Reviews

The practical management of intracerebral hemorrhage

associated with oral anticoagulant therapy
Luca Masotti1, Mario Di Napoli2, Daniel A. Godoy3, Daniela Rafanelli4,
Giancarlo Liumbruno5, Nicholas Koumpouros6, Giancarlo Landini7, Alessandro Pampana1,
Roberto Cappelli8, Daniela Poli9, and Domenico Prisco9

Oral anticoagulant-associated intracerebral hemorrhage is increasing in incidence and is the most feared complication of
therapy with vitamin K1 antagonists. Anticoagulant-associated
intracerebral hemorrhage has a high risk of ongoing bleeding,
death, or disability. The most important aspect of clinical
management of anticoagulant-associated intracerebral hemorrhage is represented by urgent reversal of coagulopathy, decreasing as quickly as possible the international normalized
ratio to values r1.4, preferably r1.2, together with life support
and surgical therapy, when indicated. Protocols for anticoagulant-associated intracerebral hemorrhage emphasize the immediate discontinuation of anticoagulant medication and the
immediate intravenous administration of vitamin K1 (mean
dose: 1020 mg), and the use of prothrombin complex concentrates (variable doses calculated estimate circulating functional
prothrombin complex) or fresh-frozen plasma (1530 ml/kg) or
recombinant activated factor VII (15120 lg/kg). Because of cost
and availability, there is limited randomized evidence comparing different reversal strategies that support a specific treatment
regimen. In this paper, we emphasize the growing importance
of anticoagulant-associated intracerebral hemorrhage and describe options for acute coagulopathy reversal in this setting.
Additionally, emphasis is placed on understanding current consensus-based guidelines for coagulopathy reversal and the

Correspondence: Luca Masotti, UO Medicina Interna Ospedale di

Cecina, Via Montanara, Localita` Ladronaia, 57023, Cecina (Li), Italy.
E-mail: luca.masotti@tin.it
1
Internal Medicine, Cecina Hospital, Cecina, Italy
2
Neurological Service, San Camillo de Lellis General Hospital, Rieti, Italy
3
Neurointensive Care Unit, Sanatorio Pasteur, Catamarca, Argentina
4
Transfusion Medicine, Pistoia Hospital, Pistoia, Italy
5
Transfusion Medicine and Clinical Pathology, San Giovanni Calibita
Fatebenefratelli Hospital, Rome, Italy
6
Neurosurgery, S.S. Filippo e Nicola Hospital, Avezzano, Italy
7
Internal Medicine, Santa Maria Nuova Florence Hospital, Florence, Italy
8
Thrombosis Center, University of Siena, Siena, Italy
9
Department of Medical and Surgical Critical Care, University of Florence,
Thrombosis Center, Florence, Italy
Conflict of Interest: None declared.
DOI: 10.1111/j.1747-4949.2011.00595.x

228

challenges of determining best evidence for these treatments.

On the basis of the available knowledge, inappropriate adherence to current consensus-based guidelines for coagulopathy
reversal may expose the physician to medico-legal implications.

Key words: adverse affects, factor VII, fresh-frozen plasma,

intracerebral hemorrhage, prothrombin complex concentrate,
treatment, vitamin K antagonists, warfarin

Introduction
Vitamin K antagonists (VKA) are a class of anticoagulants that
represent one of the main classes of drugs used in cardiovascular medicine; 11
5% of the population in western countries
have been the subject of VKA or so-called oral anticoagulant
therapy (OAT) (1), with widespread use over the past two
decades (2, 3). However, clinical practitioners resist using OAT
(4, 5), especially in elderly patients, due to their difficult
management and the risk of severe bleeding complications
(6). Intracerebral hemorrhage (ICH) represents the most
serious and feared complication of VKA.
This review is focused on the therapeutic strategies used to
reverse coagulopathy in patients who develop acute nontraumatic ICH while on OAT.
Physicians should embrace new practices:
 reverse the coagulopathy as soon as possible to avoid further
hematoma growth
 treat the initial underlying cause of ICH independently to
the treatment of the coagulopathy
 treat small hemorrhage sizes aggressively and quickly because patients with a better prognosis could worsen with
hematoma expansion, and
 revert anticoagulation in patients with a therapeutic international normalized ratio (INR), and not necessarily with a
major level of INR (Table 1).

Basic principles in VKA therapy

The available VKA are represented by warfarin, acenocoumarol, and phenprocoumon, which differ for the different

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Table 1 The NIKE principles in the reversal of anticoagulant-associated intracerebral hemorrhage

N 5 Normalize
I 5 Immediate
K 5 Vitamin K1
E 5 Elevation of INR

Normalize INR (and other coagulation parameters) as soon as possible

All patients should have immediate coagulopathy reversal, even if hemorrhage is small and clinical condition is good
Initial correction must include longer-acting agents (e.g. vitamin K1) to avoid rebound INR elevation later.
Level of INR elevation does not influence timing of reversal. All levels of INR elevation (modest o2
0, therapeutic 2
03
0,
supratherapeutic 43
0) require urgent correction

INR, international normalized ratio.

Extrinsic pathway

Intrinsic pathway
FXII

FXIIa
Tissue injury
FXI

FXIa
FIX

FVIII

FVIIIa

FIXa
FX

FVIIa
FXa

Thrombin (FIIa)

Prothrombin (FII)
FV

FVII

FVa
Fibrinogen

Fibrin monomer

Fibrin multimer

Crosslinked fibrin

Odds Ratio for intracranial

bleeding risk

Fig. 1 Sites of action (red) of oral anticoagulants in the clotting cascade.

10
8
6
4
2
0
1.9-2.0

2.4-2.7
3.1-3.4
3.7-4.3
4.9-5.7
6.6-8.0
Estimated International Normalized Risk (INR) values

Fig. 2 Risk of intracerebral hemorrhage in outpatients according to INR levels. INR, international normalized ratio.

plasma half-life. VKA drugs act on the liver by inhibiting gcarboxylation of glutamate residues on the N-terminal regions
of vitamin K-dependent coagulation factors (factor II, VII, IX,
and X) (6) (Fig. 1).
The main indicators for OATare represented by prophylaxis
in patients with cardioembolic sources, primary or secondary
prophylaxis of venous thromboembolism, and thromboembolic prophylaxis in patients with prothrombotic syndromes
(79). The efficacy and safety of OAT depends on the quality
control monitoring of the therapy. The bleeding complications
increase with increasing INR values. The risk of bleeding
doubles with each increment of one unit in the INR value.
INR44
5 represents the most significant risk factor for

bleeding in patients with OAT increasing bleeding risk by

about six times (7, 10) (Fig. 2).
Bleeds secondary to OAT are classified as either major or
minor (11). Bleeds are classified major if it:
 occurs in critical organs, the brain, retro-peritoneum,
peritoneum, chest, spinal cord, joints, gastro-intestinal tract
 results in a hemorrhagic shock, a decrease of 2 g/dl in
hemoglobin levels, requires surgical or invasive maneuvers, or
 results in death.
The remaining bleeds are classified as minor bleeds (11).
Bleeding complications can be reduced, and the accurate
selection of patients absolute and relative contraindications
for OAT, patient monitoring in an anticoagulation clinic

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(a)

(b)

Points

Liver disease

Renal disease

Alcoholism

Cancer

Age > 75 yeras

Platelets count < 75000/mm 3

Concomitant antiplatelets treatment

Previous bleeding

Uncontrolled arterial blood hypertension 1

Haemotocrit < 30%

CYP2C9*2 or CYP2C9*3 presence

High risk of falls or cognitive

impairment

Previous stroke

Fig. 3 (a) The HEMORR2HAGES score. (b) Annual risk of hemorrhage according to HAEMORR2HAGES score.

(specifically designed for monitoring OAT patients), together

with the self OAT monitoring (6), have contributed (12).
The risk factors for bleeds in patients with OAT are as
follows:
 advanced age
 severe liver and kidney diseases
 severe thrombocytopenia
 history of previous bleeding
 anemia
 dementia, and
 risk of falls (6).
Some genetic polymorphisms for enzymes involved in the
metabolism of VKA drugs, such as hepatic cytochrome P450
(CYP2C92 and CYP2C93) and enzyme vitamin K epoxide
reductase complex sub unit 1 (VKORC1), represent adjunctive
risk factors, identifying patients who require small doses of
VKA to reach the therapeutic range (13, 14).
Practical scores may help in identifying the bleeds risk of
each patient on OAT.
The Outpatients Bleeding Risk Index considers four independent predictors of bleeding:
 age 465 years
 prior stroke
 prior gastrointestinal bleeding, and
 any of four comorbidities (recent myocardial infarction,
anemia, diabetes, or renal insufficiency) (15).
The most recent HEMORR2HAGES score, which includes
genetic polymorphisms, is shown in Fig. 3a and b (16).
However, the current clinical usefulness of this one is poor
and routine use might not significantly change the choice of
OAT in elderly patients (17).
Optimal anticoagulation with VKA is clinically challenging
because of various patient food and drug interactions. Fluctuations in dietary vitamin K intake can have a significant
effect on the degree of anticoagulation in patients treated with

230

VKA. The interactions with many drugs (azole antibiotics,

macrolides, quinolones, nonsteroidal anti-inflammatory
drugs, including selective cyclooxygenase-2 inhibitors, selective serotonin reuptake inhibitors, omeprazole, lipid-lowering
agents, amiodarone, and fluorouracil) suggest that coadministration with VKA should be avoided or at least closely
monitored (18). In addition, an increase of patient use of
various dietary herbal products and supplements can
lead to undesired outcomes on anticoagulant levels of
warfarin (19), increasing bleeds risk (20). Case reports have
described an association between their use and ICH due to a
possible antiplatelet effect and VKA potentiate (21, 22).
Because this information is not from human research trials,
it is prudent to avoid the use of herbal agents in patients
who are taking VKA medications and patients and health
care providers should be vigilant of potential herbdrug
interactions (23).

VKA and intracerebral hemorrhagic risk

The OAT-associated ICH (OAT-ICH) represents major bleeding, resulting in a life-threatening condition, sometimes fatal.
The risk of OAT-ICH is of 0
20
6% per year of treatment (24,
25). The individual patient cumulative risk of bleeding is
directly related to the length of OAT. Higher frequencies of
bleeding are reported early in the course of therapy; the
frequency of major bleeding decreased from 3
0% during
the first month of outpatient OAT therapy to 0
8%/months
during the rest of the first year of therapy and to 0
3%/months
thereafter (26). Approximately 70% of OAT-ICH are intracerebral, whereas 30% are in the subarachnoid space. The
OAT-ICH represent about 15% of all ICH, with incidence
estimated in the general population of about 1
8/100 000 inhabitants/year and 800010 000 new cases expected every year
in the United States (25, 27, 28). As the use of VKA has

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(a)

(b)

Brain CT scan at hospital arrival of a female, 76years old, about 60 kg of weight, in OAT for atrial
fibrillation (suggested INR therapeutic range 2.03.0, target 2.5)
INR at hospital arrival 3.2
NIHSS 6
Clasgow Coma Scale 12/15
Treatment with PCC (Uman Complex, Kedrion,
Castelvecchio Pascoli, Lucca, Italy)
at dosage of 1500 UI in five minutes followed by
raFVII (Novoseven, NovoNordisk) at dosage of
1.2 mg in five minutes and vitamin K1 (Konakion,
Roche) at dosage of 20 mg in 250 cc of saline
solution in thirty minutes

CT scan after 3 hours

NIHSS 22
Glasgow Coma Scale 7/15
INR 0.7

The patient is transfered to Neurosurgical

Department for haemorrhage evacuation

(c)

(d)

Brain CT scan after neurosurgical

haemorrhage evacuation

Brain CT scan after 25 days

Fig. 4 Example of spontaneous intracerebral hemorrhage in patient on oral anticoagulant therapy. CT, computed tomography; INR, international normalized
ratio; PCC, prothrombin complex concentrate.

increased, so has the incidence of OAT-ICH. In fact, VKA may

be associated with as many as 17% of ICH cases, up from
5% 20 years ago (29). The most important OAT-ICH incidence
increase has been seen in patients aged more than 80 years,
ranging from 2
5% in 1988 to 45
9% in 1999 (29). The
risk of ICH increases significantly when OAT is combined
with other antithrombotic therapy (acetyl salicylic acid, ticlopidine, clopidogrel, unfractioned, or low-molecular-weight
heparin) (6).
Although in many cases OAT-ICH occurs in patients with a
VKA overdose demonstrated by an outrange INR value, ICH
can also occur in conditions of INR values within the
therapeutic range. A recent casecontrol study shows that
only 6% of patients with OAT-ICH were excessively anticoagulated before the bleed, demonstrating that OAT use is
associated with an increasing risk of ICH despite appropriate

INR monitoring (30). Figure 4 shows an example of ICH in a

patient with INR in the normal range.
Triggering factors for an OAT-ICH in well-anticoagulated
patients are:
 uncontrolled arterial hypertension
 head trauma
 rupture of an unknown intracranial aneurysm or an arterial-venous malformation
 leukoaraiosis
 amyloid microangiopathy
 primary or metastatic cerebral tumors, and
 unmonitored concomitant occasional therapy leading to an
increase of INR (31).
Cerebral microbleeds (MB) are known to be indicative of
bleeding-prone microangiopathy and potential risk factors for
ICH (32, 33) with a close positional association between

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recurrent ICH and prior MB (34). Excessive MB in OAT

patients with ICH compared with other groups suggests that
MB increase the risk of OAT-ICH (35) and underlying MB are
independently associated with a higher incidence of OAT-ICH.
However, the risks and benefits of VKA medication in patients
with MB are not well defined (33).
Thirty-day acute mortality for OAT-ICH is high, ranging
from 12% to 60% (25, 36), and it is nearly doubled when
compared with nonanticoagulated patients (37). However,
hematoma volume and lower level of consciousness measured
by the Glasgow Coma Scale but not INR levels are major
determinants of a poor outcome in patients with OAT-ICH
(38, 39). Hematoma enlargement is a major determinant of a
poor prognosis in OAT-ICH. The OAT-ICH is associated with
a greater baseline median ICH volume, more hemorrhage
expansion, and greater mortality than spontaneous ICH (40).
Experimental ICH animal models demonstrate that hematoma volume increases drastically between two- and 24 h,
hematoma volume increases steadily with increasing of INR
values, and mortality is critically associated with hematoma
volume (41). Although, in OAT-ICH patients, initial hematoma volume seems not to be significantly different compared
with non-OAT-ICH until INR r3
0, it is larger in OAT-ICH
with INR higher than 3
0 (4244). It has been demonstrated
that VKA-treated patients continue to bleed more often and
for a longer duration compared with non-OAT-ICH (37).
Approximately 50% of OAT-ICH patients present a secondary
volume expansion compared with 17% of non-OAT-ICH
patients (37).
The time factor represents the most important variable in
the OAT-ICH patient prognosis (45). Patients with suspected
or confirmed OAT-ICH should be treated as a medical
emergency. OAT reversal should start as soon as possible after
symptom onset to prevent hematoma expansion (27). OAT
reversal, together with surgical treatment, and support therapies such as reduction of blood hypertension and hemostatic
therapy represent the possible effective options to restrict
secondary hematoma expansion in OAT-ICH (46).

Practical management of OAT-ICH

Post OAT-ICH, it is possible and important to make an urgent
OAT reversal. Key measures to reverse OAT in patients with
OAT-ICH can be achieved through the immediate discontinuation of OAT and three different pathways:
 direct competition by administering vitamin K1
 replacement of native coagulation factors by using freshfrozen plasma (FFP) or a prothrombin complex concentrate
(PCC), and
 by-passing the central part of the coagulation cascade
through the use of recombinant activated factor VII (rFVIIa)
(6, 47).
The goal of these therapeutic measures is to decrease the
INR values to levels r1
4, preferably r1
2 (6, 8, 25, 4853).
The different pharmacological and blood product options

232

have specific characteristics related to ease of administration,

timing and duration of effect, and cost, which may potentially
influence the choice of their use. The specific options for OAT
reversal should be used complementary to general therapeutic
measures for ICH and life support (51).

Vitamin K1
The administration of vitamin K1 (phytomenadione) is the
first point of any warfarin reversal strategy. However, it has a
slow action onset, making it a poor choice as a single agent. To
effectively reverse the effect of warfarin, vitamin K1 usually
takes at least two- to six-hours, and frequently 1224 h (6, 8,
25, 49, 50). The effect of vitamin K1 is more rapid when given
intravenously (IV) (53, 54). Vitamin K1 is inexpensive, but
anaphylaxis (three per 10 000 doses) from an IVadministration
has reduced its use (27, 54). Because of the short half-life and
duration of action of other OAT reversal measures, vitamin K1
should be administered in all patients in order to avoid a
rebound in coagulopathy (1020 mg in 250 ml of normal saline
in about 30 mins, infusion rate being 1 mg/min), with the aim
of inducing de novo hepatic synthesis of vitamin K-dependent
coagulation factors and of achieving the stabilization of OAT
reversal (6, 8, 25, 4853). Subcutaneous and oral administrations represent alternative routes because they do not carry the
same anaphylaxis risk as the IV route; however, the onset of
action is not as rapid or reliable, especially when neurological
status is compromised. Therefore, in OAT-ICH, the IV route is
preferred (6, 8, 25, 4853).

PCC
Prothrombin complex concentrates represent a generic term
for several products that are derived from plasma and contain
factors II, VII, IX, and X in different concentrations. PCC is
considered the first therapeutic choice in OAT-ICH (6, 8, 25,
4853, 55). Originally designed as factor IX concentrates, there
are at least 10 different PCC products that are available in
different parts of the world and contain varying levels of factors
II and X, and low levels of factor VII (56, 57). The most
widespread types of PCC generally contain three or four
vitamin K-dependent factors. Generally, PCC with three
factors do not contain factor VII. It has been suggested that
PCC containing three vitamin K-dependent coagulation factors could be less effective in reversal OAT, and thus, in some
situations, the addition of rFVIIa may be warranted (58).
However, in a prospective study, considering about 90 patients
with spontaneous and traumatic ICH, Imberti et al. (36)
reached the goal to obtain an INRr1
5 30 mins postadministration of a PCC containing three factors (factors II, IX, and X)
in 75% of patients, and maintained this benefit until 96 h after
administration in 98% of patients, with a very low 30-day
mortality (about 12%). A meta-analysis (n 5 460 patients) has
demonstrated the effectiveness of the PCC in determining the
rapid OAT reversal, the superiority of the PCC over the FFP

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Table 2 How to choose the dose of PCC or FFP for urgent warfarin
reversal: calculated or fixed dose
INR value

Estimated functional PC

Calculated dose
First step: Convert INR to % of estimated circulating functional
prothrombin complex (PC)
Z5
5%
4
04
9
10%
2
63
2
15%
2
22
5
20%
1
92
1
25%
1
71
8
30%
1
41
6
40%
1
01
3
100%
Second step
Calculate the dose:
IU of PCC or ml of FFP needed to be infused 5 (Target in % of PC to be
reachedcurrent estimated % of PC)  kg of body weight
Example:
Present INR 4
5 corresponding to estimated functional PC 10%
Target INR 1
4 corresponding to estimated functional PC 40%
Body Weight 70 kg
IU needed to be infused 5 (4010)  70 5 2100 IU of PCC or 2800 ml
of FFP
INR value

Table 3 Average composition of 250300 ml of fresh-frozen plasma

after thawing at 41C

PCC dose (IUkg)

FFP dose (ml/kg)

Fixed dose
1
52
0
20
15
2
04
0
3040
1530
Z4
0
50
1530
Example:
Present INR 4
5
Body weight 70 kg
IU needed to be infused 5 3500 IU of PCC or 10502100 ml of FFP
Adapted from Aguilar et al. (25).INR, international normalized ratio;
PCC, prothrombin complex concentrate; FFP,fresh-frozen plasma.

and/or vitamin K1, reducing the times of OAT reversal, without cases of disseminated intravascular coagulation and low
thrombotic risk (1
5%) (59).
The PCC are available as a concentrate, which can be
reconstituted to a total volume of about 50150 ml and
delivered in 1030 mins depending on the volume and rate
of infusion. The PCC infusion dose is dependent on body
weight; it is related to INR and is based on a dose of factor IX
necessary to reversal (56). For each international unit of
PCC per kg of body weight, the plasma concentration of factor
IX increases by 1% (60). Table 2 summarizes the recommended
dose of PCC to be infused in patients with OAT-ICH. Optimal
PCC dosing (INR-based vs. a standardized fixed dose) remains
somewhat controversial, although individualized dosing
may ensure INR correction more rapidly. PCC can correct
the INR within minutes (36). Thus, they are very good agents
for acute OATreversal because of the small volume, the range of
coagulation factors provided, and the rapid onset of action.
However, PCC are significantly more expensive than vitamin

Fibrinogen
Factor II
Factor V
Factor VII
Factor VIII
Factor IX
Factor X
Factor XI
Factor XII
Factor XIII
Antithrombin
Von Willebrand
factor

Levels after
thawing (41C)

Levels
after 24 h

Levels after
five days

260270 mg/dl
80 IU
80 IU
90 IU
90 IU
100 IU
85 IU
100 IU
80 IU
100 IU
100 IU
80 IU

220230 mg/dl
80 IU
75 IU
80 IU
50 IU
/
85 IU
/
/
/
/
/

220230 mg/dl
80 IU
65 IU
70 IU
40 IU
/
80 IU
/
/
/
/
/

Adapted from British Committee for Standards in Hematology, Blood

Transfusion Task Force (62).

K1 and FFP (6, 8, 25, 4853, 55). When using PCC preparations with low amounts of factor VII, coadministration of
one- to two-units of FFP or rFVIIa may also be considered
(8, 50, 55).

FFP
Fresh-frozen plasma is the most common agent utilized in
OAT-ICH, especially in the United States, where 60% of
consumed FFP is used for OAT reversal (61). The FFP is a
blood product that contains all the coagulation factors. However, the actual levels of vitamin K-dependent clotting factors
in each unit of FFP are not standardized and may vary widely.
Table 3 shows the average content of individual coagulation
factors present in a single unit of FFP as reported by Blood
Transfusion Task Force of British Committee for Standards in
Haematology (62). Anyway, the ordinary FFP unit is inevitably
subject to the biological variability associated with a single
donor (63). Furthermore, the infusion of FFP has some risks.
In particular, it may be necessary to use large volumes of
plasma to correct the coagulation defect. Initial doses of 15 ml/
kg of FFP are suggested (6, 8, 25, 49, 50, 62), although there is
evidence that a dose of 30 ml/kg produces more complete
correction of coagulation factor levels (60, 6467). Although
the required volume of FFP somewhat depends on the initial
INR, the target INR is the more relevant issue. According to a
recent study, the difference in the predicted FFP transfusion
volume between an INR goal of 1
3 and 1
7 is two-liters of
plasma at all initial INRs. This represents a significant patient
overload volume with potentially dangerous effects in the
elderly and cardio pulmonary disease patients (66). Furthermore, in these patients, the infusion rate should not be too
quick and this can lead to delays in OAT reversal. The FFP

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requires compatibility testing and thawing before administration; there is an inherent delay in initiating FFP transfusion
(62, 67). Thanks to the introduction of several preventive
measures, the residual risk for the three major viral infections
(i.e., hepatitis B virus, hepatitis C virus, HIV/AIDS) is currently very low (68). Anyway, other equally life-threatening
risks of FFP transfusion are far more common, such as severe
allergic reactions (69), transfusion-associated circulatory overload (70), and transfusion-related acute lung injury (71).
Because of these considerations, FFP should be used in the
OAT- ICH if PCC is not available (60).

rFVIIa
Recombinant activated factor VII is an approved medication
for the treatment of hemophilia.
Randomized clinical trials (RCT) have evaluated the benefit
of avoiding enlargement of hematoma in the acute phase of
spontaneous noncoagulopathic ICH and using off-label for
VKA-related ICH as well as traumatic hemorrhage (7275).
The rFVIIa promotes hemostasis at sites of vascular rupture,
limiting hematoma enlargement after ICH. Preliminary results
have shown a reduction in hematoma volume increase,
mortality, and better functional status after a three-month
administration of rFVIIa, despite a 5% increase in arterial
thromboembolic phenomena (76). The phase III FAST trial
showed no significant difference in mortality or severe disability at 90 days between different dosages of rFVIIa and
placebo, but confirmed the hemostatic effect and thromboembolic complications (77). In conclusion, the use of rFVIIa
reduces the growth of the hematoma but does not improve
patient survival or functional outcome after ICH; in addition,
rFVIIa increases the incidence of arterial thromboembolic
complications (78). On the basis of these results, routine
utilization of rFVIIa as ultra-early hemostatic therapy for all
patients with ICH cannot be recommended. However, the use
of rFVIIa in conjunction with FFP is associated with shortened
times to correction of INR and reduced the total dose of FFP

required for the correction of coagulopathy in OAT-ICH

patients (79).
As with PCC, rFVIIa has the advantage of limited volume
infusions; even low doses of rFVIIa correct prothrombin time.
INR values cannot be used as a reliable indicator of cessation of
bleeding in patients who have received rFVIIa. A single IV dose
can normalize the INR within minutes; however, it is very
important to keep in mind that INR might increase in
subsequent hours due to the short-half-life of rFVIIa, and
therefore, the drug infusion requires strict follow-up and
monitoring (80). It is not known whether other emerging
coagulation tests such as thromboelastography might be
useful. The dose of rFVIIa for OAT-ICH is not standardized
and optimal dosing is not known. The rFVIIa is administered
as a single, one-time bolus over two- to five-minutes ranging
from 15 to 120 mg/kg (mean dose 8090 mg/kg) (25, 27). Large
doses are associated with a longer duration of effect (81).
Until now, rFVIIa has not been a recognized for the
treatment of OAT-associated bleeding and therefore its use in
these situations is considered off-label (81, 82), even though
suggested by the 2008 American College of Chest Physicians
Guidelines on Antithrombotic Therapy as an alternative to
PCC or FFP with a grade of recommendation IC (6). Among all
the current warfarin-reversal options, rFVIIa, however, is the
most expensive.
Whatever measures are chosen, the INR should be checked
at the end of the infusion, and then every three-hours when the
INR is corrected to confirm its stability. If INR monitoring
reveals a value Z1
5, an additional dose of reversal therapy
should be administered (6, 8, 50, 55). Table 4 summarizes the
advantages and limitations of each measure of OAT reversal.

The role and timing of surgery in OAT-ICH

When reaching the goal of OATreversal, neurosurgical evacuation of the hematoma should be warranted when indicated
(51, 52, 83). Figure 4 (c,d) shows an example of neurosurgical
hematoma evacuation after OATreversal. Given the absence of
strong scientific evidence to indicate a prominent role of

Table 4 Options for urgent warfarin reversal

Agent

Pros

Cons

Usefulness for
urgent reversal

Vitamin K1

Widely available; inexpensive; directly reverses

warfarin effect; small volume infused; low infective and thrombotic risk
Widely available; contains all coagulation factors;
low thrombotic risk

Slow onset of action; possible allergy

Poor

Large volumes usually needed; requires crossmatching and thawing; slow onset of action; not
negligible infective risk, possible TRALI
Expensive; variable factor concentrations in different preparations; not negligible thrombotic risk
Very expensive; acts directly on only a single factor;
INR correction may be lab artifact; off label use

Fair

Fresh-frozen plasma

Prothrombin complex
concentrate
Recombinant activated
factor VII

Rapid onset; small volume infused; low infective

risk
Rapid onset; small volume infused; thrombin
burst; low infective risk

Good
Good

TRALI, transfusion acute lung injury.

234

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L. Masotti et al.

surgery in determining the outcome, this measure should be

performed in a tailored manner. With the exceptions of the
placement of a ventricular drain in patients with hydrocephalus and evacuation of a large posterior fossa hematoma, the
timing and nature of other neurosurgical interventions is also
controversial. In practice, surgery is performed as a life-saving
measure in patients with large hematomas or cortical hemorrhages and secondary neurologic deterioration. American and
European guidelines recommend surgery for patients with
lobar supratentorial hemorrhages within 1 cm of the cortical
surface, particularly for those with good neurological status
who are deteriorating clinically. For patients with profound
sited hemorrhages (basal ganglia, thalamic) and mass effect,
guidelines suggest evacuation with minimally invasive methods within 12 h (51, 52). Urgent surgical removal of infratentorial hematomas larger than 3 cm is frequently associated
with remarkable recoveries. There is substantial evidence that
the management of patients with ICH in a neurointensive care
unit, where treatment is directed toward monitoring and
managing cardiorespiratory variables and intracranial pressure, is associated with improved outcomes. Attention must be
paid to fluid and glycemic management, minimizing the risk of
ventilator-acquired pneumonia, fever control, provision of
enteral nutrition, and thromboembolic prophylaxis.
There is a robust theoretical basis supporting early surgery.
An aggressive management in the acute phase can be translated
into improved outcomes after ICH (84). Specific treatment
approaches include early diagnosis and hemostasis, aggressive
management of blood pressure, open surgical and minimally
invasive surgical techniques to remove clot, techniques to
remove intraventricular blood, and management of intracranial pressure (84). The OAT-ICH may produce a great volume
hematoma with mass effect, edema, obstructive hydrocephalus, midline shift, intracranial hypertension, herniations, and
death; thus, surgery is a therapeutic possibility. Surgical
evacuation may prevent hematoma expansion, decrease intracranial pressure, mass effect, and prevent the release of
neurotoxic products. Despite these hypothetical benefits,
surgery remains controversial, without a clear demonstration of efficacy when compared with standard medical therapy
(83, 85).
Most surgeons follow guidelines for clot removal similar to
those applied for spontaneous hematomas of nonanticoagulated patients (51), although the analysis of available clinical
data suggests that patient subgroups that mostly benefit from
surgery are different from anticoagulated patients. The literature lacks evidence on the effect of early surgery in anticoagulated and rapidly worsening patients because most studies
on the surgical evacuation of ICH have considered patients
already treated for correction of INR (83, 86). A study
performed at the Mayo Clinic suggests that emergency evacuation for deteriorating patients with large OAT-ICH is compatible with a favorable outcome independent of anticoagulation
reversal (87). Time shortening of OAT reversal is crucial both
for spontaneous and for posttraumatic ICH to be submitted to

neurosurgery evacuation (88). Ultra-rapid reversal of anticoagulation could reduce the time to biological and surgical
hemostasis, and might improve outcome (89). In this case,
neurosurgery could be performed immediately with results
comparable to those of nonanticoagulated patients. However,
guidelines note than there is evidence that ultra-early surgery
(within four-hours) is associated with an increased risk of
rebleeding and higher mortality (475%) (90). Future randomized studies should aim to individuate with higher accuracy
patients who certainly may benefit from surgical treatment.
Furthermore, the role of surgery in OAT-ICH should be
reevaluated in the light of recent technological advances.
Minimally invasive techniques may allow a more efficient
and less traumatic evacuation of the hematoma (91, 92).

Current evidence: benefits, concerns,

and challenges
Currently, there are no prospective, randomized, controlled
clinical trials comparing the various VKA-reversal strategies.
There are no controlled trials assessing whether or not PCC or
rFVIIa are superior to a strategy of FFP and vitamin K1, or
comparing PCC and rFVIIa regarding clinical outcome. However, several small retrospective and prospective studies evaluated the effectiveness of INR reversal obtained with the
various agents (44, 74, 93, 94). In summary, they show that a
reversal of INR within two-hours from hospital admission is
associated with low rates of hematoma enlargement and is
achieved in the majority of patients (84%) treated with PCC,
while FFP infusions show only a partial effect in reducing
hematoma enlargement (39%) and vitamin K1 has no effects
(93). In patients with ICH-related coagulopathies of different
etiologies who need neurosurgical interventions, the reversal
of INR before surgery attempted with FFP and rFVIIa is
quicker (mean seven-hours), without thrombotic complications, with a better functional outcome (95). The beneficial
effect after the reversal of anticoagulation using different
agents is also evident in patients with acute clinical worsening
and a marked mass effect who have emergency surgical
evacuation of hematomas (87). These studies show that there
is limited evidence to support a specific treatment regimen for
VKA-related ICH. Randomized trials using patient mortality
and neurological function as outcomes have been proposed.
However, they do not appear to be easy to carry out due to the
large sample size required, the frequent poor outcome of OATICH patients, and variability in available products in different
areas of the world. Thus, current approaches derive more from
consensus-based guidelines driven from concern for rapid and
safe coagulopathy correction.
The risk of thrombotic events after OATreversal is a problem
that has affected this type of treatment strategy in patients with
acute OAT-associated bleeding for a long time, although the
percentages of thrombosis are variable on the basis of the
different OATreversal treatments used, ranging from 0% to 7%
(25). In many cases, physicians do not have alternative choices

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235

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L. Masotti et al.

Fig. 5 Proposed algorithm for Hyperacute VKA reversal. CT, computed tomography; FFP, fresh-frozen plasma; INR, international normalized ratio; PCC,
prothrombin complex concentrate; OAT-ICH, oral anticoagulant-associated intracerebral hemorrhage; rFVIIa, recombinant activated factor VII; VKA, vitamin
K antagonist.

to reverse OAT adverse effects, particularly if hemorrhage is

severe enough to endanger the life of the patient. Goldstein
and colleagues have shown that the 30-day incidence of
arterial and venous thromboembolic events is about 5% for
patients with OAT-ICH in which OAT is discontinued,
lower than that reported in patients with non-OATICH (7
2%) (96), whereas Imberti et al. (36) did not
observe thrombotic complications during hospitalization of
OAT-ICH treated with PCC. However, thrombotic events in
the acute phase of OAT-ICH seem not to influence 30-day
mortality (96). Mechanical prophylaxis should be prescribed to patients with OAT-ICH to prevent venous thromboembolism (97).
The time for OAT should be restarted after an ICH is an
important question. For each patient, the balance between the
thrombotic risk due to the coexistent thromboembolic disease
for which OAT was prescribed and the risk of bleeding
recurrence should be carefully evaluated.
A casecontrol study enrolling approximately 50 patients
compared a group of patients in which OAT was restarted
after ICH with one in which OAT was not restarted, and
showed that the risk of ICH recurrences could be low in
those who restarted therapy, whereas the incidence of thrombotic events could not be negligible in those who did not
restart OAT (98). A very recent review of clinical studies and
case series by Romualdi et al. (99) has demonstrated an
incidence of 2
9% of ICH recurrence after restarting OAT in
patients with prosthetic heart valves suffering from a first
episode of ICH. It is suggested by experts to restart OAT
therapy in patients with prosthetic mechanical heart valves, in
most cases one-week from the hemorrhagic event, while
some concerns exist in restarting OAT in nonvalvular atrial
fibrillation (25).

236

In patients after OAT-associated major bleeding,

ACCP guidelines suggest the possibility of reducing OAT
intensity, for example prescribing a range of INR between
2
0 and 2
5 in prosthetic mechanical heart valves and
between 1
5 and 2
0 in patients with atrial fibrillation together
with a close monitoring of INR to avoid the risk of overdose
(6) or to replace mechanical with bioprosthetic valves in
selected patients (6). For OAT-ICH in patients with venous
thromboembolism, caval filters placement is indicated
to prevent a first episode or a recurrence of pulmonary
embolism (100).

Treatment algorithms and guidelines

Despite the lack of evidence from RCT, there are several
international consensus-based guidelines that address the
treatment regimen in OAT-ICH patients (6, 11, 5052, 55).
All guidelines emphasize the high morbidity of OAT-ICH,
the urgency of rapid reversal of coagulopathy, the use of
vitamin K1 (usually IV), and the use of PCC, given the rapid
onset of action with these agents and the shortcomings of
FFP alone. However, none provides a specific target INR
for an adequate reversal and the lack of clear evidence
limits the ability to make strong recommendations about the
agent and the dose to be used. Any intracranial bleeding
in a patient on VKA, independent of INR levels when
Z1
5, should be considered as a life-threatening condition
regardless of the hematoma size or the patients clinical status
at the first evaluation, because of the high risk of ongoing
hemorrhage, the high fatality rate, and the residual severe
disability from OAT-ICH (Fig. 5). The main recommendations
are summarized in Table 5.

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L. Masotti et al.

Table 5 Summary of recommendations for oral anticoagulant therapy (OAT) reversal from the main International Scientific Societies

Scientific Society

First choice (always in association

with intravenous vitamin K1)

Second choice

Levels of evidence

Grade of
recommendation

AHA (51)
ACCP (6)
BSH (9)
ASTH (50)
ESO (52)
FCSA (8)
SIMTI (55)

PCC or FFP
PCC or FFP or rFVIIa
PCC
PCC1FFP
PCC
PCC
PCC

/
/
FFP
/
FFP
FFP
FFP

IIa
I
III
Expert consensus
IV
Expert consensus
II

B
C
B
/
/
/
C1

PCC, prothrombin complex concentrate; FFP, fresh-frozen plasma; AHA, American Heart Association; ACCP, American College of Chest Physician;
BSH, British Society of Hematology; ASTH, Australasian Society of Thrombosis and Haemostasis; ESO, European Stroke Organization; FCSA,
Federation of Centers for the Diagnosis of Thrombosis and Surveillance of Antithrombotic Therapies; SIMTI, Italian Society of Transfusion
Medicine.

Conclusion
The incidence of OAT-ICH has increased recently because it is
associated with a high risk of ongoing bleeding, death, or
disability. Urgent reversal of coagulopathy is the highest
priority. Several agents such as vitamin K1, PCC, rFVIIa,
and/or FFP are available, and there are pros and cons in the
use of each of them. They should be included in the qualification of every physician who might have to treat a patient
receiving such therapy. The incorrect or the late management
of therapeutic measures for OAT reversal in the case of ICH
may expose the physician to the risk of legal prosecution,
because effective and safe antidotes are available (101). Therefore, it is not acceptable that the reversal of OAT is delayed or
incomplete or even omitted. A call for action is needed to
develop a uniform approach for physicians in the management
of patients on OAT, and it is particularly desirable that each
hospital is equipped with internal protocols derived from
recognized guidelines (Fig. 5).
All protocols for OAT-ICH emphasize the immediate cessation of the anticoagulant medication and the immediate
administration of vitamin K1 (IV). The use of PCC or rFVIIa
may reverse coagulopathy more rapidly than FFP alone;
however, randomized trials testing this are yet to be initiated.
Furthermore, the cost and availability of these agents may limit
their widespread use. In the near future, new oral antithrombotic drugs will be used (and will possibly replace VKAs) for
the prophylaxis and treatment of arterial and venous thromboembolic disease. Among these, dabigatran, rivaroxaban, and
apixaban are the most studied and have already been shown to
be effective and safe (102105). After the recent Phase III trial
RE-LY (randomized evaluation of long-term anticoagulation
therapy), the use of dabigatran in atrial fibrillation is more
clearly defined. The results show that the 110-mg dose of
dabigatran was associated with similar rates of stroke and
systemic embolism (primary end points) and lower rates of
major hemorrhage when compared with warfarin; the 150 mg
dose of dabigatran was associated with lower rates of stroke

and systemic embolism but with a similar rate of major

hemorrhage (106).
However, among the main limitations of these new drugs,
the absence of a specific antidote in bleeding complications
could influence their use in clinical practice. Whatever the
antidotes tested for the treatment of the new antithrombotic,
drug-related bleedings consist of PCC, FFP, and rFVIIa;
hence, their knowledge could also be useful for this new
scenario (107, 108).

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