From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
The Use of Factor
Eight
Inhibitor
By-Passing
Activity
(FEIBA
Immuno)
Product
for Treatment
of Bleeding
Episodes
in Hemophiliacs
With
Inhibitors
By
FEIBA
(factor
was
used
VIII
inhibitors
3
eight
titers
with
muscle
emergency
episodes
clotting
factor
factor
patient
in joints.
tissue,
soft
with
alone
large
been subjected
sion to decrease
effective
of the
the New
York,
Baltimore,
Supported
Vienna,
York
in part
by an
The
the Children’s
is
comprise
a publication
the
Study
of
Margaret
York,
N. Y.; Charles
tral
al:fornia.
York
Elaine
Center,
York,
Park
M.D.,
Hershey.
PA.;
Marvin
Medicine,
New
York,
Maryland
Medical
Md.;
california,
Sacramento,
N. Y.;
Jack
Hospital.
Mich.;
Tourbaf,
Submitted
M.D.,
November
Address
reprint
land
Medical
more,
Md.
Erie
requests
cc
County
5, 1981;
Research
21210.
by Grune
Region,
to Gene!!
Institute,
Stratton,
0006-4971/83/6101-0005$01.00/0
600
Inc.
School
Dr.
Institute,
Inc.,
Miser,
Central
Children’s
M.D.,
Ohio;
John
Rochester,
Center,
PH.,
Gene!!
M.D.,
August
of
Md.;
Inc.,
Medical
accepted
Angeles,
UCD-Northern
Angela
York,
Medical
Sinai
M.D.,
Lusher,
Columbus,
Center-Rochester
Mt.
Baltimore,
M.D.,
N. Y.;
Los
Research
Jeanne
Ph.D.,
New
Hershey
Klimt,
Inc.,
Medical
Detroit,
Children’s
S.
Christian
Institute.
Calif.;
M.D.,
Sinai
Buffalo,
Hospital.
M.D.,
CenMt.
Medicine,
Milton
Lazerson,
HospitalofMichigan.
Hemophilia
The
Maryland
Baltimore,
of
Gilbert,
Research
M.D.,
Co!um-
Olson,
M.D.,
N. Y.; and
Buffalo,
more
side
in 36
in more
effects.
and
patients.
of
not
in 1 2 hr.
36
the
product
the
were
hrs,
than
while
the
7%
infusion
infusions
with
control.’
and
hr.
an
There
inhibitor
titer
continued
N.Y.
2, 1982.
L. Knatterud,
Ph.D.,
Mary-
Wyndhurst
Avenue,
Balti-
Animal
short-term
amnestic
response
treatment
often
to
be
that
follows
produces
for
the
been
patient
any
genitally
deficient
concentrates
(PCC)
bleeding
in patients
deficiencies
the products
complications
effective
patients.2
were found
with factor
and
of
the
One
from
level
episodes
although
inhibitor,
has
inhibitors
in con-
Pnothnombin
complex
effective
for control
of
VIII inhibitors,3’4
but
complications
patients
with
prothnombin
in hemostaticongenital
complex.5
As
and
the
the PCC
risk of
became
these
less
patients,6
although
a small
por-
beneficial
effect
made
to produce
remained.7
activated
were
was
improved
reduced,
in inhibitor
tion of their
subsequently
an acquired
an-
factor
in inhibitor
bleeding
therapy,
in controlling
has
the
clotting
an increase
with
successful
VIII
However,
that makes
the control
of subsequent
more difficult.
Immunosuppressive
useful
factor
success.
complex
concentrates
that would
in the control
of bleeding
episodes
Study
Center,
UCD-Northern
Ambrus,
Orthopaedic
M.D.,
M.D..
Medical
Institute,
School
the
investigators
Aledort,
N. Y.; Julian
M.D.,
Ph.D..
M.D.,
Louis
Sinai
Eyster.
L. Knatterud,
by
and
by one
controlled
hemostatic
used
factor
Ag,
in part
Hilgartner,
Memorial
Mt.
Dietrich,
Calif.;
Immuno
while
controlled
1 or
the
percent
controlled.
produced
thromboembolic
cally
normal
patients
Center,
Group
University
Calif.;
New
Rosewell
Diaz.
from
Study
Abildgaard,
Sacramento,
N. Y.; Shelby
36
to
institute.
is sponsored
The following
Hospital/Cornell
ofMedicine,
to 1 983
Medical
grant
FEIBA
group:
study
New
F.A.C.P.,
the
Group.
New
Kamal
factor
Research
Group
Research
Chairman,
bus
University
1 0 of
achieve
not
Foundation.
Medical
Michael
clotting
Medical
unrestricted
FEIBA
Blood
Maryland
School
with
Maryland
have
Md.
Austria.
This
inhibitor
the
in a
in
or exchange
transfuto allow for a more
titer
no serious
in
been
In the past, patients
with bed rest and ice
Hospital/Cornell
N. Y. and
to
clotting
They
were
with
rose
Ninety-three
were
14% were
were
Group
efficacious.
been used
transfused
factor.
42%
Study
procedures.
36%
additional
were
of an inhibitor
a major
problem
of clotting
to plasmaphenesis
the inhibitor
binding
From
New
doses
another
system
a congenital
development
represents
of bleeding
episodes.
have been treated
10
FEIBA
episodes
and
UI
the
surgical
controlled:
in mucous
nervous
has long
inactivates
that
management
with inhibitors
or with
20
4
bleeding
and
50-70
and
3 central
in a patient
deficiency.
The
with hemophilia
with
occurred
HE TERM
INHIBITOR
describe
an antibody
units.
and
and
factor
One-hundred
treated
and
including
with
4 Bethesda
inhibitors.
L. Knatterud,
Immuno
patients
than
were
these episodes
of
33
T
IX
Genell
activity)
in 46
episodes
membranes,
Hilgartner,
by-passing
greater
factor
bleeding
102
W.
hemostasis
with
patients
kg;
inhibitor
to achieve
sixty-five
Margaret
Efforts
were
pnothrombin
be safe and
in inhibitor
effective
patients.
such
product,
FEIBA
Immuno,
was prepared
normal
human
plasma
by Oesterreichisches
Institut
Fuer
Haemodenivate
and contains
a property
that appears
to by-pass
factor
VIII in hemostasis.
FEIBA
has been used extensively
in Europe
since
1 9748.9
inhibitors
to
treat
bleeding
episodes
in
who have few available
therapy
patients
with
alternatives.
Since
approximately
14% of patients
with factor
VIII
deficiency
in the United
State&#{176}have developed
inhibitors to factor
VIII,
it has become
necessary
to investigate
effective
bleeding
of this
and
demonstrate
in
FEIBA
Immuno
in
hemophilia
enable
become
agement
safe
methods
episodes
in these
Familiarization
investigators
for
the
treatment
patients.
Therefore,
Study
was
twofold:
the U.S.
the efficacy
and
for the treatment
of bleeding
patients
in the
familiar
with the
of serious
bleeding
with
U.S.
inhibitors,
to gain
safety
of
episodes
and
,
(2)
experience
use of FEIBA
for
episodes
in these
Blood,
Vol. 6 1 No.
of
the goal
(1) to
to
and
the manpatients.
1 (January),
1983
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
FEIBA
IMMUNO
Nine
TREATMENT
FOR HEMOPHILIACS
hemophilia
throughout
treatment
the
study.
Each
United
center
States,
was
37
centers,
scattered
participated
in
responsible
for
Treatment
Center
at the
Institute
in Baltimore,
tnate
for this
familiarization
STUDY
function
and
extension
taken
study.
DESIGN
Patients
known
the
study
to have
at
the
baseline
joint
function
Patients
with
inhibitors
with
acquired
study
but
added
(HB,Ag,
HB,Ab),
inhibitor
normal),
were
study
assessed
for
history
had
effect
was judged
present
They
FEIBA
treatment.
The
(2) mucous
membrane:
When
FEIBA
central
mucous
bleeding
membrane
resuspended
material
exactness.
infusion
was
Therefore,
dosage.
70 U/kg
which
were
not
patient
There
were
to evaluate
at I 2-hr
discarded
too
whether
antibody
had
to
in the
intervals,
and
except
for
6 hr. Although
patients
who
dosage
variation
received
in
greater
dose increased
Table
bottle,
with
in a slight
a larger
with
U),
to the nearest
efficacy.
1 . Summary
effects
at 2-3
hepatitis
B surface
(HB,Ab),
hives,
time,
antigen
basis
Blood
chills,
was
with
platelets,
were
Number of
Episodes
of Outc ome
Joint
102
1 Infusion
12 hr
41(40%)
One-hundred
with FEIBA
episodes,
blood
studies
(HB,Ag)
and
auditory
episodes
20
were
were
treated
102 were joint
mucous
membrane,
33
and 10 were emergency
bleed3 central
nervous
system,
4
and 3 listed as “other”
bridge
of the nose, chest
and required
20 or more
72 hr for complete
resolution.
in
of Treatment
the
first
With
FEIBA
3 categories
1 Infusion
36
hr
44(43%)
that were
wall, and
infusions
Of the
(Table
I
),
Not Controlled
>72 hr
15(75%)
5(25%)
17(52%)
7(21%)
33(100%)
0
2(67%)
3(100%)
0
3
-
1(33%)
Stgery
4
-
3(75%)
Other
3
1(33%)
60(36%)
Total
98(96%)
9(27%)
165
hr
1(5%)
33
(% of episodes).
>36
13(13%)
Muscle/softtissue
Total
B
canal.
hemorrhage
more than
5(25%)
No. of episodes
for
hepatitis
A total of 9 1% of these 165 episodes
were controlled
within
72 hr. Three
cases (2%) were extremely
severe
episodes
that included
I CNS,
I ilipsoas,
and I thigh
9(45%)
system
for
and SGPT.
soft tissue,
including
surgical
procedures,
miscellaneous
sites:
20
nervous
to
pro-
fibrinogen,
monitored
with
and sixty-five
episodes
in 49 patients.
Of these,
muscle
and
ing episodes
Mucousmembrane
Central
drawn
studies
(DIC)
Controlled
Site
of
for acute
wheezing,
for clotting
patients
postinfusion,
bleedings,
on the
clotting
The
wk
other
levels.
pressure.
thromboplastin
products.
as
was
RESULTS
bleeding
tissue
treated
(500
to comply
resulted
few
and
partial
improved
bleeding
post-infusion
the infusion
the
a
and nonsur-
bottle
side
blood
1 hr after
to
and ankle;
and soft
every
at 50 U/kg
size
surface
and (4) emergen-
seen
was treated
was calculated
knee,
Muscle
to the nearest
of 2 U/kg/mm
bleeding,
dosage
titer,
(CNS).
patients
calculated
inhibitor
reaction
(surgical
(3)
the
included
hip,
cavity
of
I 2 hr prior
were
and abdominal;
system
occurred,
at a rate
the FEIBA
in oral
hematuria;
nervous
at 50 U/kg,
administered
and
within
hand,
chronic
as shock,
intravascular
split
the
if they
allergic
time,
fibrinogen
for
and the poten-
ineligible
agent
and
and
of
felt
circumference
assessed
for 120 mm
and
disseminated
was
such
a previous
A positive
extension
and hematocrit
monitored
reactions,
into
membrane
Control
CNS,
hemoglobin
in temperature
for
or
the
had been
study.7
when
Mucous
to be
evaluate
and the physician
flexion
(3)
values
had
physicians
the current
bleeding.
and
were
allergic
to the infusion
monitor
thrombin
twice
when
could
improved,
values.
of
plus
patients
effects:
or changes
or severe
than
because
products
episodes
retroperitoneal
acute
ineligible
previous
wrist,
bleeding
of an
disease
also
any
elbow,
epistaxis,
including
cy: including
were
of bleeding
shoulder,
in origin),
bleeding:
than
types
) joints:
a history
had
cessation
judgment
The
side
status
of greater
liver
had an antifibrinolytic
following
(1
collected
transami-
for
and
pain
and
pain
for entrance
for
at
the
of fiexion
to baseline
physician
the patient
when
intra-abdominal,
clinical
antibody
without
clotting
disease,
muscle,
prior
who
considered
of severe
thromboembolism.3
or had
study:
were
activated
observed
patients
again
when
possible;
criteria,
and center
instructed
assessed.
the
of pain-severe,
where
these
Patients
baseline
by
to assess
measurements
the
were
I cm,
not
at home
used
as compared
Of
in the use of the gonimeter
by
titer.
or more,
of thromboembolic
FEIBA,
gical
evidence
and
by an SGPT
Patients
of not clearing
antigen
units
data
pyruvate
joint,
study.
and
to the
were
by goniometer
instructed
compared
was
first
patient
evaluation
study
decreased
of the
criteria
However,
stopped,
bleeding
evaluated
circumference,
and function.
had
if
by the
qualitative
assessed
patient.
circumference
was
Three
(I)
to the
by the
and,
bleeding
of the involved
which
part
Laboratory
glutamic
4 yr of age
(as assessed
eligible.
if they
possibility
tial
disease
were
not originally
date.
recruited
during
nonhemophilic
were
inhibitor
over
were
status
and
serum
and current
of 4 Bethesda
liver
medical
IX
B surface
patients
titer
chronic
count,
hepatitis
Hemophilic
general
at a later
VIII
examination,
inhibitors
blood
(SGPT),
to factor
routine
to factor
VIII
complete
nase
of
and
factor
were
included
inhibitors
time
as
hr
subsequently
(2) joint
at entrance
bleeding
into
infusion:
or mild:
joint
joint
as necessary.
of an
moderate,
to compare
efficacy
with a control
product
or
another
activated
prothrombin
complex
conceninitial
intervals
efficacy
made
with
of
72
was given.
1 hr and
within
I 2-hr
for
therapy
control
physician
Maryland
Medical
Md. No attempt
was
continued
alternate
Clinical
recruiting,
examining,
and entering
patients
into the study
for
treatment.
The data generated
by these clinical
centers
were collected,
processed,
stored,
and analyzed
by the
Coordinating
Research
was
controlled,
this
-
70(42%)
4(4%)
-
3(75%)
1(25%)
-
1(33%)
2(67%)
23(14%)
153(93%)
12(7%)
and
155
38%
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
HILGARTNER,
38
responded
within
I 2 hr with
one on more
infusions
responded
within
72
manly
by the patient’s
cian’s
subjective
one
infusion
judgment
35, a 1-4 cm decrease
efficacy
system
and
43%
Table
with
that
the
bleeding
in 24, and
of FEIBA
surgical
an increase
for control
bleeding
was
sites,
the
I of the
controlled
category
3 responded
within
bleeding
72
episodes
treated
with
including
prednisone.
were
a
I 2 hr
The
not
variety
bleeding.
stopped,
Minor
adverse
18 of 489 (3.7%)
nausea,
and
reactions
Laboratory
were
studies
carried
out
revealed
a decrease
300
mg/dl
in one
maximum
patient
from
patient
from
platelet
a high
fall
a high
was
of4lO,000/cu
to
and
However,
the study,
no clinical
evidence
150.0
72
patients
FEIBA
epiup
deficiency.
inhibitor
the
of
in titer
following
product
for
the
treat-
response
3/49
had
patients
had a factor
IX
an acquired
factor
VIII
of these
congenitally
was judged
latter
deficient
primarily
on the
patients
was
patients.
The
subjective
evalu-
ations.
In those patients
where
the other
criteria
were
evaluated,
no more information
was gained.
This is a
similar
finding
to that
of the NHLBI
study,7
and
therefore,
valid.
the subjective
evaluation
alone
was
deemed
No attempt
was made to evaluate
the time between
onset of bleeding
and therapy,
although
this might be a
valuable
observation.
One such detailed
report
done by
Anonstam
ton patients
in one
to be a safe
to the
response
mg/dl.
defined
The
identical
in a hospital-school
setting
with noninhibibleeding
into the elbow shows the need for
within
2 hr
of
onset
for
efficacy
using
10
U
factor
VIIl/kg.
Since
the patients
in the current
study
had to travel
to the hospital
and wait for the
infusion
material,
it seems
most
unlikely
that
they
were
B infection.
rise,
a fall
episodes
in patients
with factor
VIII
with
either
congenital
on acquired
In this study,
and 2 patients
inhibitor.
mouth.
units.
Inhibitor
titers
were measured
by the investigators and the control
laboratory
in Vienna
and showed
appears
ment of bleeding
or IX inhibitors
therapy
of hepatitis
had
DISCUSSION
mm.
A significant
of the
units,
was seen within
2-3
a change
in efficacy
of the
infusions
(Table
2). The
were
monitor
in the APTT
of 450
40.2
6,720.0
therapy.
seen in only
chills,
fever,
260,000
1,177.6
greater
than
10 Bethesda
wk in 10 patients,
without
product
with
subsequent
majority
not
joint
hr
in the
to
40.0
3,840.0
480.0
since all patients
had HB,Ab
on entrance
the increase
in the SGPT
of greater
than
consistency.
12.0
1,800.0
2.0
to
40
U in 9 patients
was considered
due to another
viral
agent.
There
appeared
to be no difference
in patient
response
between
those
patients
with
titers
of 2
Bethesda
units as opposed
to those with 3840 Bethesda
surprising
94.4
2.8
The long-term
changes
monitored
at 2 wk or more
after
the infusion
revealed
no HB,Ag
in any of the
patients,
no serologic
changes
in the hepatitis
B marker,
66.0
9
4
greater
than
10 sec from the pretransfusion
level in
54% of the cases, and a rise in 3%: there was a decrease
in the PT in 4% of the cases.
However,
the change
in
the APTT
and PT could
not be used as a measure
of
clinical
efficacy.
The maximum
fall in fibninogen
was
The
54.0
3
10
bleeding
prolonged,
taste
48.0
20.0
noticed.
of DIC
appearance
12.0
21.0
8
IX concentrates
and
were used for mucous
an unusual
1
measures,
reactions
were
and included
Rise
to evaluate
treated,
Of the
Rise
Units
Maximum
14.4
conventional
All nonresponsive
but were markedly
Level in Bethesda
2
5
GROUP
With
76.0
2 were
at
in Patients
7
whose
controlled
of
systemic
infusions
dizziness,
major
and
STUDY
wk Post-FEIBA)
Baseline
4
miscellaneous
patients
factor
VIII and factor
Packing
and Amicar
membrane
sodes finally
to 20 days.
No
in
hr.
Titer
(2-3
lnhibit
cm
FEIBA
6
episodes
72 hr.
or
in Inhibitor
THE
nervous
ofcentral
“other”
AND
Units
Patient
patients
treated
for surgical
procedures,
3 were controlled
in 36 hr and I required
more
than
72 hr for
hemostasis
and was therefore
considered
a failure
of
In
Change
of 10 or More
out
in
of 1-2
is difficult
Maximum
con-
were carried
with no change
because
of small numbers.
Of 3 CNS
I responded
in 36 hr and
I within
response.
2.
in 36 hr; a total
of 93%
hr. Response
was judged
pnievaluation
of pain and physi-
trolled.
Circumference
measurements
in 65 of the joint bleeding
episodes
in 6.
The
and
KNATTERUD,
dosage
The
patients
a
within
2 hr of onset
would
be
study.
response
treated
of
with
very
bleeding
FEIBA
of bleeding.
useful
in
a
episodes
is similar
Such
patient
with
VIII
onthopedically
included.7
an
inhibitor
deficient
normal
as factor
patients
in inhibitor
to the response
and
VIII
when
those
with
an
subsequent
seen in noninhibitor
patients
treated
with factor
FEIBA
appears
to work as well fonjoint
bleeding
factor
as
treated
observation
all
does
VIII.
in the
for
the
joints,
both
synovitis,
are
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
FEIBA
IMMUNO
As in the
VIII deficient
FEIBA
TREATMENT
FOR HEMOPHILIACS
treatment
patients,
of bleeding
episodes
the need for repeated
for the
NHBLI
patients
inhibitor
patient
factor
VIII
inhibitor
had an average
of
treated
themselves
bleeding
74
episode)2
judge
whether
the
continued
bleeding
is not
in factor
doses of
unusual.
In the
study,
the noninhibitor
34 bleeds
per year
and
times,
There
39
on
are
more
once
per
criteria
to
because
Since
of
all
than
no objective
patient
was retreated
or for
prophylaxis.
mouth.
The first three
have never been well explained
and
may
be related
to protein
load
and
speed
of
infusion.
The taste in the mouth
measures
circulation
time
and
processing.
is probably
related
There
have been
tions.
The monitoring
rise of inhibitor
to the factor
titer
of long-term
side effects
did show
in 10 of 49 patients
as a response
VIIIC:Ag
known
patients
were on a home-cane
program,
direct
medical
observation
was impossible.
When
using FEIBA,
79%
of the patients
were
controlled
with
one on more
However,
three
of these
with
factor-VIIIC:Ag-containing
infusions
when
within
36 hr.
The question
yet unanswered.
chosen
based
as to minimal
doseage
The present
dose
on previous
studies.
for efficacy
of 50 U/kg
Insufficient
were collected
to prove
that a smaller
dose
useful.
Certainly,
the 100 U/kg
for surgical
and
50-70
appear
U/kg
for thejoints
and
muscle
is as
was
data
would
be
episodes
or soft
tissue
adequate.
The laboratory
the APTT
50%
dosage.
The same
of patients.
number
sure
data show a minimal
shortening
of
of the time, which was unrelated
to the
of efficacy.
was seen
Neither
In one
in the PT in a smaller
could
be used as a mea-
patient,
the
fibrinogen
fell
300
wk prior
to using
other
complex
iments
One
is that
substance
predictive
laboratory
since
measure
for
there
efficacy
is
in
patient,
care and caution
should
be maintained
considering
its use for elective
surgical
procedures.
hepatitis
markers.
B monitoring
The transient
no
the
when
The
revealed
no changes
in these
rise in SGPT
is postulated
as
due
to non-A,
non-B virus disease.
The systemic
side effects
appear
to be the
those
seen in a small
number
of hemophiliacs
treated
nausea,
with factor
VIII
dizziness,
chills,
concentrate,
i.e., headache,
and an unusual
taste
in the
principle
is only
of
unknown.
two possible
conepi-
weight
slightly
of
inhibited
theory
prothrombin
In vitro experexplanations.
is a factor-Xa-like
a molecular
inhibitor.’5
safety
seems
120,000-
by
suggests
to
is present.
The
this
is a clinical
that
2
seen
of bleeding
plasmatic
that
the
may
be complex
factor
VIIIC:Ag,
phospholipid,
which
is less inhibited
factor
VIII
Clinical
ever,
active
Another
principle
IXa, and
been
complex
treatment
remains
suggest
has
and
are psychologically
negative
response.
be
proven
investigators
active
factor
by the
and
clinical
recognize,
study
based
primarily
on patient
The patients
were educated
activated
same as
when
the
that
I 30,000
has
prothrombin
for
pretneated
within
with factor
VIII inhibitors;
an even
of patients
showed
an anamnestic
products.13
This finding
is therefore
since
FEIBA
is known
to contain
concentrate
with FEIBA
efficacy
However,
rise
small amounts
of factor
VIIIC:Ag.
The in vivo mechanism
of action
used
U/kg.
same
a
in FEIBA.
had been
materials
This
used
sodes in patients
greater
number
response
to these
not unexpected,
inhibitors.’4
50-100
FEIBA.
were
to be present
patients
nonactivated
centrations
mg, but there was neither
a rise in split products
nor a
fall in platelet
count.
Since
the minor
changes
in
fibninogen
and platelet
count
were minimal,
and there
were no split products,
FEIBA
is indeed
safe and does
not cause
disseminated
intravascular
clotting
when
at
to a residue
from
the
no other
systemic
reac-
with
how-
observations
interpretations
tojudge
response,
on results.
but they
set for a positive
rather
than
a
The efficacy
as related
to the only
pnothrombin
complex
(Autoplex)
licensed
for use in inhibitor
evaluated.
This study,
as well
study,
must be done.
already
patients
has
as a controlled
not been
clinical
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1983 61: 36-40
The use of factor eight inhibitor by-passing activity (FEIBA immuno)
product for treatment of bleeding episodes in hemophiliacs with inhibitors
MW Hilgartner and GL Knatterud
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