Download Safety of Recombinant Activated Factor VII in Patients With

Safety of Recombinant Activated Factor VII in Patients
With Warfarin-Associated Hemorrhages of the Central
Nervous System
Maisha T. Robinson, MD; Alejandro A. Rabinstein, MD;
James F. Meschia, MD; William D. Freeman, MD
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Background and Purpose—Recombinant Factor VIIa decreases hematoma growth after spontaneous intracerebral
hemorrhage (ICH) and rapidly decreases international normalized ratios in patients on warfarin but is also associated
with an increased risk for thromboembolic complications. In this study, we assessed the risk of thromboembolic events
in patients receiving recombinant Factor VIIa after ICH associated with warfarin treatment.
Methods—We reviewed the medical charts, laboratory data, and radiological findings of consecutive patients with
anticoagulation-related hemorrhages of the central nervous system who received recombinant Factor VIIa at Mayo
Clinic Rochester and Mayo Clinic Florida between 2002 and 2009. The primary end point was the frequency of new
thromboembolic events, including myocardial infarction, deep vein thrombosis, ischemic stroke, and pulmonary
embolism.
Results—We identified 101 patients; 54% had ICH and 30% subdural hematomas. The most common indications for
anticoagulation were atrial fibrillation, deep vein thrombosis, and prosthetic valve. Thirteen patients (12.8%) had new
thromboembolic events (10 deep vein thromboses and 3 ischemic strokes) within 90 days after recombinant Factor VIIa
administration. Eight of these adverse events occurred within 2 weeks of treatment. In patients with ICH, the rate of
thromboembolic complications was 5% and all events were venous.
Conclusion—The risk of thromboembolic events in patients who received recombinant Factor VIIa for anticoagulationassociated ICH was not higher than that seen in patients treated for spontaneous ICH in the Factor Seven for Acute
Hemorrhagic Stroke (FAST) trial. Spontaneous deep vein thrombosis was the most common complication in our
series. (Stroke. 2010;41:1459-1463.)
Key Words: Factor VII 䡲 intracranial hemorrhage 䡲 safety 䡲 warfarin
I
ntracerebral hemorrhage (ICH) associated with oral anticoagulation is a significant and growing problem that is
associated with increasing hematoma size and poor outcome.1–3 The manner in which anticoagulation increases the
risk of ICH is not absolutely clear, but it is thought to
exacerbate underlying, subclinical hemorrhages.4 The rate of
hematoma growth is rapid, primarily occurring within the
first 3 hours.5 Therefore, anticoagulation should be reversed
promptly,6,7 and effective therapies to stop immediate bleeding and hematoma expansion are necessary.8 In addition,
other forms of intracranial hemorrhage such as subdural
hematomas, epidural hematomas, and subarachnoid hemorrhage can also be more severe and worsen more rapidly in
anticoagulated patients. When emergency neurosurgical interventions are necessary, ultrafast reversal of anticoagulation
becomes paramount.
Medical treatments such as fresh-frozen plasma (FFP) and
vitamin K are efficacious in reversing anticoagulation. How-
ever, reversal with these agents is both slow and potentially
risky.9 Efficacy of FFP is limited by the hazard of allergic and
transfusion reactions (such as transfusion-related acute lung
injury) and thawing and processing times. Many anticoagulated patients have cardiovascular disease and the administration of large volumes of FFP could precipitate volume
overload or lung injury in these patients. These limitations
and concerns may delay full reversal of anticoagulation with
FFP.7 Additionally, hematoma growth may continue despite
full reversal of the international normalized ratio (INR) with
FFP.10 Recombinant Factor VIIa (rFVIIa) has been shown to
be a rapidly acting hemostatic agent that works at the
bleeding site.5 It is effective at lowering the INR11–16 and
reducing hematoma growth,17–19 although it has not been
shown to improve outcome in patients with spontaneous
ICH.19 Previously published experience using rFVIIa for
warfarin-associated intracranial hemorrhage has been limited
to small series.11–14,20
Received February 11, 2010; accepted March 9, 2010.
From the Departments of Neurology, Mayo Clinic, Rochester, Minn (M.T.R., A.A.R.) and Jacksonville, Fla (J.F.M., W.D.F.).
Correspondence to Alejandro A. Rabinstein, MD, Mayo Clinic, Department of Neurology, W8B, 200 First Street SW, Rochester, MN 55905. E-mail
[email protected]
© 2010 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.110.581538
1459
1460
Stroke
July 2010
A known complication of rFVIIa is the precipitation of
thromboembolic events secondary to its hemostatic nature.17–19 In patients who received rFVIIa for spontaneous
ICH, the risk of thromboembolic events was 5.4% versus
1.7% in the placebo group across 3 randomized studies.17
Reversing the effects of anticoagulation in patients with
anticoagulation-associated ICH might be riskier because
these patients have a known risk of thromboembolic events.
On the other hand, patients who receive rFVIIa for spontaneous ICH may become prothrombotic, whereas patients who
receive rFVIIa for anticoagulation-associated ICH may only
return to their normal coagulation state. Therefore, it may
actually be less risky to administer rFVIIa to this group of
patients. The aim of this study was to determine the risk of
thromboembolic complications in patients who received
rFVIIa for anticoagulation-related intracranial hemorrhage.
Methods
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We reviewed the medical charts of all patients with warfarinassociated intracranial and intraspinal hemorrhages who received
rFVIIa at Mayo Clinic Rochester and Mayo Clinic Florida between
December 22, 2002, and February 16, 2009. Recombinant Factor
VIIa has been approved in our institutions for compassionate use in
patients with anticoagulation-associated hemorrhages. The study was
approved by the Mayo Foundation Institutional Review Board.
Recombinant Factor VIIa is used in our hospitals according to
internal guidelines. The administration of rFVIIa is considered in
patients with acute intracranial hemorrhages (and in selected cases of
intraspinal hemorrhage) associated with warfarin use and an INR
⬎1.4 within 6 hours of symptom onset. Exclusion criteria for rFVIIa
use include end-stage renal disease, previous allergic or adverse
reaction to the drug, or moribund condition. Administration of
rFVIIa is decided on a case-by-case basis by the treating neurologist
or neurosurgeon. Patients are treated with a single bolus of intravenous rFVIIa administered over 2 to 5 minutes. Initially we agreed
that the dose would be 40 to 80 ␮g/kg, but we began administering
smaller doses adjusted to the initial INR in Rochester since 2007. All
patients also receive 5 to 10 mg of intravenous vitamin K on first
evaluation. FFP is often initiated at the referring hospital or in our
emergency department before consultation with neurology or neurosurgery. FFP infusion is not continued after rFVIIa administration
unless INR is ⬎1.4. INR is rechecked 15 to 30 minutes after rFVIIa
administration and every 4 to 6 hours thereafter, at least for the first
24 hours. Repeat doses of rFVIIa are used only in cases of
neurosurgical emergency. An INR ⱕ1.4 is deemed safe to proceed
with neurosurgical interventions.
Inclusion criteria included radiologically documented symptomatic intracranial or intraspinal hemorrhages, treatment with warfarin,
and administration of rFVIIa. A data retrieval system was used to
identify patients with intracerebral hemorrhage and matched with
patients who received rFVIIa by the pharmacy registry. Medical
records and brain CT scans were reviewed and the type of hemorrhage was identified. The 6 types of hemorrhages were ICH, ICH
with intraventricular extension (ICH with intraventricular hemorrhage), subdural hemorrhage (SDH), intraventricular hemorrhage,
epidural hemorrhage, and subarachnoid hemorrhage.
We collected clinical information, including hemorrhage type,
age, sex, warfarin indication, comorbidities (coronary artery disease,
stroke history, deep venous thrombosis or pulmonary embolus),
initial INR, post rFVIIa INR, rFVIIa dose, weight, FFP dose, vitamin
K dose, neurosurgical intervention, thromboembolic complications,
timing of thromboembolic events, and survival to dismissal. We also
documented whether electrocardiogram, troponin levels, or Doppler
ultrasounds were obtained and their results.
Thromboembolic complications were defined as myocardial infarction (MI), deep venous thrombosis (DVT), pulmonary embolism
(PE), and ischemic stroke. Criteria were based on the electrocardio-
gram and cardiac biomarkers for coronary events (troponin T
elevation ⬎0.1 ng/mL with significant delta over 6 hours), venous
ultrasounds for DVT (obtained because of clinical suspicion), or
chest CT angiogram for PE and brain imaging for stroke. We relied
on the interpretation of electrocardiogram by a cardiologist and the
report of the imaging studies by a radiologist to ascertain the end
points of MI and DVT/PE, respectively. For patients with a history
of stroke before receiving Factor VIIa, a recurrent stroke (after the
infusion of Factor VIIa) was defined as a stroke involving a vascular
territory distinct from the prior stroke based on neurological examination and brain imaging. We reviewed all brain imaging scans
independently for this study. Patients who experienced a thromboembolic event were stratified into 4 categories based on the temporal
relationship between the event and the hemorrhage. The categories
were 2 weeks, 30 days, 60 days, and 90 days posthemorrhage. All of
the complications were reviewed by at least 2 of the investigators to
confirm each thromboembolic event and final ascertainments were
reached by consensus.
Data are presented primarily through descriptive analysis. Statistical analyses were performed to assess for predictors of thromboembolic events. Age, initial INR, common indications for anticoagulation (atrial fibrillation, mechanical valve, and history of DVT or
PE), dose of rFVIIa, dose of FFP, and hemorrhage type (intraparenchymal versus extraparenchymal) were the variables included in the
analysis. Categorical data were analyzed using the 2-tailed Fisher
exact test and continuous variables using the Student t test.
Results
We identified 101 consecutive patients who were eligible for the
study (Table 1). Fifty-two patients (51.4%) were women and the
average age was 76 years (range, 29 to 94 years). Forty patients
(39.6%) had no history of coronary artery disease (CAD),
stroke, DVT, or PE. Seventeen patients (16.8%) had a
documented history of CAD, 15 patients (14.8%) had a
history of stroke, and 17 patients (16.8%) had a history of
either DVT or PE. Twelve patients (11.8%) had ⬎1 of these
previous diagnoses. Indications for anticoagulation therapy
were atrial fibrillation, prosthetic valve, congestive heart
failure, DVT, PE, pulmonary hypertension, left ventricular
thrombus, internal carotid artery stenosis, patent foramen
ovale and transient ischemic event, aortic thrombi, and stroke.
The most common indications were atrial fibrillation in 55
patients (54.4%), DVT in 7 patients (6.9%), and prosthetic
valve in 6 patients (5.9%). Fourteen patients (13.8%) had ⬎1
indication for oral anticoagulation and in 1 patient (0.9%), the
indication was unknown. The mean (range) INR at admission
was 3.04 (1.2 to 16.2). The mean (range) INR after rFVIIa
was 1.03 (0.7 to 2.1). Six patients (5.9%) did not have an INR
checked or recorded after administration of rFVIIa because of
poor prognosis leading to withdrawal of life support, death, or
emergency neurosurgical intervention.
Thirty-two (31.6%) patients had intraparenchymal hemorrhages, 23 (22.7%) patients had intraparenchymal hemorrhages with intraventricular extension, 30 (29.7%) patients
had subdural hematoma, 7 (6.9%) patients had subarachnoid
hemorrhages, 6 (5.9%) patients had intraventricular hemorrhages, and 3 (2.8%) patients had an epidural hematoma
(2 intraspinal). The mean total dose of rFVIIa was 51.7
␮g/kg⫾28.99 (median 43.9 ␮g/kg; range, 4.4 to 186.8 ␮g/kg).
The mean dose of FFP was 2.5 U⫾2.37 (median 2 U; range,
0 to 13). The mean dose of vitamin K was 9.5 mg⫾7.42
(median, 10 mg; range, 0 to 41). INR was ⱕ1.4 after the
initial dose of rFVIIa in 91 of 95 patients in whom a
Robinson et al
Table 1. Demographic and Clinical Characteristics of 101
Patients With Warfarin-Associated ICH Treated With rFVIIa
Demographics
Sex (female/male)
Age, mean (range), years
52/49
76 (29–94)
Comorbid conditions, total patients (percentage)
CAD
17 (16.8)
Stroke
15 (14.8)
DVT/PE
17 (16.8)
⬎1
12 (11.8)
None
40 (39.6)
Warfarin indication, total patients (percentage)
Atrial fibrillation
55 (54.4)
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Prosthetic valve
6 (5.9)
DVT
7 (6.9)
⬎1
14 (13.8)
Other
19 (18.8)
INR
Admission mean (range)
3.04 (1.2–16.2)
Post rFVIIa mean (range)
1.03 (0.7–2.1)
Type of hemorrhage, total patients (percentage)
Intracerebral
32 (31.6)
Subdural hematoma
30 (29.7)
Intraparenchymal with intraventricular extension
23 (22.7)
Safety of Factor VII in Warfarin-Associated ICH
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fracture and 1 DVT occurred in a paretic leg (Patient 4).
Three early DVTs occurred in patients with a history of DVT
(Patients 5, 6, and 7). Five days posthemorrhage, 1 patient
with a mechanical valve had a stroke that was deemed likely
cardioembolic (Patient 8). At the time of dismissal, this
patient had mild distal left upper extremity weakness. At 30
days posthemorrhage, 3 additional patients had thromboembolic events (2 DVTs and 1 stroke). Patient 11 had multiple
embolic strokes 1 month after receiving rFVIIa, resulting in
akinetic mutism. The family withdrew life support measures
and the patient subsequently died. The stroke was classified
as cardioembolic due to atrial fibrillation. At 60 days, Patient
12 had a stroke in the middle cerebral artery distribution
causing hemiparesis; the brain infarction was deemed related
to his atrial fibrillation. The patient recovered without any
significant, permanent deficits. At 90 days, Patient 13 had a
DVT. In total, 7 DVTs affected an upper extremity and 3
DVTs were associated with Peripherally Inserted Central
Catheter lines. No patients in our study had PE or MIs.
Statistical analysis showed no association between the
occurrence of thromboembolic events and the presence of
any of the variables analyzed, including age (P⫽0.87),
initial INR (P⫽0.40), atrial fibrillation (P⫽0.53), mechanical valve (P⫽0.61), DVT or PE (P⫽0.95), initial or total
rFVIIa dose (P⫽0.82 and 0.98), FFP dose (P⫽0.60),
intraparenchymal hemorrhage (P⫽0.24), or extraparenchymal hemorrhage (P⫽0.74).
Subarachnoid hemorrhage
7 (6.9)
Intraventricular hemorrhage
6 (5.9)
Discussion
Spinal epidural hemorrhage
2 (1.9)
Epidural hematoma
1 (0.9)
In this study of patients with warfarin-associated intracranial
and intraspinal hemorrhages who received rFVIIa, the risk of
thromboembolic complications was slightly higher than previously reported in patients with spontaneous ICH.17,19 However, most of our patients had minor DVTs without embolism. The difference between this patient population and
those included in prior studies is that at baseline, our patients
may have had a higher risk of developing thromboembolic
events due to the pre-existent conditions that led to the
anticoagulation. Despite this baseline risk, there were no fatal
or incapacitating thromboembolic complications within the
first month. Delayed strokes, which occurred several weeks
after rFVIIa administration, were most likely related to
unprotected atrial fibrillation rather than a direct consequence
of rFVIIa use.
Anticoagulation-related hemorrhages are becoming an increasingly concerning public health problem because of the
exponential growth in the number of anticoagulated patients
in the general population.21 In addition, anticoagulation
increases the risk of hematoma expansion and poor outcome.22 Rapid reversal of anticoagulation might decrease
this risk. Recombinant Factor VIIa can reverse the INR
quickly.11,13–15 Our results indicate that rFVIIa therapy rapidly reduces the INR and carries a relatively low risk of
thromboembolic complications in patients who were prescribed warfarin because of pre-existing thromboembolic
disease. In theory, the thromboembolic complications might
be lowered further by using smaller doses of rFVIIa, which
proved to be sufficient in some of our patients.
Therapies
rFVIIa mean (SD)
FFP mean (SD)
Vitamin K mean (SD)
Neurosurgical intervention, total patients (percentage)
51.7 ␮g/kg (⫾28.99)
2.5 U (⫾2.37)
9.5 mg (⫾7.42)
43 (42.5)
follow-up INR was obtained. Forty-three (42.5%) patients
had neurosurgical intervention, including placement of an
external ventricular drain, craniotomy with evacuation of the
hematoma, or placement of an aneurysm clip (in only 1
patient). No patients were excluded from surgery because of
delayed or insufficient reversal of anticoagulation.
Sixty-seven patients (66.3%) survived until dismissal from
the hospital. Seventy-one patients (70.2%) had troponin
levels drawn and 79 patients (78%) had at least 1 electrocardiogram during the first 24 hours after rFVIIa administration.
Thirty-five patients had (34.6%) extremity ultrasounds performed during their hospitalization.
Thirteen patients (12.8%) had new thromboembolic events
(10 DVTs and 3 ischemic strokes) over a 90-day period after
administration of rFVIIa (Table 2). Eleven patients (10.8%)
had events within the first 30 days, including 7 acute DVTs
and 1 ischemic stroke, which occurred within the first 2
weeks. Two of these early DVTs (Patients 1 and 2) were
associated with Peripherally Inserted Central Catheter lines.
One of the DVTs (Patient 3) was associated with a radial head
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Stroke
July 2010
Table 2.
Detailed Information of Patients With Thromboembolic Events After Administration of rFVIIa*
Medical History
(CAD, DVT/PE,
Stroke)
Type of
Hemorrhage
Pre-rFVIIa
INR
Post-rFVIIa
INR
Dose of
FFP, U
Type of
Event
Timing of
Event (Days
After rFVIIa)
Sex
1
78
M
None
Atrial Fibrillation
ICH
2.3
0.8
45.6
3
DVT
10
2
49
M
Stroke
Atrial Fibrillation
SAH
5.3
2.1
44.1
0
DVT
11
3
86
M
CAD, stroke
Atrial fibrillation, stroke
SAH
2.6
0.8
86
1
DVT
11
4
83
M
CAD
Atrial fibrillation
ICH
1.7
1.1
52.2
4
DVT
10
5
59
F
DVT
DVT
ICH with IVH,
SAH, SDH
1.2
0.8
78.8
6
DVT
2
6
70
F
DVT
Atrial Fibrillation
SDH
2
1.3
33.8
3
DVT
3
7
80
F
DVT
DVT
SDH
1.9
0.8
90.9
4
DVT
1
8
92
F
Stroke
Atrial fibrillation,
mechanical valve
SDH
5.5
0.9
11.1
4
Stroke
5
Patients
Indication for
Anticoagulation
Dose of
rFVIIa,
␮g/kg
Age,
Years
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9
86
M
CAD, PE
Mechanical valve
SDH
2.6
0.8
49.1
4
DVT
21
10
75
M
None
Atrial fibrillation
ICH
3.1
0.9
62.3
7
DVT
30
11
78
F
None
Atrial Fibrillation
SDH
2.4
1.1
19.2
0
Stroke
30
12
58
M
None
Atrial fibrillation
EDH
2.1
1
15
0
Stroke
40
13
86
M
None
Atrial fibrillation
ICH and EDH
2.1
0.9
39.7
0
DVT
90
*Clinical data for patients with thromboembolic complications.
M indicates male; F, female; SAH, subarachnoid hemorrhage; IVH, intraventricular hemorrhage; EDH, epidural hematoma.
In the Factor VII for Acute Hemorrhagic Stroke (FAST)
trial,19 the rate of thromboembolic events was 22% in the
20-␮g/kg group and 32% in the 80-␮g/kg group (versus 25%
in the placebo group).23 Arterial adverse events, primarily
non-ST-elevation MIs, predominated. The risk of minor
cardiac events was higher in patients treated with 80 ␮g/kg of
rFVIIa.23 In contrast with the FAST study, the majority of our
patients with thromboembolic events had venous thromboembolic complications, which are known to be prevalent in
hospitalized patients with ICH, especially with limb immobility.24 Of the 10 patients with DVTs, 3 were possibly
associated with Peripherally Inserted Central Catheter lines
and may not have been directly related to rFVIIa because they
all occurred ⬎1 week after rFVIIa administration. Although 3
patients in our study had strokes, 2 of them took place several
weeks after rFVIIa infusion in patients with atrial fibrillation
who had remained off warfarin since the bleeding. Only 5 of
the thromboembolic complications in our series (all venous)
occurred in patients with ICH at baseline (ie, the group of our
population that can be compared more directly with the FAST
trial); consequently, the rate of thromboembolism in this
subgroup was 5%. The remainder of the adverse events
occurred in patients with extraparenchymal hemorrhages.
In the FAST trial, age and prior use of antiplatelet agents
were determined to be risk factors for serious thromboembolic events.19 In our study, no predictors of thromboembolic
events were identified in an analysis that included age, initial
INR, common indications for anticoagulation (mechanical
valve, atrial fibrillation or history of DVT or PE), dose of
rFVIIa, dose of FFP, or location of hemorrhage (intraparenchymal versus extraparenchymal).
Previous smaller series of patients with warfarin-associated
intracranial hemorrhage treated with rFVIIa have been published.11–14,20 In 1 study comparing 15 patients treated with
FFP alone with 12 patients who also received rFVIIa, those
treated with rFVIIa showed faster anticoagulation reversal
and no complications except in patients with dialysisdependent end-stage renal failure (2 patients had very slow
INR correction and 1 of them developed disseminated intravascular anticoagulation after receiving 3 doses of rFVIIa and
large volumes of FFP).20 Although not considered attributed
to rFVIIa, 1 patient had a DVT 2 weeks after treatment with
the hemostatic agent. In another study of 54 patients presenting
with warfarin-associated intracranial hemorrhage, correction of
INR was achieved faster and requiring less FFP volume in the 30
patients treated with rFVIIa.12 One patient had an acute MI after
receiving rFVIIa but recovered uneventfully.
Prothrombin complex concentrate is another alternative for
rapid reversal of warfarin anticoagulation.25–27 It contains
high concentrations not only of Factor VII, but also of Factors
II, IX, and X. The total fluid volume administered is much
lower than with FFP, thus reducing the risk of cardiopulmonary complications. The risk of thromboembolic complications in patients treated with prothrombin complex concentrate appears to be relatively low25–27 but remains to be
examined in a large population.28 Thus far, experience with
the use of prothrombin complex concentrate for anticoagulation reversal in patients with anticoagulation-associated intracranial hemorrhages is very limited.25,29,30
Our study has several limitations. The patients were not
routinely followed to assess for thromboembolic events and,
thus, asymptomatic DVTs, PEs, MIs, or strokes could have
been missed. Diagnostic studies were performed based on
clinical suspicion. Consequently, not all patients had ultrasounds, cardiac biomarkers, electrocardiograms, chest CTs,
or serial brain imaging scans. Additionally, patients in this
study were selected to receive rFVIIa based on the need for
emergency invasive intervention, the size of the hemorrhage,
the concern for hematoma expansion, and the risk of complications related to the volume of FFP. This selection bias must
Robinson et al
be taken into account when interpreting our results. Our
patients also received vitamin K and FFP and it is not
possible to determine with certainty in our population if the
observed cases of thromboembolism were related to rFVIIa,
these other hemostatic agents, or unrelated to all. In fact,
venous thromboembolism is a relatively common complication after ICH in the absence of hemostatic agent use; rates of
asymptomatic DVT between 4% and 40% have been
reported.24,31,32 All patients were not followed for 90 days
posthemorrhage and therefore, some thromboembolic
events beyond the acute hospitalization or rehabilitation
periods could have been missed. Our ability to assess for
predictors of thromboembolic complications was limited by
the low number of events.
Conclusion
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The risk of thromboembolic complications in patients with
anticoagulation-associated central nervous system hemorrhages treated with rFVIIa was not higher than that reported
in the FAST trial. Most of the thromboembolic events in our
patients were minor DVTs. These results suggest that it
would be safe to compare rFVIIa versus FFP for reversal of
warfarin-associated ICH in a randomized controlled trial.
Disclosures
None.
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Safety of Recombinant Activated Factor VII in Patients With Warfarin-Associated
Hemorrhages of the Central Nervous System
Maisha T. Robinson, Alejandro A. Rabinstein, James F. Meschia and William D. Freeman
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Stroke. 2010;41:1459-1463; originally published online June 3, 2010;
doi: 10.1161/STROKEAHA.110.581538
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