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Intraventricular Hemorrhage: the Role of Blood Components in Secondary

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Transl. Stroke Res.
DOI 10.1007/s12975-016-0480-8
COMMENTARY
Intraventricular Hemorrhage: the Role of Blood Components
in Secondary Injury and Hydrocephalus
Thomas Garton 1 & Richard F. Keep 1 & D. Andrew Wilkinson 1 & Jennifer M. Strahle 1 &
Ya Hua 1 & Hugh J. L. Garton 1 & Guohua Xi 1,2
Received: 20 June 2016 / Accepted: 22 June 2016
# Springer Science+Business Media New York 2016
Intraventricular hemorrhage (IVH) is characterized by an in-
flux of blood into the ventricles of the brain. It has a highly
morbid prognosis and develops in more than 12,000 prema-
ture infants every year in the USA [1, 2]. Within the last two
decades, about 31 % of successfully resuscitated very preterm
infants—born prior to 30-week gestational age—experienced
IVH, one third of which were of grade 3 or 4 severity [3].
Furthermore, the incidence of severe IVH has increased over
the last 20 years. In addition to the severe neurological deficits
associated with the disease, high-grade IVH can lead to post-
hemorrhagic hydrocephalus (PHH), with 48 % of patients
sustaining grades 3 and 4 IVH developing PHH. When com-
bined, IVH-PHH is a dauntingly critical condition, and one
whose pathology is not completely understood.
In addition to infants, IVH is also seen in patients with
intracerebral hemorrhage (ICH) and subarachnoid hemor-
rhage (SAH), two major types of hemorrhagic stroke with
high morbidity and mortality [4–10]. IVH occurs in up to
50 % of patients with primary ICH and 45 % of patients with
aneurysmal SAH [11–13]. Recent studies have found IVH is a
predictor of poor outcome after ICH [11, 12]. The internation-
al surgical trial in intracerebral hemorrhage showed that in
ICH patients, IVH lowers the rate of favorable outcomes and
is associated with hydrocephalus in more than 50 % of adult
patients [11]. IVH is also an independent prognostic factor for
poor outcome in SAH patients, and acute hydrocephalus
* Guohua Xi
guohuaxi@med.umich.edu
1
Department of Neurosurgery, University of Michigan, Ann
Arbor, MI, USA
2
Department of Neurosurgery, R5018 Biomedical Science Research
Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
occurs in 20–30 % of such patients [13]. In addition, blood
in the ventricle may contribute to hydrocephalus after traumat-
ic brain injury [14].
Despite this, there is a scarcity of research into the field of
IVH when compared to ICH or SAH. Studies of ICH and
SAH have shown increasing recognition of the importance
of particular blood components in brain damage [6, 15–17].
Although the body of literature regarding the role of blood
components in IVH is far smaller than in ICH or SAH, a
similar focus is apparent—the roles of hemoglobin and its
degradation products, plasma components and the coagulation
cascade, platelets, and leukocytosis in the pathogenesis of
IVH are becoming more apparent (Fig. 1).
Hemoglobin and Its Degradation Products
After hemorrhage and hemolysis, hemoglobin is released into
the extracellular space and subsequently exhibits cytotoxic
effects, depleting nitric oxide levels and increasing the inflam-
matory response [18]. Consequently, the role of hemoglobin
following hemolysis after IVH has recently become a topic of
interest. Gram et al. showed that intraventricular hemoglobin
induces a pro-inflammatory response characterized by in-
creased cerebrospinal fluid (CSF) levels of the pro-
inflammatory cytokine tumor necrosis factor-α (TNF-α), as
well as by periventricular brain damage [19, 20].
Intraventricular hemoglobin has been shown to induce signif-
icant neurodegeneration in the hippocampus via JNK signal-
ing pathways within 3 days of hemorrhage [21].
In addition to playing a role in cellular damage, hemoglo-
bin is also involved in the development of PHH. In a neonatal
rat model, intraventricular injection of hemoglobin results in a
significant (3.6-fold) enlargement of the ventricular system
compared to an injection with artificial CSF [22]. Although

Fig. 1 An overview of blood
components and brain injury after
intraventricular hemorrhage
the underlying mechanism is still not fully elucidated, intra-
ventricular hemoglobin has been shown to induce structural
and cellular damage to the choroid plexus, which is not only
thought to be the primary site of CSF production, but which is
also a crucial component of the blood-CSF barrier [19]. Such
damage is accompanied by upregulation of cellular activation,
inflammatory response, and oxidative stress in the choroid
plexus. Furthermore, hemoglobin alters the expression of
aquaporins (AQPs), which play a major role in the production
and circulation of CSF and have been implicated in the for-
mation of hydrocephalus. Exposure of choroid plexus epithe-
lial cells to hemoglobin results in a significant changes in
mRNA and protein levels of AQP1 and AQP5 [23]. AQP5
overexpression is linked to increased cell proliferation via the
RAS signaling pathway [24], which, if occurring in the cho-
roid plexus may contribute to increased CSF production, al-
though this has not been investigated. Thus, the ability of
hemoglobin to affect the expression of AQPs in the choroid
plexus may be linked to the pathogenesis of PHH.
The mechanism by which hemoglobin induces
periventricular tissue damage and hydrocephalus is closely
tied to the process of its degradation. After hemolysis, hemo-
globin dissociates into αβ dimers, which are quickly scav-
enged from the extracellular space by haptoglobin, the plasma
protein with the highest binding affinity for hemoglobin [25].
From there, the hemoglobin heterodimers undergo receptor-
mediated endocytosis via CD163, a receptor expressed in
monocytes and macrophages, and potentially neurons (though
this finding warrants further investigation) [21]. Once inside
the cell, the heme moieties are degraded by either heme oxy-
genase (HO)-1 or HO-2 to form biliverdin, carbon monoxide,
and free iron [26]. The iron released by HO has the ability to
participate in oxidative Fenton reactions and, therefore, has
been a primary subject of studies examining hemoglobin-
mediated hydrocephalus and brain injury following IVH.
Intraventricular injection of lysed red blood cells increases
HO-1 activity in the brain and induces expression of ferritin,
an endogenous iron chelator, indicating that the hemoglobin
Transl. Stroke Res.
released is being degraded into free iron [27]. Moreover, this
iron may then be released into CSF. In a small study of infants
with post-hemorrhagic ventricular dilatation, 75 % had non-
protein-bound iron in their CSF, compared to 0 % in controls
[28]. In addition, iron accumulation following ICH/IVH is
correlated with ventricular dilation and brain damage [29].
In a germinal matrix hemorrhage-IVH model, iron accumula-
tion was correlated with lateral ventricular expansion, brain
edema, neuronal degeneration in the basal ganglia, and a de-
crease in long-term motor function [30]. These effects were
significantly reduced by minocycline, although whether this
was due to the ability of that compound to chelate iron and/or
inhibit microglia is uncertain. Intraventricular injection of iron
also leads to significant ventriculomegaly, while treatment
with the iron chelator def eroxamine ameliorates
hemoglobin-induced effects on ventricle size and hippocam-
pal damage [21, 22, 27]. Injection of protoporphyrin IX (es-
sentially an iron-less heme compound) does not induce hydro-
cephalus [22], implicating iron as the key component of the
heme moiety in the mechanism behind PHH. It has also been
suggested that iron induces hydrocephalus by activating the
WNT signaling pathway after IVH, which is closely implicat-
ed in subarachnoid fibrosis in chronic hydrocephalus [31].
Thus, there is considerable evidence that hemoglobin and
hemoglobin degradation products play an important role in the
pathogenesis of hydrocephalus and brain injury following
IVH. While much of the effort to target this process therapeu-
tically has focused on iron chelation, Gram et al. suggested
injecting the scavenger protein haptoglobin as a way to reduce
the effects of free hemoglobin [19]. In plasma, haptoglobin
plays a key role in clearing free hemoglobin. Although a small
amount of haptoglobin in circulating blood will enter the brain
with the IVH, normal adult CSF levels are very low suggest-
ing that there may be insufficient haptoglobin to bind hemo-
globin released after hemolysis [32]. In addition, in the neo-
nate, plasma haptoglobin expression is extremely low, which
might contribute to the high morbidity of neonatal hemor-
rhage [33]. Haptoglobin is limited as a therapy as it is a high
Transl. Stroke Res.
molecular weight protein and would likely require direct ad-
ministration into the brain.
In addition to hemoglobin and its degradation products,
there may be other erythrocyte components that play a role
in IVH-induced injury. For example, in ICH-induced brain
injury, there is evidence that red blood cell carbonic anhydrase
can have deleterious effects [34]. Further study into both he-
moglobin and other red blood cell breakdown products is
warranted including treatments specific to these pathways.
Plasma Components and the Coagulation Cascade
Plasma-derived factors also have a role in IVH-induced brain
injury, with most of the existing evidence focusing on the role
of the coagulation cascade. Thrombin is a key factor in the
coagulation cascade. Also known as factor IIa, thrombin is
created by the cleavage of prothrombin by the prothrombinase
complex (factors Xa/Va). As a serine protease, the primary
function of thrombin in the coagulation cascade is to limit
further hemorrhage by cleaving fibrinogen into insoluble fibrin.
However, thrombin plays a variety of other distinctly detrimen-
tal roles upon release into the ventricles following IVH. Some
of the actions of thrombin are via a family of protease-activated
receptors (PARs) and most significantly PAR-1. PAR-1 is a G-
protein-coupled receptor activated directly by thrombin proteo-
lytic activity which initiates a wide range of intracellular cas-
cades [35, 36]. Thrombin production in IVH activates PAR-1
and thereby induces both significant ependymal wall damage
and hydrocephalus [37]. One PAR-1-mediated pathway is ac-
tivation of the Src family of kinases. These proteins can phos-
phorylate metalloproteinases, known to be a significant cause
of damage in other types of intracranial hemorrhage, although
their specific roles in IVH and clot clearance are unknown [38].
Indeed, SCH79797, a PAR-1 antagonist, has been shown to
significantly reduce this damage [37], while inhibiting Src fam-
ily kinases with PP2 blocks brain edema and blood brain barrier
disruption [38]. Thrombin-induced hydrocephalus is reduced
by CSF production inhibitors such as acetazolamide (a carbon-
ic anhydrase inhibitor), but even after this treatment, rats
injected with thrombin had ventricular volumes double those
of vehicle controls [39].
In SAH animal models, transforming growth factor β1
(TGF β) has been shown to be a mediator of thrombin-
induced inflammation [40]. TGF β is released into CSF by
extravasated platelets following IVH, and some have theo-
rized that it may play a role in the pathogenesis of obstructive
hydrocephalus [41]. While there is some controversy, recent
studies of kaolin-induced hydrocephalus suggest that the TGF
β antagonist, decorin, reduces ventricle size and white matter
injury [42, 43]. Further research into this topic is necessary to
elucidate the role of TGF β and downstream signaling in
hydrocephalus, including PHH.
Thrombin’s downstream target fibrinogen has also been of
interest in intracranial hemorrhage, mostly in patients on an-
ticoagulants who are at risk for hemorrhage because of inad-
equate fibrin formation or in the use of fibrinolytics to clear
hematomas. An example of the latter is the Clot lysis: evalu-
ating accelerated resolution of intraventricular hemorrhage
phase III (CLEAR III) trial which is investigating tissue plas-
minogen activator (tPA) as an effective intraventricular fibri-
nolytic agent. However, recent evidence indicates that extra-
vascular fibrinogen is a powerful pro-inflammatory mediator
[44, 45] and may also play a role in mediating brain injury in
IVH. The role of fibrinogen in IVH-induced brain injury and
hydrocephalus merits investigation.
It should be noted that one of the proposed functions of the
blood–brain barrier is to prevent the entry of potentially neu-
roactive compounds from blood to the brain. However, there
may also be plasma components in addition to prothrombin
(converted to thrombin) and fibrinogen (converted to fibrin)
that enter the brain during IVH and induce or modulate brain
injury. As noted previously, haptoglobin may be one such
component that warrants further study, but this has received
little attention.
Platelets
Platelets are an integral component of the hemostatic system,
but in general, the role of platelets in IVH-induced injury has
received little attention compared to the role of erythrocytes.
Indeed, this is the case for all forms of cerebral hemorrhage.
Platelet aggregation (platelet plug) is involved in hemostasis.
Activated platelets release a range of potent chemical media-
tors, including adenosine diphosphate, serotonin, and throm-
boxane A2. As noted above, one mediator released by platelets,
TGF β, has been implicated in inducing hydrocephalus [43].
Leukocytes
Leukocytes are the body’s mobile immune cells, tasked with
protecting against infection and foreign bodies. Leukocytes
are broadly categorized into two main types, the lymphoid
cells (B cells, T cells, NK cells) and myeloid cells (basophils,
neutrophils, eosinophils, and monocytes). All of these cells
can be found circulating through the blood and migrating to-
wards the site of injury during an inflammatory response [46,
47]. The brain’s resident immune cell is the microglia, a dif-
ferentiated monocyte that can be activated classically or alter-
natively. The classical M1 pathway is pro-inflammatory and
has been linked to increased brain injury following hemor-
rhage, while the alternative M2 pathway is involved in reso-
lution of inflammation [48]. In the neonatal brain, microglial
density is already the highest in periventricular white matter.

Following IVH, microglia and neutrophils accumulate in the
periventricular area to a greater extent than in the cortex with a
time course beginning at about 48-h post-hemorrhage [49].
This infiltration and activation of microglial cells may result
in increased phagocytic activity [50]. Moreover, M1-activated
microglia release pro-inflammatory cytokines, which can be
cytotoxic to the surrounding brain matter [48].
While attention has almost entirely focused on the role of
leukocytes infiltrating into the brain after cerebral hemor-
rhage, it should be noted that they are also a component of
the initial hemorrhage. They have a relatively short half-life
[51] but are a potential source of inflammatory mediators;
whether or not they impact the brain inflammatory response
after an IVH has not been examined directly.
Conclusions
The current state of research investigating the roles of specific
blood components following IVH leaves vast gaps for future
studies to fill. More research is needed on the mechanisms by
which the blood components such as hemoglobin, plasma prod-
ucts, platelets, and leukocytes induce brain damage. In particu-
lar, the mechanism by which hemoglobin induces hydrocepha-
lus is not fully understood. While the release of free iron is
clearly a significant factor, it probably does not account for
the entirety of the damage found, suggesting that other poten-
tially non-oxidative mechanisms play a role. Furthermore,
while deferoxamine’s efficacy against iron-induced ventricular
damage in animal and clinical studies of ICH has been prom-
ising, clinical trials in ICH are still ongoing [52], and no trial
investigating deferoxamine in IVH has been proposed.
Overall, few studies have examined the role of extravasated
blood in IVH and PHH. IVH is an extremely morbid disease
but, as of yet, there is no effective treatment as is evidenced by
its unchanging incidence and morbidity over the past decades
[3, 53]. For infants with grade 4 IVH, mortality rates remain as
high as 40 % in the USA [53]. Preclinical IVH research is
beginning to indicate that blood components play a significant
role in IVH-induced brain injury and PHH, but the volume of
literature and replication is still low. Future studies investigat-
ing these topics could yield significant advancements towards
finding effective therapeutic treatments.
Acknowledgments This study was supported by grants NS-073595,
NS-079157, NS-084049, NS-090925, NS-091545, NS-096917, and
NS-007222 from the National Institutes of Health (NIH) and 973
Program-2014CB541600.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Transl. Stroke Res.
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