth of >10.2 ml/h was found by this
analysis to be the most powerful predictor of hematoma
growth. The amount of blood ejected over time in the early
phase may thus determine the amount of secondary hemor-
rhage and further hematoma enlargement.
Secondary Hematoma Expansion
A major question in the pathophysiology of ICH growth is
whether the formation of an initial hematoma is followed by a
secondary growth phase fundamentally different in its mech-
anism from the initial phase. While some authors assume con-
tinued bleeding from the primary bleeding source to be re-
sponsible for the entire hemorrhage volume, accumulating
evidence supports the theory of secondary shearing and bleed-
ing from multiple ruptured vessels in the surrounding of the
initial hematoma [22, 40, 41]. Fisher, who first introduced the
idea of an avalanche model in his historic paper from 1971,
believed that the final blood volume of an intracerebral hem-
orrhage results from multiple vessels, although most of the
bleeding would stem from the primary vessels plus a few
additional affected bigger vessels [9] (Fig. 4). Further evi-
dence supporting the idea of multiple sites of bleeding is the
variability of hematoma growth in space and time. Hemato-
mas often assume irregular shapes and can change their pace
of growth in different axial directions over time [36, 41]. This
can be partly explained by local differences of the affected
tissue but may instead reflect secondary bursts of local clusters
of vessels. It remains unclear whether these secondary rup-
tures occur randomly or instead preferentially favor local spots
260
Fig. 4 Schematic figure of a pontine hemorrhage illustrating secondary
hemorrhage with arterial bleeding sites arranged in one plane. The
bleeding arteries mainly lay in the boundary zone between hemorrhage
and surrounding brain tissue. A and B indicate the arteries which
presumably constituted the most significant portion of the hemorrhage.
(From Fisher CM. J Neuropathol Exp Neurol. 1971 Jul;30(3):536–50)
with more diseased vessels and more brittle walls [30]. A
recent study found that closer proximity of a given point on
the hematoma surface to the hematoma center predicted a
higher expansion rate [42], suggesting that the ability to gen-
erate secondary hemorrhage may be greatest close to the initial
bleeding site. The likelihood for a hemorrhage to cease grow-
ing may similarly increase with greater distance from the he-
matoma center, as counter pressure of the surrounding tissue
rises and flow of extravasting blood stagnates in the periphery
of the bleed. Hematomas may thus have a tendency to become
more spherical as they grow.
The CT spot sign, which likely represents active bleeding,
also supports the possibility of secondary hemorrhage. The
CT spots, particularly when multiple or located in the periph-
ery of the bleed [42–44] are suggestive of contrast medium
leakage from secondary ruptured vessels. In fact, simulta-
neous extravasation out of multiple vessels has been observed
during angiography [45]. Recently, a computational model for
hematoma expansion based on secondary vessel rupture pre-
dicted a bimodal distribution of irregular shaped micro- and
macrobleeds similar to what is observed in patients with lobar
ICH [40, 46].
Assuming that secondary vessel rupture occurs, what prin-
ciples does it follow? First, is there a volume or growth speed
threshold for the initial hematoma to generate the force nec-
essary to rupture vessels? Fisher himself published a study in
2003 where he identified only one ruptured vessel (the prima-
ry bleeding site) and no additional ruptured vessels in a 2×
1 cm hypertensive thalamic hemorrhage, indicating that sec-
ondary bleeding might not be a feature of every ICH [29]. It is
certainly true that a very slowly expanding lesion such as a
Transl. Stroke Res. (2015) 6:257–263
brain tumor, even if of notable size, typically does not cause
significant bleeding. Vessels may instead need to be stretched
by a rather fast and voluminous evolving hematoma in order
to break. This would presumably apply especially to larger
and more robust vessels. Secondly, these assumptions might
be substantially different in certain subgroups of patients, such
as individuals with small vessel disease or anticoagulated pa-
tients. In the latter group, bleeding from secondary ruptured
vessels will be facilitated by greater volume of bleeding from
ruptured vessels than occur under normal coagulation. There-
fore, the proportion of the amount of blood contributing to the
total hematoma volume coming from the primary vessel and
secondary vessels might differ across diverse patient sub-
groups. These questions are difficult to answer with clinical
data only, however, since clinical imaging provides us only
with images at a few time points. A translational approach
might instead be needed to approach and answer these
questions.
Experimental Models
In laboratory research, two models are in most widespread use
to investigate ICH: the collagenase model and the autologous
blood injection model [47]. Their advantages and disadvan-
tages have been discussed in detail in earlier works [48]. We
focus here on the ability of the models to reproduce the pos-
tulated mechanisms of human ICH discussed above as well as
a recently reported model of ICH induced by focused ultra-
sound and measured by serial MRI.
Collagenase Model
Collagenase, an enzyme derived from the anaerobic bacteria
clostridium hystolyticum, is injected stereotactically into the
striatum of mice or rats. After injection, it digests vessel walls
leading to hemorrhage. Bleeding occurs after approximately
10 min, with further hematoma growth over at least the next
2 h [49, 50]. Further variations on the collagenase model in-
tegrate anticoagulation and anticoagulation-reversal [50–54].
Regarding the natural course of ICH, the collagenase model
also begins with ruptured vessels in situ and subsequent ex-
pansion. How closely this in fact simulates the conditions in
human ICH is uncertain. There is no doubt that vessel rupture
induced by high concentrations of exogenous collagenase is
profoundly different from spontaneous human ICH, where
presumably a single vessel ruptures from some combination
of chronic structural damage and intrinsic effects of intravas-
cular blood pulsations. In this experimental model, multiple
vessels likely undergo progressive protease-related injury over
a longer time period and collagenase may diffuse into loca-
tions remote from the initial injection site. It is thus unclear
whether secondary hemorrhage occurs because of shearing by
Transl. Stroke Res. (2015) 6:257–263
the expanding initial hematoma rather than ongoing vessel
rupture from continued enzyme activity. However, the colla-
genase model is a simple, highly reproducible model, which
may closely mimic the pathophysiology of secondary cell
death and edema caused by a hematoma.
Blood Injection Model
For the blood injection model, either donor or autologous
blood is injected stereotactically into the striatum of mice or
rats. The amount of injection volume and the infusion rate
vary between authors [55–58]. Technical issues reported with
this model have been backflow along the needle track and
extension into the subdural space with more rapid injection
speed [47]. Regarding its ability to simulate human ICH, a
weakness of the blood injection model is that the primary
bleeding does not stem from ruptured vessels. It is possible,
however, that blood escaping from an initial single bleeding
site (the needle) may mimic initial rupture in human ICH more
closely than the collagenase model, where the enzyme causes
multiple vessel ruptures over time. Moreover, the hematoma
forms immediately after injection. Assuming that a growing
initial hematoma ruptures secondary vessels, which cause fur-
ther bleeding and contribute in avalanche fashion to the rup-
ture of tertiary vessels, one would assume that the mass effect
of the intracerebral injection of blood potentially leads to sub-
stantial secondary hematoma expansion. In fact, an increase of
intracerebral hematoma volume has been shown in diabetic rats
compared to nondiabetic controls after the intracerebral infu-
sion of blood [59], suggesting that secondary bleeding can
occur in this model. Other authors have reported stable hema-
toma volumes without expansion in this model [48, 55, 60, 61].
Future studies will therefore be needed to determine whether
the autologous blood injection model provides the opportunity
to study the phenomenon of secondary hemorrhage.
MRI Guided Ultrasound-Induced ICH-Model
In this recently developed model, MR imaging was used to
localize vessels in the basal ganglia of male Yorkshire swine
and focused low-frequency sonography (230 kHz) was deliv-
ered which resulted in vessel rupture in the target area [38, 62].
MRI including a dynamic contrast enhanced (DCE) sequence
was obtained thereafter. The authors were able to characterize
the hemorrhage on DCE-MRI by rate of leakage, duration,
and volume expansion in three-dimensional resolution. The
authors note the high costs and limited 20-min observation
time (because of constraints pertaining to temporal DCE res-
olution and scan duration) as limitations of the model [38].
Similar to the collagenase model, ultrasound-induced ICH
begins with rupture of vessels in situ. Histological post
mortem examination revealed that multiple vessels were af-
fected and gave rise to the initial hematoma [62]. Despite the
261
artificial nature of the initial rupture, this novel model could be
useful for reproducing secondary bleeding seen in human
ICH, based on the idea that secondary vessel rupture and fur-
ther hematoma growth might be driven only by the physical
properties of the evolving initial hematoma.
Conclusions
The ability to limit hematoma expansion has the potential to
improve markedly outcomes in patients suffering from intra-
cerebral hemorrhage. While several risk factors for expansion
have been identified, we are far from understanding its under-
lying mechanisms. Novel insights into the pathophysiology of
hematoma expansion may lead to new clinical trials. Since it is
difficult to understand the dynamics of the disease with clin-
ical data alone, further translational approaches to address
these questions might be warranted.
Conflict of Interest Frieder Schlunk and Steven Greenberg declare that
they have no conflict of interest.
Ethical Approval This article does not contain any studies with human
participants or animals performed by any of the authors.
References
1. Jakubovic R, Aviv RI. Intracerebral hemorrhage: toward physiolog-
ical imaging of hemorrhage risk in acute and chronic bleeding.
Front Neurol. 2012;3:86.
2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, 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. Lancet Neurol. 2010;9:167–
76.
3. Wang X, Arima H, Al-Shahi Salman R, Woodward M, Heeley E,
et al. Clinical Prediction Algorithm (BRAIN) to Determine Risk of
Hematoma Growth in Acute Intracerebral Hemorrhage. Stroke.
2015;46:376–81.
4. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, et al.
Hematoma growth is a determinant of mortality and poor outcome
after intracerebral hemorrhage. Neurology. 2006;66:1175–81.
5. Anderson CS, Chalmers J, Stapf C. Blood-pressure lowering in
acute intracerebral hemorrhage. N Engl J Med. 2013;369:1274–5.
6. Goldstein J, Brouwers H, Romero J, McNamara K, Schwab K, et al.
SCORE-IT: the Spot Sign score in restricting ICH growth horizon-
tal line an Atach-II ancillary study. J Vasc Interv Neurol. 2012;5:
20–5.
7. Mayer SA. Recombinant activated factor VII for acute intracerebral
hemorrhage. Stroke. 2007;38:763–7.
8. Krafft PR, Rolland WB, Duris K, Lekic T, Campbell A, et al. Modeling
intracerebral hemorrhage in mice: injection of autologous blood or
bacterial collagenase. J Vis Exp. 2012;(67):e4289. doi:10.3791/4289.
9. Fisher CM. Pathological observations in hypertensive cerebral
hemorrhage. J Neuropathol Exp Neurol. 1971;30:536–50.
10. Sutherland GR, Auer RN. Primary intracerebral hemorrhage. J Clin
Neurosci. 2006;13:511–7.
262
11. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of
injury and therapeutic targets. Lancet Neurol. 2012;11:720–31.
12. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, et al.
Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:
1450–60.
13. Intiso D, Stampatore P, Zarrelli MM, Guerra GL, Arpaia G, et al.
Incidence of first-ever ischemic and hemorrhagic stroke in a well-
defined community of southern Italy, 1993–1995. Eur J Neurol.
2003;10:559–65.
14. Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis
after intracerebral haemorrhage: systematic review and meta-anal-
ysis. J Neurol Neurosurg Psychiatry. 2014;85:660–7.
15. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V.
Worldwide stroke incidence and early case fatality reported in 56
population-based studies: a systematic review. Lancet Neurol.
2009;8:355–69.
16. Brouwers HB, Greenberg SM. Hematoma expansion following
acute intracerebral hemorrhage. Cerebrovasc Dis. 2013;35:195–
201.
17. Aguilar MI, Brott TG. Update in intracerebral hemorrhage.
Neurohospitalist. 2011;1:148–59.
18. Brouwers HB, Chang Y, Falcone GJ, Cai X, Ayres AM, et al.
Predicting hematoma expansion after primary intracerebral hemor-
rhage. JAMA Neurol. 2014;71:158–64.
19. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume
of intracerebral hemorrhage. A powerful and easy-to-use predictor
of 30-day mortality. Stroke. 1993;24:987–93.
20. Flaherty ML, Haverbusch M, Sekar P, Kissela B, Kleindorfer D,
et al. Long-term mortality after intracerebral hemorrhage.
Neurology. 2006;66:1182–6.
21. Dowlatshahi D, Smith EE, Flaherty ML, Ali M, Lyden P, et al.
Small intracerebral haemorrhages are associated with less
haematoma expansion and better outcomes. Int J Stroke. 2011;6:
201–6.
22. Mayer SA. Ultra-early hemostatic therapy for intracerebral hemor-
rhage. Stroke. 2003;34:224–9.
23. LoPresti MA, Bruce SS, Camacho E, Kunchala S, Dubois BG, et al.
Hematoma volume as the major determinant of outcomes after in-
tracerebral hemorrhage. J Neurol Sci. 2014;345:3–7.
24. Delcourt C, Huang Y, Arima H, Chalmers J, Davis SM, et al.
Hematoma growth and outcomes in intracerebral hemorrhage: the
INTERACT1 study. Neurology. 2012;79:314–9.
25. Takebayashi S, Kaneko M. Electron microscopic studies of rup-
tured arteries in hypertensive intracerebral hemorrhage. Stroke.
1983;14:28–36.
26. Masawa N, Yoshida Y, Yamada T, Joshita T, Sato S, et al.
Morphometry of structural preservation of tunica media in aged
and hypertensive human intracerebral arteries. Stroke. 1994;25:
122–7.
27. Ooneda G. Pathology of stroke. Jpn Circ J. 1986;50:1224–34.
28. Russell RW. How does blood-pressure cause stroke? Lancet.
1975;2:1283–5.
29. Fisher CM. Hypertensive cerebral hemorrhage. Demonstration of
the source of bleeding. J Neuropathol Exp Neurol. 2003;62:104–7.
30. Rosand J, Muzikansky A, Kumar A, Wisco JJ, Smith EE, et al.
Spatial clustering of hemorrhages in probable cerebral amyloid
angiopathy. Ann Neurol. 2005;58:459–62.
31. Frackowiak J, Zoltowska A, Wisniewski HM. Non-fibrillar beta-
amyloid protein is associated with smooth muscle cells of vessel
walls in Alzheimer disease. J Neuropathol Exp Neurol. 1994;53:
637–45.
32. Wisniewski HM, Wegiel J, Vorbrodt AW, Mazur-Kolecka B,
Frackowiak J. Role of perivascular cells and myocytes in vascular
amyloidosis. Ann N Y Acad Sci. 2000;903:6–18.
Transl. Stroke Res. (2015) 6:257–263
33. Revesz T, Holton JL, Lashley T, Plant G, Rostagno A, et al.
Sporadic and familial cerebral amyloid angiopathies. Brain
Pathol. 2002;12:343–57.
34. Biffi A, Greenberg SM. Cerebral amyloid angiopathy: a systematic
review. J Clin Neurol. 2011;7:1–9.
35. Vonsattel JP, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED,
et al. Cerebral amyloid angiopathy without and with cerebral hemor-
rhages: a comparative histological study. Ann Neurol. 1991;30:637–49.
36. Edlow BL, Bove RM, Viswanathan A, Greenberg SM, Silverman
SB. The pattern and pace of hyperacute hemorrhage expansion.
Neurocrit Care. 2012;17:250–4.
37. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, et al. Early
hemorrhage growth in patients with intracerebral hemorrhage.
Stroke. 1997;28:1–5.
38. Liu R, Huynh TJ, Huang Y, Ramsay D, Hynynen K, et al. Modeling
the Pattern of Contrast Extravasation in Acute Intracerebral
Hemorrhage Using Dynamic Contrast-Enhanced MR. Neurocrit
Care. 2015;22:320–4.
39. Rodriguez-Luna D, Rubiera M, Ribo M, Coscojuela P, Pineiro S,
et al. Ultraearly hematoma growth predicts poor outcome after
acute intracerebral hemorrhage. Neurology. 2011;77:1599–604.
40. Greenberg CH, Frosch MP, Goldstein JN, Rosand J, Greenberg
SM. Modeling intracerebral hemorrhage growth and response to
anticoagulation. PLoS One. 2012;7, e48458.
41. Barras CD, Tress BM, Christensen S, MacGregor L, Collins M,
et al. Density and shape as CT predictors of intracerebral hemor-
rhage growth. Stroke. 2009;40:1325–31.
42. Boulouis G, Dumas A, Betensky RA, Brouwers HB, Fotiadis P,
et al. Anatomic pattern of intracerebral hemorrhage expansion: re-
lation to CT angiography spot sign and hematoma center. Stroke.
2014;45:1154–6.
43. Brouwers HB, Falcone GJ, McNamara KA, Ayres AM, Oleinik A,
et al. CTA spot sign predicts hematoma expansion in patients with
delayed presentation after intracerebral hemorrhage. Neurocrit
Care. 2012;17:421–8.
44. Romero JM, Heit JJ, Delgado Almandoz JE, Goldstein JN, Lu J,
et al. Spot sign score predicts rapid bleeding in spontaneous intra-
cerebral hemorrhage. Emerg Radiol. 2012;19:195–202.
45. Komiyama M, Yasui T, Tamura K, Nagata Y, Fu Y, et al.
Simultaneous bleeding from multiple lenticulostriate arteries in hy-
pertensive intracerebral haemorrhage. Neuroradiology. 1995;37:
129–30.
46. Greenberg SM, Nandigam RN, Delgado P, Betensky RA, Rosand J,
et al. Microbleeds versus macrobleeds: evidence for distinct enti-
ties. Stroke. 2009;40:2382–6.
47. Ma Q, Khatibi NH, Chen H, Tang J, Zhang JH. History of preclin-
ical models of intracerebral hemorrhage. Acta Neurochir Suppl.
2011;111:3–8.
48. Kirkman MA, Allan SM, Parry-Jones AR. Experimental intracere-
bral hemorrhage: avoiding pitfalls in translational research. J Cereb
Blood Flow Metab. 2011;31:2135–51.
49. Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M.
Collagenase-induced intracerebral hemorrhage in rats. Stroke.
1990;21:801–7.
50. Won SY, Schlunk F, Dinkel J, Karatas H, Leung W, et al. Imaging of
contrast medium extravasation in anticoagulation-associated intra-
cerebral hemorrhage with dual-energy computed tomography.
Stroke. 2013;44:2883–90.
51. Schlunk F, Schulz E, Lauer A, Yigitkanli K, Pfeilschifter W, et al.
Warfarin Pretreatment Reduces Cell Death and MMP-9 Activity in
Experimental Intracerebral Hemorrhage. Transl Stroke Res.
2014;6(2):133–9. doi:10.1007/s12975-014-0377-3.
52. Lauer A, Cianchetti FA, Van Cott EM, Schlunk F, Schulz E, et al.
Anticoagulation with the oral direct thrombin inhibitor dabigatran
does not enlarge hematoma volume in experimental intracerebral
hemorrhage. Circulation. 2011;124:1654–62.
Transl. Stroke Res. (2015) 6:257–263
53. Foerch C, Arai K, Jin G, Park KP, Pallast S, et al. Experimental
model of warfarin-associated intracerebral hemorrhage. Stroke.
2008;39:3397–404.
54. Schlunk F, Van Cott EM, Hayakawa K, Pfeilschifter W, Lo EH,
et al. Recombinant activated coagulation factor VII and prothrom-
bin complex concentrates are equally effective in reducing hemato-
ma volume in experimental warfarin-associated intracerebral hem-
orrhage. Stroke. 2012;43:246–9.
55. Lei B, Sheng H, Wang H, Lascola CD, Warner DS, et al. Intrastriatal
injection of autologous blood or clostridial collagenase as murine models
of intracerebral hemorrhage. J Vis Exp. 2014. doi:10.3791/51439.
56. Ni W, Okauchi M, Hatakeyama T, Gu Y, Keep RF, et al. Deferoxamine
reduces intracerebral hemorrhage-induced white matter damage in
aged rats. Exp Neurol. 2015. doi:10.1016/j.expneurol.2015.02.035.
57. Li G, Fan RM, Chen JL, Wang CM, Zeng YC, et al. Neuroprotective
effects of argatroban and C5a receptor antagonist (PMX53) following
intracerebral haemorrhage. Clin Exp Immunol. 2014;175:285–95.
263
58. Marinkovic I, Strbian D, Mattila OS, Abo-Ramadan U, Tatlisumak
T. A novel combined model of intracerebral and intraventricular
hemorrhage using autologous blood-injection in rats.
Neuroscience. 2014;272:286–94.
59. Liu J, Gao BB, Clermont AC, Blair P, Chilcote TJ, et al.
Hyperglycemia-induced cerebral hematoma expansion is mediated
by plasma kallikrein. Nat Med. 2011;17:206–10.
60. James ML, Warner DS, Laskowitz DT. Preclinical models of intra-
cerebral hemorrhage: a translational perspective. Neurocrit Care.
2008;9:139–52.
61. Wang J, Fields J, Dore S. The development of an improved preclin-
ical mouse model of intracerebral hemorrhage using double infu-
sion of autologous whole blood. Brain Res. 2008;1222:214–21.
62. Aviv RI, Huynh T, Huang Y, Ramsay D, Van Slyke P, et al. An
in vivo, MRI-integrated real-time model of active contrast extrava-
sation in acute intracerebral hemorrhage. AJNR Am J Neuroradiol.
2014;35:1693–9.