J Neurol
DOI 10.1007/s00415-011-6153-3
REVIEW
Oral anticoagulant-associated intracerebral hemorrhage
Alvaro Cervera Sergio Amaro Angel Chamorro
Received: 30 May 2011 / Accepted: 16 June 2011
Springer-Verlag 2011
Abstract The incidence of oral anticoagulation-asso-
ciated intracerebral hemorrhage (OAC-ICH) is growing
due to the increasing use of warfarin and the older age of
treated patients. Recent population studies reveal that
OAC-ICH currently occurs at a frequency comparable to
that of subarachnoid hemorrhage. Most frequently, OAC-
ICH are located in deep or lobar regions of the brain,
although it may also occur in the brainstem. These
hemorrhages are larger than spontaneous hematomas and
may be fatal in at least 50% of cases. The primary cause
of brain injury in patients with OAC-ICH is the direct
mechanical disruption of the brain tissue but secondary
damage may occur through the intervention of matrix
metalloproteinases, glutamate, cytokines, heme, iron, and
the chemical toxicity of products such as thrombin, which
are released from the clot. The pathogenesis of OAC-ICH
also includes the effects of aging, the level of anticoag-
ulation, genetic factors, and a high prevalence of con-
current cerebrovascular conditions, such as cerebral
amyloid angiopathy, leukoaraiosis or previous strokes.
The treatment of OAC-ICH is challenging and involves
rapid reversal of anticoagulation with hemostatic drug
therapies such as vitamin K, fresh frozen plasma, pro-
thrombin complex concentrates or recombinant factor
VIIa. These therapies may not always be sufficient to
stabilize the patients clinical condition and lacking ran-
domized controlled trials, the best hematological approach
to reverse oral anticoagulation is debated. Other difficult
A. Cervera
S. Amaro
A. Chamorro (&)
Comprehensive Stroke Center, Hospital Clinic, Institut
dInvestigacions Biomediques August Pi i Sunyer (IDIBAPS),
University of Barcelona, 170 Villarroel, 08036 Barcelona, Spain
e-mail: achamorro@ub.edu
decisions reviewed in this article are whether anticoagu-
lation should be restarted after OAC-ICH, and when
anticoagulant treatment should be resumed. The newer
oral anticoagulants, which are increasingly being intro-
duced for thromboembolism prevention, may confer a
lower risk of intracranial bleeding than warfarin, although
they do not have an antidote and their anticoagulant effect
is difficult to monitor.
Keywords Intracerebral hemorrhage
Warfarin

Oral anticoagulation
Outcome
Introduction
Warfarin is the most widely used oral anticoagulant (OAC)
in the world, although acenocoumarol, phenprocoumon or
anisindione are also frequently prescribed in several
countries. Warfarin inhibits the vitamin K-dependent post-
translational carboxylation of glutamate residues on the
N-terminal regions of coagulation factors II, VII, IX and X
by inhibiting the conversion of vitamin K 2, 3-epoxide to
reduced vitamin K [1]. The mechanism of action is com-
parable in the above cited OAC, being the major differ-
ences their half-lives and the duration of effect.
The benefits of OAC for thromboembolic protection are
supported by a high level of evidence in patients with
several cardiac conditions, atrial fibrillation or a history of
venous thromboembolism [2]. Nonetheless, OAC are also
notorious for having a narrow therapeutic index, numerous
drug and dietary interactions, and a significant risk of
serious bleeding that includes hemorrhagic stroke [3]. In
this review, we analyze the epidemiology, time trends,
main risk factors and pathophysiology of OAC-associated
intracerebral hemorrhage (OAC-ICH). The review also
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critically discusses highly controversial therapeutic deci-
sions that are required during the early and late phases of
this devastating condition, including the pros and cons of
different hematological approaches aimed to control the
acute bleeding, the dilemma of deciding whether oral
anticoagulation should or not be restarted, and how and
when to do it in individual cases.
Epidemiology
Approximately 1% of the population in Europe is currently
receiving OAC with vitamin K antagonists, and this pro-
portion has increased to 1.7% in some countries [4]. About
512% of ICH is related to OAC, leading to an estimated
annual incidence in the USA of nearly 3,000 [57]. In
randomized trials, the risk of major bleeding associated
with vitamin K antagonists varied according to the clinical
condition that motivated the treatment, mechanical heart
valves (18.3%), atrial fibrillation (06.6%), coronary heart
disease (019.3%), venous thromboembolism (016.7%),
or ischemic cerebrovascular disease (213%) [8]. The most
frequent complication of OAC is gastrointestinal bleeding,
but intracranial hemorrhage (ICH) is the main cause of
fatal bleeding.
In a pooled analysis of five trials using warfarin in
patients with AF the annual rate of OAC-ICH was 0.3%
[9]. The rate of OAC-ICH is about 29 per 100,000 pop-
ulation/year, an incidence 7- to 10-fold higher than in the
not treated population [10]. Moreover, the incidence of
OAC-ICH is increasing and ranked only slightly behind the
incidence of subarachnoid hemorrhage in recent studies
[7]. This relentless increment can be explained by the
larger number of elderly patients that receive OAC, the
increased use of combined anticoagulant regimens or the
addition of antiplatelets, or the expanded use of OAC for
secondary stroke prevention [11]. Although the increased
number of bleeding complications is counterbalanced by a
more effective prophylaxis of thromboembolic events, the
identification of those patients at higher risk of bleeding
complications must be improved.
Pathophysiology
The primary cause of brain injury in patients with ICH or
OAC-ICH is the direct mechanical disruption of the brain
tissue [12], although secondary damage frequently occurs
as the result of mass effect, midline shift and herniation
of brain structures, particularly in subjects with large
brain hemorrhages. Several molecules have been impli-
cated in the mechanisms of brain injury after ICH
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including matrix metalloproteinases [13], glutamate [14],
activated cytokines [15], heme [16], and iron [17]. It is
more controversial whether a reduction of cerebral blood
flow in areas surrounding the hematoma is also relevant
in patients [18, 19], as it appears to be in animal studies
[20].
An important clinical question is whether the majority of
brain damage is caused at the time of vessel rupture, or if
secondary damage may also occur through more protracted
mechanisms. The relevance of secondary damage is sup-
ported by neuroimaging and pathological studies that
identify areas of necrotic brain tissue and edema formation
around the clot, which are attributed to the direct effects of
mechanical forces and the chemical toxicity of products
such as thrombin which are released from the clot [21].
This observation has encouraged the design of clinical
trials aimed at improving outcome at expenses of limiting
secondary hematoma growth [22].
The role of thrombin in brain edema formation
The formation of brain edema around the hematoma is
attributed to the effects of increased hydrostatic pressure
[23], increased bloodbrain barrier permeability [24], and
clot retraction with movement of serum molecules from the
hematoma into the surrounding tissue [2527]. The latter
process emphasizes that intracerebral blood may itself be
toxic and contribute to secondary brain damage [12].
Thrombin is a serine protease that is released from the
hematoma and may affect the behavior of the hemorrhage.
At low concentrations, thrombin is essential to stop the
bleeding [28], but at higher concentrations, it can kill
neurons and astrocytes [29] and may facilitate perihemat-
omal edema formation [30]. Therefore, it is plausible that
thrombin might contribute to amplify the clinical effects of
the initial bleeding. The toxic effect of blood (and
thrombin) is further supported by experimental studies
showing that the injection of blood into the brain is more
harmful than the injection of an oilwax mixture [21].
Contrarily, injection of heparinized blood results in less
perihematomal edema formation [31], and brain edema
formation is also reduced after the administration of
thrombin inhibitors [32]. Thrombin formation is inhibited
by the effect of warfarin or other related compounds [33],
and it is conceivable that a lower concentration of thrombin
at the clot in patients with OAC-ICH facilitates the for-
mation of larger hematomas and longer bleedings. Yet, the
lower disposal of thrombin within the clot would also result
in less toxicity to the surrounding brain parenchyma.
Overall, the available clinical data highlight the predomi-
nant negative effect of larger hematoma volumes in anti-
coagulated patients.
J Neurol
Risk factors of OAC-ICH
Pharmacological and non pharmacological interactions
Many factors contribute to the variability in warfarin dose
requirements, the fluctuation in the anticoagulant response
and the risk of bleeding [34]. Warfarindrug interactions
have been shown to increase the risk of serious bleeding
[35]. In a recent retrospective study [36], warfarin inter-
action with at least one drug was considered the main
contributor to bleeding in almost a half of the cases.
Groups of drugs prone to interact with warfarin include
anti-fungal agents, lipid-lowering drugs, acetaminophen,
non-steroidal anti-inflammatory drugs, selective serotonin
reuptake inhibitors, amiodarone, omeprazole, fluorouracil,
and cimetidine [37]. The main mechanism of interaction
implies the inhibition of cytochrome P450 2C9 isoenzyme
(CYP2C9), which increases the plasma concentration of
S-warfarin and leads to enhanced anticoagulation and
higher bleeding risk. Also, drugs that impair platelet
function raise the risk associated with warfarin therapy
[38]. Conversely, the anticoagulant effect of warfarin could
be inhibited by drugs which increase hepatic clearance, like
barbiturates, rifampicin, and carbamazepine.
Microhemorrhages, leukoaraiosis, previous stroke
and their relationship with OAC-ICH
There are a number of predisposing factors of cerebral
hemorrhage in anticoagulated patients, as shown in
Table 1. Several brain abnormalities have also been asso-
ciated with a greater risk of complications in anticoagu-
lated patients, including microhemorrhages, leukoaraiosis,
and previous strokes [3941]. Microhemorrhages are small,
dot-like signal loss best visualized on gradient-echo mag-
netic resonance imaging, which are regarded as hemosid-
erin deposits caused by minor bleeding from advanced
microangiopathy [42, 43]. Individuals with microhemor-
rhages are more likely to be hypertensive, and have history
of stroke, leukoaraiosis, or old hemorrhages. In patients
with acute ischemic stroke, those with coexistent micro-
hemorrhages more frequently develop subsequent ICH
[44]. Sporadic reports also suggest that microhemorrhages
are preferential focuses of ICH in patients receiving war-
farin, most likely because the drug unmasks ICH that
would otherwise remain asymptomatic [39]. Microhemor-
rhages, leukoaraiosis and previous stroke frequently coex-
ist and this may confound the interpretation of the risk of
spontaneous or drug related cerebral bleeding.
Leukoaraiosis has been independently associated with
OAC-ICH in a dose-dependent manner [40], even among
patients with an INR B 3.0 [41]. In other studies, patients
with advanced leukoaraiosis but without microhemorrhages
Table 1 Predisposing factors of cerebral hemorrhage in anticoagu-
lated patients [3, 5]
Proven risk factors
Advancing age (especially [75 years)
Hypertension (especially systolic blood pressure [160 mm Hg)
History of cerebrovascular disease
Intensity of anticoagulation (mainly if INR [ 4.0)
Possible risk factors
Increased variation of INR
Concomitant use of aspirin
Cerebral amyloid angiopathy
Tobacco smoking
Heavy alcohol consumption
Diabetes
Serious heart disease
Liver disease
Malignancy
Imaging and genetic markers
Leukoaraiosis detected by brain CT/MRI
Microbleeds by T2*-weighted MRI
Apo e2 or e4 genotype
tended to experience ischemic strokes rather than ICH [45].
Yet, the presence of microhemorrhages was a predictor of
ICH in patients with no or mild leukoaraiosis [45]. Recently,
leukoaraiosis was not found independently associated with
the incidence of OAC-ICH after adjustment for the presence
of microhemorrhages [46]. In light of these inconsistent
findings, the use of OAC should not be avoided in patients
with leukoaraiosis or microhemorrhages.
Prediction of OAC-ICH
Several methods have been developed to estimate the risk
for OAC-related bleeding and improve the identification of
patients in whom the risks of therapy might outweigh the
benefits [4749]. The main characteristics and predictive
value of these models are shown in Table 2. These methods
are valid but should not be used in isolation to decide
whether to initiate or not a therapy with OAC in individual
patients. Moreover, none of these methods have differen-
tiated between the risks of intracranial or systemic bleed-
ings, or incorporated the predictive role of INR values.
More recently, the European Society of Cardiology has
proposed a new score, the HAS-BLED (hypertension,
abnormal renal/liver function, stroke, bleeding history,
labile INR, [65 years-old, intake of drugs or alcohol) to
assess the bleeding risk in AF patients [50]. A score C3
indicates a high-risk, and caution is advised before starting
antithrombotic treatment.
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Table 2 Bleeding prediction models
Author Follow-up High-risk Medium-risk
(months) (%) (%)
Beyth et al. [47] 48 53 12
Kuijer et al. [48] 3 7 4 1
Shireman et al. [49] 3 5.4 2.0
Genetics of OAC-ICH
It has been estimated that a third of all cases of lobar ICH
are attributable to the presence of an apolipoprotein e4 or
e2 allele [51], but testing for them does not appear to
facilitate the selection of patients that can safely be treated
with warfarin [52]. Randomized clinical trials have con-
sistently demonstrated an increased risk of bleeding among
patients in whom the target intensity of anticoagulation is
higher [3]. While a minor part of the variability in dose
requirement has been attributed to demographic and clin-
ical factors such as age, drug interactions, concomitant
diseases, or vitamin K intake, the major contributors to the
risk of bleeding are genetic factors [53].
Genetic variants of cytochrome P450 2C9 (CYP2C9)
and vitamin K epoxide reductase (VKORC1) may influ-
ence warfarin dose and appear to modulate the risk of
bleeding, mainly at the beginning of drug intake [54, 55].
CYP2C9 encodes the enzyme cytochrome P450 2C9 that
mediates the metabolic clearance of the enantiomer
S-warfarin, which is more potent than R-warfarin, and
three different alleles termed CYP2C9*1 (wild allele),
CYP2C9*2 and CYP2C9*3 have been described. Patients
with allele variants require a lower dose of anticoagulants,
take a longer time to reach a stable dose, and are at higher
risk for over-anticoagulation and serious bleeding during
the start of treatment [54]. It has been recently suggested
that CYP2C9 genotyping could identify patients at higher
risk of bleeding [56].
VKORC1 recycles vitamin K epoxide to the reduced
form of vitamin K, an essential cofactor in the activation of
clotting factors II, VII, IX, and X [57]. VKORC1 poly-
morphisms account for over a 30% of the variance in the
dose of warfarin [58], and they are associated with a lower
warfarin dose during long-term therapy [55]. The increased
risk of bleeding attributable to VKORC1 is limited to the
beginning of anticoagulant therapy, while CYP2C9
sequence variants may be associated with a continued risk
of hemorrhage [59]. However, recent prospective data
show that [70% of OAC-ICH occur in patients who have
been receiving warfarin for 1 year or longer, suggesting
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Low-risk Variables included in models
(%)
3 Age [65 years, history of GI bleeding, history of stroke, at
least one of recent AMI, renal insufficiency, anemia or
diabetes mellitus
Age C60 years, gender, malignancy, body surface area [2,
coumarin type (long vs. short acting agents)
0.9 Age C70 years, gender, remote bleeding; recent bleeding,
alcohol/drug abuse, diabetes; anemia, antiplatelet use
that interventions aimed to adjust initial warfarin dose
based on genetic information are unlikely to prevent the
majority of intracerebral bleedings [60].
Clinical aspects and prognosis of OAC-ICH
ICH is the most threatening stroke subtype, particularly in
men, with a mortality rate between 30 and 55% [61, 62].
The higher mortality risk of ICH compared with ischemic
stroke (HR, 1.56) is maintained after adjustment for age,
gender, stroke severity and cardiovascular risk factors [63].
The increased mortality risk is more relevant during the
first 3 months of stroke, and detrimental factors include
decreased level of consciousness, hemorrhage volume,
hematoma expansion, and intraventricular extension of
hemorrhage [6466]. The prognosis of OAC-ICH varied in
different studies, as shown in Table 3, although most
studies were small, retrospective, lacked a control group,
did not have clear diagnostic protocols, and the care of
patients was not standardized. Aggregated data shows that
the outcome of patients with OAC-ICH is worse than in
patients with spontaneous ICH, and that increased mor-
tality obeys as much to a higher incidence of larger hem-
orrhages, as to the older age and severe comorbidity
frequently observed in patients with OAC-ICH [61, 67].
The severity of OAC-ICH is influenced by the specific
brain anatomy of the bleeding. The localization of the
hemorrhage is similar to the observed in spontaneous ICH
[68]. Thus, the relative frequency of lobar bleedings is
similar in anticoagulated and non anticoagulated patients.
OAC-ICH showed a predilection for the cerebellum in
several studies [69, 70], although this preference was not
confirmed in aggregate data [71]. OAC-ICH is reported to
be significantly larger than spontaneous ICH [66, 72],
although this is not confirmed in other studies [73]. In one
study patients with OAC-ICH showed a greater risk of
hematoma expansion, and more protracted bleedings than
patients with spontaneous ICH [73]. Higher initial systolic
BP [74] and hyperglycemia [73] were found to be associ-
ated with greater ICH expansion in some studies, although
 J Neurol

Table 3 Prognosis in OAC-ICH in different studies

Study Ref Year OAC-ICH ICH control Mean age Mortality or Predictors of Predictors of ICH Correlation of Early
n poor outcome mortality or expansion volume INR with ICH ICH worsening
(time of assessment) rebleeding expansion (%)

Franke [66] 1990 79 No 67 4667% UK UK No UK

(230 days)
Bertram [97] 2000 15 No 62 20% UK INR prolongation UK 47
(4 days)
Berwaerts [119] 2000 42 No 71 43% ICH volume No
Sjoblom [75] 2001 151 No 75 5464% IV extension, UK No 47
(30 days6 months) ICH volume
Flibotte [73] 2004 42 142 [18 53% Warfarin use, Warfarin use No 54
(90 days) Hyperglycemia
Rosand [67] 2004 102 333 76 52% Warfarin use, Age, UK Yes
(30 days) Diabetes, Lobar ICH
Flaherty [61] 2006 190 891 75 3366% Warfarin use UK UK UK
(1 day1 year)
Huttner [76] 2006 55 No 69 78% Age, ICH volume, Higher INR UK 27
(1 year) Hematoma growth
Cucchiara [65] 2008 21 267 75 62% Age, Male gender Initial ICH volume UK 56
(90 days) Warfarin use Warfarin use
Flaherty [72] 2008 51 207 69 UK INR [ 2.1 Lobar hemorrhage Only if INR [ 3 UK
Zukov [74] 2008 88 No 76 4043% GCS, Hyperglycemia SBP No 17
(730 days) ICH volume expansion
GCS Glasgow Coma Scale, ICH Intracerebral hemorrhage, INR International normalized ratio, IV Intraventricular, SBP Systolic blood pressure, UK Unknown

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acute blood pressure was not predictive of mortality in a
retrospective case control study [75]. Larger hematomas
[72], and greater hematoma growth have been correlated
with higher INR values in some studies [76]. Accordingly,
excessive anticoagulation may increase morbidity and
mortality in patients with OAC-ICH [77, 78].
should be actively reversed after OAC-ICH [80]. The
requirement of OAC reversal is mandatory if surgery of the
hematoma is planned. There are different options to reverse
OAC, and usually these are combined in order to achieve a
permanent reduction in the INR (Table 5).
Discontinuation of OAC therapy

Treatment of AOC-ICH To restore INR to its normal values is essential to stop

Reversal of anticoagulation after OAC-ICH
There is scanty evidence-based information about the proper
treatment of OAC-ICH; there are no randomized clinical
trials, current therapeutic guidelines differ in their recom-
mendations (Table 4), and expert opinions are also variable
[79]. Nevertheless, the consensus is that anticoagulation
OAC therapy. This is not associated with a relevant
increase in thromboembolic complications, as shown in a
large retrospective series of patients with OAC-ICH [81].
In patients with mechanical heart valves, there were no
embolic events or valve thrombosis after stopping OAC
[82]. Therefore, a short discontinuation of OAC in patients
at a high embolic risk can be performed safely in most
instances.

Table 4 Guidelines on OAC reversal

Guidelines Bleeding definition Preferred treatment Indications

Australasian Society of
Thrombosis and Haemostasis
[120]
British Committee for Standards in
Hematology [121]
European Stroke Initiative [122]
AHA/ASA [123]
ACCP [124]
Any clinical significant IV Vitamin K1, PCC and Cease warfarin
bleeding FFP IV Vitamin K1 510 mg
Prothrombinex (2550 IU/kg) and FFP
(150300 mL)
Major bleeding IV Vitamin K ? PCC Reversal of anticoagulation in patients with
major bleeding requires administration of a
factor concentrate in preference to FFP (grade
B, level III), and administration of intravenous
rather than oral vitamin K (grade B, level IIa)
OAC-associated ICH IV Vitamin K ? PCC or In patients with OAC-associated ICH and
FFP INR [ 1.4, OAC should be discontinued, and
the INR should be normalized with PCC or
FFP. Intravenous vitamin K should be added
(Class IV evidence)
Warfarin-associated ICH Vitamin K ? PCC or factor Patients with warfarin-associated ICH should be
IX complex or rFVIIa treated with IV Vitamin K to reverse the effects
of warfarin and with treatment to replace
clotting factors (Class I, Level of Evidence B)
PCC, factor IX complex concentrate, and rFVIIa
normalize the laboratory elevation of the INR
very rapidly and with lower volumes of fluid
than FFP but with greater potential of
thromboembolism. FFP is another potential
choice but is associated with greater volumes
and much longer infusion times (Class IIb,
Level of Evidence B)
Life-threatening Vitamin K ? FFP, PCC or In patients with life-threatening bleeding (e.g,
bleeding rFVIIa intracranial hemorrhage) and elevated INR,
regardless of the magnitude of the elevation,
we recommend holding warfarin therapy and
administering FFP, PCC, or rFVIIa
supplemented with vitamin K, 10 mg by slow
IV infusion, repeated, if necessary, depending
on the INR (Grade 1C)

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Table 5 Recommendations for use of specific reversal agents in OAC-ICH [78, 93]
Treatment Dose
Discontinuing OAC therapy
Vitamin K 2.510 mg IV over 30 min
Fresh frozen plasma 15 mL/kg
Prothrombin complex concentrate 25100 UI/kg
Recombinant factor VIIa 1090 lg/kg
Vitamin K
Vitamin K slowly reverts INR to its normal values, needing
224 h to be effective. All patients with OAC-ICH must be
given vitamin K. Otherwise, INR will not be corrected
completely and a rebound coagulopathy might develop
[83]. Vitamin K should be administered IV, because the
effect is too slow using the oral route. The usual doses and
infusion time are shown in Table 5.
Fresh frozen plasma
Fresh frozen plasma (FFP) has been used for many years as
the main therapy for OAC reversal, and is still the most
frequent treatment in North America. The administration of
FFP rapidly restores clotting factor levels, although rapid
correction of the INR has not been shown to improve
mortality and morbidity [84]. FFP is given IV at a dose of
15 mL/kg, although a lower dose can be used, and it
requires the concomitant administration of vitamin K. FFP
has some important disadvantages: the administration can
suffer delays due to thawing and preparation, the risk of
volume overload has to be considered in older patients, and
there is a small risk of viral transmission, passive alloim-
mune thrombocytopenia, anaphylactoid reactions and sep-
ticemia [85].
Prothrombin complex concentrates
Prothrombin complex concentrates (PCC) are prepared
from pooled plasma that is virally inactivated and contains
vitamin K-dependent factors. PCC is the most widely OAC
reversal agent used in Europe. There are two main types of
PCC: the three-factor concentrates contain therapeutic
amounts of factors II, IX, and X, while the four-factor
concentrates additionally contain factor VII. [86]. PCC are
given as shown in Table 5, although some authors defend
dose adjustment based on baseline INR [87]. The INR has
Timing of OAC reversal Special considerations
514 days
224 h Anaphylactoid reaction
Infusion 36 h Volume overload
Reversal 1232 h
Infusion 10 min to 1 h Three-factor concentrates may not
Reversal 15 min adequately correct INR, limited
availability, cost, variable cofactor
content based on manufacturer,
potentially prothrombotic
Bolus injection Short half-life, cost, potentially
Reversal 15 min prothrombotic, uncertain safety
to be monitored within 15 min of the dosage [88], and
vitamin K should be added to avoid a rebound coagulop-
athy [83]. PPC are administered more quickly than FFP, as
they not require blood checking or thawing, and there is no
risk of volume overload [86]. INR reversal with PPT is
very fast, and it may prevent hematoma enlargement and
poor outcome after OAC-ICH [89]. The main disadvantage
of PCC is a higher cost. In some patients it is not possible
to lower INR despite the administration of vitamin K and
factor supplementation. In these cases, liver disease, or
some coagulopathy have to be suspected [83].
Recombinant factor VIIa
Recombinant factor VIIa (rFVIIa) is able to reverse anti-
coagulation in patients with OAC-ICH and yields a very
rapid normalization of the INR [90, 91]. However, due to
its short half-life, a rebound increase in INR may occur.
The combination of rFVIIa and FFP achieves a better
correction of INR, and reduces the total dose of FFP nee-
ded [92], although this effect has not been reflected in a
better outcome. rFVIIa is also costly, and may increase the
risk of thromboembolic events [22].
PCC has been shown in some [80, 93, 94] but not all
[75, 76] studies to be more effective than FFP to reverse
the INR. In an experimental model of OAC-ICH in mice
PPC and FFP were similarly able to prevent hematoma
growth, and they were more effective than rFVIIa [95].
Yet, based on the available evidence, PCC plus IV vitamin
K should be the treatment of choice for most patients with
OAC-ICH [96].
Risk/benefits of early anticoagulation in patients
with OAC-ICH
A therapeutic dilemma arises when a patient who requires
full-dose anticoagulation for high-risk of thromboembo-
lism is admitted with OAC-ICH. As shown in Table 6, the
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Table 6 Main results of early
Author
versus late anticoagulation with
full-dose heparin or warfarin in Lieberman et al. [98]
patients with OAC-ICH
Kawamata et al. [68]
Nagakawa [101]
Leker and Abramsky [100]
Butler and Tait [99]
Bertram et al. [97]
Phan et al. [81]
Early anticoagulation (AC) was
restarted within 72 h and in Summary of findings
many of these patients within Early AC
24 h of stroke onset; late AC Late AC
was restarted after day 14
database addressing this difficult issue is rather small.
Bertram and colleges [97] retrospectively studied 15
patients with serious cardiac conditions and ICH which
occurred under anticoagulation. In all instances, INR nor-
malization was attempted as early as possible and, there-
fore, patients received full-dose intravenous or low-dose
subcutaneous heparin. All patients that achieved a 1.5- to
2-fold elevation in activated partial thromboplastin time
(aPTT) after normalization of the INR were discharged
without complications. On the other hand, patients with
incomplete correction of the INR experienced rebleeding
within 3 days, and patients with normalized INR and no
significant increase in aPTT developed cerebral embolism.
Small retrospective studies also showed with few excep-
tions [98, 99] that none of the patients experienced reb-
leeding or embolic events after initiation of full-dose
heparin within 3672 h of OAC-ICH onset [100, 101]. In
one study [68], early resumption of anticoagulation did not
cause intracranial rebleeding even in patients that undergo
early surgery of the hematoma.
A retrospective series of 141 patients at the Mayo Clinic
showed that the risk of having an ischemic stroke after
discontinuation of warfarin therapy within 30 days of the
ICH was less than 5%, although the mortality was 48%
[81]. All embolic events occurred within the first 5 days
after warfarin discontinuation. Of the 34 patients in whom
anticoagulation therapy was restarted by day 14, none had
recurrence of ICH during hospitalization. Tinker and Tar-
han [102] also observed in 159 patients with mechanical
heart valves undergoing elective surgery that none of the
patients had in-hospital thromboembolic complications
after discontinuing warfarin therapy.
Based on this small data base, the early initiation of full-
dose anticoagulation in patients with OAC-ICH cannot be
recommended (or opposed). While early initiation of full-
dose anticoagulation was not followed in these studies by a
clear reduction of the risk of embolism, the low statistical
power of the studies cannot rule out significant differences.
Moreover, few patients had the biological effects of
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n Anticoagulation Rebleeding Embolism
1 Early 1 0
12 Early 0 0
4 Early 0 0
4 Early 0 0
13 Early 1 3
15 Early 3 3
34 Late 0 3
83 5 (6.0%) 9 (10.8%)
49 5 (10.2%) 6 (12.2%)
34 0 3 (8.8%)
heparin adequately monitored in these studies [97], which
is a crucial step for heparin safety [103]. Also, weight-
adjusted heparin has been used safely in other bleeding
conditions including hemorrhagic stroke [104, 105] or
cerebral venous infarctions [106, 107]. Lacking random-
ized clinical trials to establish the value of full anticoagu-
lation in patients with OAC-ICH, therapeutic decisions
should be consider case by case. Yet, clinicians should be
aware that full anticoagulation must not be started before
stable blockade of warfarin effects. The greater safety of
weight-adjusted anticoagulant nomograms, and the
importance of strict monitoring of the biological effects of
heparin have also to be considered [108].
Long-term secondary stroke prevention after OAC-ICH
Another difficult decision in clinical practice is whether
anticoagulants should be restarted and maintained indefi-
nitely in patients with a history of OAC-ICH. Stroke pre-
vention in this situation needs to balance the risk/benefit of
different antithrombotic options and the estimated risk of
CNS bleeding recurrence. To this aim, an important step is
to establish the most likely cause of the bleeding. Whereas
hypertensive vasculopathy appears to be the most impor-
tant mechanism for ICH in deep hemispheric regions of the
brain, cerebral amyloid angiopathy, may be the most
common underlying pathophysiology for lobar ICH [51,
109]. The risk of recurrent hypertensive ICH can be
decreased by an adequate control of hypertension [110],
whereas cerebral amyloid angiopathy lacks any known
treatment. In a prospective study of elderly patients who
survived lobar ICH, recurrent ICH occurred in 22% at
2 years [111]. The rate of recurrent ICH in survivors of
deep hemispheric ICH was estimated to be 2.1% per
patient-year [112]. Therefore, in patients with lobar hem-
orrhage and major sources of embolism, decision analysis
models based on retrospective data suggest that the strategy
of do not anticoagulate appears robust [112]. Contrarily,
the risks and benefits of anticoagulation are more closely
J Neurol
balanced when applied to patients with deep hemispheric
ICH. In the latter case, oral anticoagulation might be jus-
tified if the estimated risk of ischemic stroke is high.
New oral anticoagulants
Dabigatran is a potent, direct, competitive inhibitor of
thrombin that does not require regular monitoring [113]. In
the RE-LY trial (Randomized Evaluation of Long-Term
Anticoagulation Therapy) two fixed doses of dabigatran
(110 or 150 mg, twice daily) administered in a blinded
manner were compared to open-label use of warfarin in
18,113 patients with AF [114]. Both doses were non-infe-
rior to warfarin, and the 150 mg dose was shown to be
superior to warfarin (RR 0.66, 95% CI 0.530.82). Hem-
orrhagic stroke happened in 0.38% per year with warfarin,
0.12% per year with 110 mg dabigatran, and 0.10% per
year with 150 mg dabigatran. The conclusion of this trial
was that both doses of dabigatran were non-inferior to
warfarin in the prevention of stroke or systemic embolism.
Moreover, the dose of 150 mg was superior to warfarin for
embolic prevention, and the dose of 110 mg produced less
hemorrhagic events. Therefore, the authors suggested that
the dose of dabigatran could potentially be tailored to take
into consideration the risk characteristics of a specific
patient [114]. Nevertheless, it has to be taken in consid-
eration that the number of patients needed to be treated
with dabigatran at a dose of 150 mg to prevent one non-
hemorrhagic stroke, in comparison to warfarin, is approx-
imately 357 [115]. There is no antidote to dabigatran, but in
case of life-threatening hemorrhage, administration of
rFVIIa or PCC can be considered [116].
Another kind of OACs are the factor Xa inhibitors, such
as rivaroxaban and apixaban. There is an unpublished study
that shows the non-inferiority of rivaroxaban versus war-
farin to prevent ischemic events in patients with AF
(ROCKET-AF study) with less ICH (HR 0.67) and fatal
bleeding [117]. On the other hand, in the AVERROES
study, apixaban was superior to aspirin for thromboembolic
prevention in patients with AF unsuitable for warfarin
treatment, with a similar risk of ICH [118]. As it occurs
with dabigatran, there is not a known antidote for apixaban
or rivaroxaban.
Concluding remarks
The benefits of warfarin are well established in many
patients with AF and other prevalent clinical conditions.
Recent clinical trials have shown very encouraging results
using new OAC agents [114] and this new knowledge
anticipates that warfarin might not be in the short future the
most frequently used OAC. However, a predictable wider
use of OAC also foretells that the incidence of OAC-ICH
will remain a sizeable clinical problem. Therefore, several
diagnostic and therapeutic questions remain to be clarified
in patients with this condition, including the best tools to
recognize the individuals at greater risk of bleeding, the
value of pharmacogenetics, and the most appropriate he-
mostatic therapy.
Acknowledgments Search strategy and selection criteria
References for this Review were identified through searches of
PubMed by use of the search terms warfarin or oral anticoagu-
lation and intracranial hemorrhage, from December 1986 to
February 2011. Only papers in English were reviewed in detail.
Further references were obtained from the bibliographies of the
papers identified through our searches. The final reference list was
generated on the basis of relevance to the topic of this Review.
Conflict of interest A Chamorro has given lectures and received
consultancy fees from Servier, Sanofi-Synthelabo, Takeda, Bristol-
Myers Squibb and Boehringer Ingelheim. A Cervera has received
consultancy fees from Boehringer Ingelheim. S Amaro declares to
have no conflict of interests.
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