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The Treatment of Hemophilia series is intended to provide general information on the treatment and management of hemophilia. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. Dose schedules and other treatment regimes are continually revised and new side-effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or to consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph.
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Content Preview

DECEMBER 2005 • NO 38


Paul Giangrande
Oxford Haemophilia Centre and Thrombosis Unit
Oxford, UK

Published by the World Federation of Hemophilia (WFH)

© World Federation of Hemophilia, 2005

The WFH encourages redistribution of its publications for educational purposes by not-for-profit
hemophilia organizations. In order to obtain permission to reprint, redistribute, or translate this
publication, please contact the Communications Department at the address below.

This publication is accessible from the World Federation of Hemophilia’s web site at
Additional copies are also available from the WFH at:

World Federation of Hemophilia
1425 René Lévesque Boulevard West, Suite 1010
Montréal, Québec H3G 1T7
Tel. : (514) 875-7944
Fax : (514) 875-8916

The Treatment of Hemophilia series is intended to provide general information on the treatment and
management of hemophilia. The World Federation of Hemophilia does not engage in the practice of
medicine and under no circumstances recommends particular treatment for specific individuals. Dose
schedules and other treatment regimes are continually revised and new side-effects recognized. WFH
makes no representation, express or implied, that drug doses or other treatment recommendations in this
publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a
medical adviser and/or to consult printed instructions provided by the pharmaceutical company before
administering any of the drugs referred to in this monograph.

Statements and opinions expressed here do not necessarily represent the opinions, policies, or
recommendations of the World Federation of Hemophilia, its Executive Committee, or its staff.

Treatment of Hemophilia Monographs
Series Editor
Dr. Sam Schulman

Table of Contents

Summary..................................................................................................................................................................... 1

Clinical Features......................................................................................................................................................... 1

Epidemiology ............................................................................................................................................................. 2

Laboratory Diagnosis................................................................................................................................................ 2

Clinical Management ................................................................................................................................................ 3

Postpartum Acquired Hemophilia......................................................................................................................... 5

References ................................................................................................................................................................... 5

Glossary ...................................................................................................................................................................... 8

Acquired Hemophilia
Paul Giangrande
the hallmark of severe congenital hemophilia,
this is unusual in acquired hemophilia where
Classical hemophilia is an inherited coagulation
the principal manifestations are bleeding into
disorder due to deficiency of either factor VIII or
skin (purpura) and soft tissues. Figures 1 and 2
IX. This is usually associated with bleeding
illustrate typical examples of extensive purpura
problems from an early age, and bleeding into
due to acquired hemophilia.
joints is a typical feature. Acquired hemophilia
is a rare condition, and is due to the production
of autoantibodies in adult life which inactivate
factor VIII. Typical clinical manifestations of the
acquired form are extensive cutaneous purpura
and internal hemorrhage: bleeding into the
joints is not a prominent feature. Both sexes are
affected and there may be identifiable under-
lying conditions. Diagnosis is based on the
finding of a low factor VIII level associated with
the presence of a time-dependent inhibitor in the
plasma. Treatment of the condition involves the
use of an activated prothrombin complex
concentrate (e.g., FEIBA) or recombinant
activated factor VII (NovoSeven) to control
Figure 1: Extensive purpura over the flanks of a
bleeding episodes. In addition, immuno-
62-year-old man with acquired hemophilia.
suppression with steroids is usually effective at

reducing inhibitor production and bringing

about a sustained rise in the factor VIII level.

Rituximab is a promising new agent in the

management of this condition.

Clinical Features

The classical form of hemophilia results in a

congenital bleeding tendency associated with a

reduction in the factor VIII (or IX) level. Like

colour blindness, the inheritance of hemophilia

is sex-linked, so males are affected although

hemophilia is transmitted by carrier females

who do not usually have significant bleeding
problems themselves. By contrast, acquired

hemophilia is typically a disorder of middle age
Figure 2: Extensive purpura over the chest and
abdomen of a 78-year-old woman with acquired
and occurs equally in both sexes. It is due to the
development of autoantibodies directed against

factor VIII and the resulting reduction in factor
The reason for the different bleeding pattern in
level is associated with a significant bleeding
acquired hemophilia remains unknown: there is
tendency. However, the pattern of bleeding seen
no demonstrable impairment of platelet
in acquired hemophilia is quite distinct from
function. In a survey of 24 cases treated in a
that seen in the more common congenital form.
single centre over a 28-year period, purpura and
Whereas bleeding into joints (hemarthrosis) is
soft tissue hemorrhage were the presenting

Acquired Hemophilia

problems in the overwhelming majority of 23
diagnosis, such as cancer or pregnancy, was
cases.[1] Bleeding into soft tissues can worsen
identified in 98 (41%) of patients in this series.
rapidly into a compartment syndrome. Other

presentations included hematuria (4 cases),

gastrointestinal bleeding (2 cases), and
Laboratory Diagnosis
prolonged postpartum bleeding (4 cases). This
study also emphasized the potential life-
The typical findings of acquired hemophilia are
threatening nature of the condition as 3 patients
a prolonged activated partial thromboplastin
(11% of the cohort) died directly of bleeding
time (APTT) and a low factor VIII level. The
complications. Other studies have demonstrated
thrombin and prothrombin times are normal, as
a similar mortality in the range of 8-22%, with
are both the platelet count and function. Mixing
the highest risk being within the first few weeks
studies can be used to demonstrate the presence
after presentation.[2,3,4] It is recognized that
of a time-dependent inhibitor of factor VIII.
there is often an underlying medical condition
Details of the methodology for the screening of
associated with this autoimmune condition. An
plasma samples for inhibitory antibodies to
association with other autoimmune conditions,
factor VIII and their quantification can be found
malignant disease, certain drugs, and pregnancy
in sections 13 and 23 of the WFH laboratory
has been recognized in various surveys. In
manual, Diagnosis of Haemophilia and Other
approximately half of all cases, there is no
Bleeding Disorders.[7] It is important to
obvious underlying cause and the condition is
distinguish anti-factor VIII inhibitors from the
labelled as idiopathic.[2]
more commonly encountered antiphospholipid

antibodies (or “lupus anticoagulant”). In such
cases, no correction of the baseline APTT will be

seen immediately after mixing text plasma with
normal plasma.
Acquired hemophilia is significantly rarer than

the inherited form, affecting around 1-4 per
The antibodies in acquired hemophilia are
million of the population. As with the
invariably directed towards factor VIII and not
conventional inherited form, the condition
factor IX. The antibodies are usually polyclonal
appears in all ethnic groups and has a
IgG4 antibodies (rarely IgM or IgA). Most
worldwide prevalence. It is certainly true to say
antibodies bind to 44-kD A2 domain and/or 72-
that the condition is often not recognized or
kD C2 domain of factor VIII and do not fix
mistaken for other acquired bleeding disorders,
such as disseminated intravascular coagulation

(DIC). Case presentations within institutions
The kinetics of the interaction between factor
and conferences can help to increase local
VIII and the inactivating antibody in acquired
awareness of the condition among healthcare
hemophilia are unusual, and differ from the
professionals in other disciplines.
usual pattern seen in congenital hemophilia

complicated by inhibitor development. The
The condition typically presents in middle age
profile shows a non-linear inactivation pattern
and beyond. It rarely arises in childhood, where
(type II kinetics), with some residual factor VIII
the presence of an inhibitor on laboratory
activity identifiable even after incubation at high
screening of a previously healthy child is much
concentrations of antibody for some time. The
more likely to represent the presence of a lupus
lack of complete inactivation of factor VIII even
anticoagulant (antiphospholipid antibody). In an
at high concentration is due to the fact that
analysis of pooled data from 20 surveys
antibodies in acquired hemophilia may react
encompassing 249 patients, the median age of
with factor VIII to form a complex with some
patients reported with acquired hemophilia was
residual factor VIII activity.[8] What this means
64 with a range of 8-93 years.[5] In a study from
in practice is that patients with acquired
the United Kingdom (population = 58 million),
hemophilia may have measurable factor VIII
240 cases were reported in the decade 1985-
baseline levels even in the presence of high titer
1996.[6] The age of these patients ranged from
inhibitory antibodies.
20-99 and only 24 (10%) were less than 50 years

old at the time of diagnosis. An underlying

Acquired Hemophilia

Clinical Management
heat vapour treatment.[10] Doses in the range
of 50-100 units are given by intravenous
Acquired hemophilia is a rare disorder and the
infusion, but it is important not to exceed a total
potential for significant bleeding problems is
of 200 units/kg within a 24-hour period as this
high. It is therefore recommended that such
may be associated with a risk of venous
patients be managed in specialist hemostasis
thromboembolism. A recent retrospective
units, which have the necessary expertise and
survey of 34 patients with acquired hemophilia
blood products available.
documented an overall complete response rate

of 86%, with a typical dosage regime of 75
It needs to be remembered that many of the
units/kg given every 8-12 hours.[11] The
patients with this condition are elderly and frail,
median number of doses required to control a
and they may thus be particularly vulnerable to
severe bleed was 10 compared to a median of 6
adverse effects of steroids such as diabetes
doses for an episode classified as “moderate”.
mellitus, psychosis, osteoporosis, and cataract
There is no easy way to monitor the response to
development. There may well also be ethical
FEIBA in the laboratory and clinical judgement
issues involved in decisions regarding how far
must be relied on.
to pursue investigations for underlying

pathology and getting truly informed consent,
Recombinant activated factor VII (NovoSeven) is
as well as the cost of treatment.[9] At the very
an alternative agent, which has the advantage of
least, a thorough medical history should be
freedom from the risk of transmission of blood-
taken to find out other medical problems and a
borne viruses and other pathogens. An early
physical examination with a limited panel of
clinical study of 74 bleeding episodes in 34
blood tests and radiological examinations to
patients with acquired hemophilia documented
highlight an underlying condition.
a good response in 75% of bleeding episodes

and a partial response in a further 17%.[4] These
Recent medication use should be carefully
patients had failed to respond to prior treatment
reviewed as the development of acquired
with other blood products, and so the response
hemophilia has been reported as a very
rate in new patients who have not yet received
occasional adverse reaction to certain drugs.
other products can be expected to be higher.
Drugs that have been implicated in published
Several smaller studies and case reports have
case reports include antibiotics (such as
since reinforced the efficacy of this agent in the
penicillin and sulphonamides and
management of acquired hemophilia. The half-
ciprofloxacin), immune-modifying drugs
life is relatively short at around 2.5 hours, so
(interferon, fludarabine), psychotropic drugs
frequent dosing may be required. A typical dose
(phenytoin, flupentixol, zuclopenthixol) and the
regime would be 90-120 micrograms/kg
antiplatelet agent, clopidogrel. However, this is
administered every 3 hours until bleeding is
by no means an exhaustive list and the
controlled. As with FEIBA, laboratory
possibility that any recent drug could have
monitoring is not easy. Response to treatment is
provoked the bleeding disorder must be
best assessed on purely clinical grounds
although a specific kit for the assay of factor

VIIa is commercially available although factor
The principal products available for the
VII assays may also be used to monitor
treatment of bleeding episodes are activated
treatment. Shortening of the prothrombin time
prothrombin complex concentrates (such as
(PT) will be observed after administration of
FEIBA, which contains activated factors VII, IX,
recombinant activated factor VII.
and X) or recombinant activated factor VII

(NovoSeven). The final choice of product and
There are published case reports of arterial
dose is determined by the site and severity of
thrombosis associated with the use of
the bleeding. It should be noted that even
recombinant activated factor VII, including a
extensive cutaneous purpura do not necessarily
case of myocardial infarction specifically in a
require treatment.
patient with acquired hemophilia.[12] It is

difficult to quantify the risk in the light of such
FEIBA is a plasma-derived concentrate which is
isolated case reports but caution seems
subjected to a single viral inactivation with dry

Acquired Hemophilia

warranted in the treatment of patients with
successfully applied in the management of
documented cardiovascular risk factors.
various autoimmune conditions, including

autoimmune thrombocytopenia. The usual
Human factor VIII is likely to be very rapidly
treatment regime involves four separate
inactivated by a significant titer of inhibitory
intravenous infusions of 375 mg/m2 each,
antibody and therefore of no practical use, even
administered at weekly intervals. A clinical
at high doses. Porcine factor VIII (Hyate: C) was
response is typically seen within a week of the
widely used in the past to manage acquired
first infusion, with a rise in the factor VIII level
hemophilia.[3] This was based on the rationale
and a corresponding fall in the inhibitor
that the structure of porcine factor VIII was
titer.[13,14,15,16] It must be remembered that
sufficiently similar to the human form to have
rituximab is not licensed by any of the major
some hemostatic effect, but was at the same time
regulatory authorities for the treatment of
sufficiently different to be less susceptible to
acquired hemophilia and its “off label” use to
inactivation by circulating antibodies. This
treat this condition is likely to need prior
plasma-derived product is no longer available,
approval in many institutions. There is now
but a new genetically engineered version is
general consensus that the use of rituximab
under development and it is quite possible that
should be considered in cases where patients
a recombinant version of porcine factor VIII may
prove resistant to first line therapy or in patients
soon be available.
in whom steroids and/or cytotoxics are best

avoided. Some groups now take the view that
Treatment of acquired hemophilia involves two
the use of rituximab should also be considered
aspects of treatment. Hemostatic agents need to
as initial therapy in cases where the initial
be given to control actual bleeding episodes but
antibody titer is high.[17]
some form of immunosuppressive treatment

also needs to be given in order to suppress
Another immunosuppressive agent which
production of the underlying inhibitory
has been tried in acquired hemophilia
antibody. It is recommended that immuno-
when other treatment does not work is
suppressive therapy be initiated as soon as the
2-chlorodeoxyadenosine, which was both
diagnosis of acquired hemophilia is established.
effective and well tolerated in a small study of
The usual treatment involves administration of
just 6 patients who had not been cured by
prednisolone (prednisone) at a dose of 1 mg/kg
conventional treatment.[18]
combined with cyclophosphamide 50-100

mg/day orally. This regime is based on the
Cyclosporin has also been used in several
results of a randomized clinical trial.[2]
cases,[19,20,21,22] and appears effective
Azathioprine may be preferred to the latter in
particularly when systemic lupus eryhtematosus
the case of women of child-bearing age.
is the underlying disorder. Long-term treatment
Treatment should be continued for up to six
will require appropriate monitoring of plasma
weeks with regular review. Most patients will
levels in order to minimize toxicity, and
respond well to such a combination of
cyclosporin is contraindicated in renal failure.
treatment. However, relapse is not uncommon

once the drugs are stopped or the dose reduced.
Infusions of immunoglobulin may also be
This is potentially problematic as it is not
helpful. A prospective (non-randomized) trial of
feasible to continue this treatment in the long
immunoglobulin assessed the response to doses
term. One option is to use periodic pulses of
of 1 g/day x 2 or 0.4 g x 5 days in 16 patients
steroid therapy to maintain a satisfactory factor
with acquired hemophilia.[23] The response rate
VIII level, but the use of other immuno-
was 30%, with range of response time of 6.5-40
suppressive agents should also be considered.
days. A better response was observed in patients

with lower initial inhibitor titers (range in
It has become clear in recent years that
patient group was 0.5-1228 BU).
rituximab may be a valuable agent in managing

acquired hemophilia. This anti-CD20
A meta-analysis of 249 cases showed a complete
monoclonal antibody is primarily used in the
remission rate of 74% after a median follow-up
management of lymphoma because of its
of 12 months.[5] The inhibitor-related mortality
affinity for B lymphocytes. However, it has been
rate was 11%. Poor prognostic features

Acquired Hemophilia

identified in the review were: age at diagnosis
was reported in an early international
(<65 better than ≥ 65 years; achievement of a
survey.[25] Data from the Italian registry of
complete remission (yes better than no); nature
acquired hemophilia showed similar results
of underlying disease (malignant disease worse
with a recurrence rate of 0/4.[26] The only study
than others).
to document any cases of recurrence was a

survey of centres in North America.[27] Three

of 14 women with postpartum acquired
Postpartum Acquired Hemophilia
hemophilia were documented as having had 6
subsequent pregnancies. There was an
This category deserves special mention as it has
anamnestic response during 4 of these and no
some distinct features. Postpartum development
recurrence in the other 2.
of acquired hemophilia is a rare but serious

complication of pregnancy. The bleeding

tendency is often severe and often requires
immediate treatment. However, the prognosis is
good and in a review of 51 cases the overall
1. Yee TT, Taher A, Pasi KJ, Lee CA. A survey
outcome was favourable with 97% survival at
of patients with acquired haemophilia in a
two years.[24] Three deaths due to bleeding
haemophilia centre over a 28-year period.
occurred amongst these patients at 1, 5, and 36
Clinical and Laboratory Haematology 2000;
months. This survey showed the highest risk
applied after first pregnancy. The median age of

the women was 28 years and the average onset
2. Green D, Lechner K. A survey of 214 non-
of symptoms was two months after delivery.
hemophilic patients with inhibitors to factor
Persistent vaginal bleeding was the most
VIII. Thrombosis and Haemostasis 1981;
common symptom, reported in 17 of the 51
cases. The antibody titer is often high in

postpartum hemophilia and the median
3. Morrison AE, Ludlam CA, Kessler C. Use of
inhibitor titer in this series was 20 Bethesda
porcine factor VIII in the treatment of
units (BU). The probability of complete
acquired haemophilia. Blood 1993;
remission (CR=absence of the inhibitor and
normalization of factor VIII activity) was almost

100% at 30 months. It seems that all postpartum
4. Hay CRM, Negrier C, Ludlam CA. The
inhibitors will eventually disappear
treatment of bleeding in acquired
spontaneously over a period of months. Giving
haemophilia with recombinant factor VIIa: a
a course of immunosuppression hastens
multicentre study. Thrombosis and
recovery by a few months but does not affect the
Haemostasis 1997; 78(6):1463-1467.
overall response rate. The median time to

achieve complete remission for patients who
5. Delgado J,.Jimenez-Yuste V, Hernandez-
received no treatment was 16 months, compared
Navarro F, Villar A. Acquired haemophilia:
with 12 months with steroids alone and 8
review and meta-analysis focused on
months with immunosuppression ± steroids.
therapy and prognostic factors. British
The physician has to decide in individual cases
Journal of Haematology 2003; 121(1): 21-35.
whether the possible beneficial effect of

immunosuppressive therapy may outweigh the
6. Rizza CR, Spooner RJD, Giangrande PLF on
small but definite risk of this treatment. In view
behalf of the UK Haemophilia Centre
of the length of time it takes for the inhibitor to
Doctors' Organisation (UKHCDO).
disappear, the women should be advised to use
Treatment of haemophilia in the United
some form of contraception until remission is
Kingdom 1981-1996. Haemophilia 2001;

The limited data available suggest that
7. Kitchen S, and McCraw A, for the WFH
recurrence of the inhibitor during subsequent
Laboratory Sciences Committee. Diagnosis of
pregnancies may occur but is by no means
Haemophilia and Other Bleeding Disorders.
inevitable. A recurrence rate of 0/11 pregnancies
Montreal, Canada: WFH, 2000. Available in

Acquired Hemophilia

printed format in English and Spanish. May
16. Stasi R, Brunetti M, Stipa E, Amadori S.
also be downloaded free of charge from
Selective B-cell depletion with rituximab for
internet via
the treatment of patients with acquired

hemophilia. Blood 2004; 103(12):4424–4428.
8. Biggs R, Austen DEG, Denson KWE, Borrett

R, Rizza CR. The mode of action of
17. Aggarwal A, Grewal R, Green RJ, Boggio L,
antibodies which destroy factor VIII. II.
Green D, Weksler BB, Wiestner A, Schechter
Antibodies which give complex
GP. Rituximab for autoimmune
concentration graphs. British Journal of
haemophilia: a proposed treatment
Haematology 1972; 23(2):137-155.
algorithm. Haemophilia 2005; 11(1):13-19.

9. Starr JM. Treating acquired haemophilia: an
18. Sallah S, Wan JY. Efficacy of 2-
ethical conundrum. Age and Ageing 2001;
chlorodeoxyadenosine in refractory factor
VIII inhibitors in persons without

hemophilia. Blood 2003; 101(3):943-945.
10. Negrier C, Goudemand J, Sultan Y,

Bertrand M, Rothschild C, Lauroua P, and
19. Schulman S, Langevitz P, Livneh A,
the members of the French FEIBA study
Mortinowitz U, Seligsohn U, Varon D.
group. Multicenter retrospective study on
Cyclosporine therapy for acquired factor
the utilization of FEIBA in France in patients
VIII inhibitor in a patient with systemic
with factor VIII and factor IX inhibitors.
lupus erythematosus. Thrombosis and
Thrombosis and Haemostasis 2003; 77(6):1113-
Haemostasis 1996; 76(3): 344-346.

20. Petrovic M, Derom E, Baele G. Cyclosporine
11. Sallah S. Treatment of acquired haemophilia
treatment of acquired hemophilia due to
with factor eight inhibitor bypassing
factor VIII antibodies. Haematologica 2000;
activity. Haemophilia 2004; 10(2): 169-173.

12. Guillet B, Pinganaud C, Proulle V, Dreyfus
21. Au WY, Lam CCK, Kwong YL. Successful
M, Lambert T. Myocardial infarction
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occurring in a case of acquired haemophilia
with cyclosporin. Haemophilia 2004; 10(1):98-
during the treatment course with
recombinant activated VII. Thrombosis and

Haemostasis 2002; 88(4):698-699.
22. Maize JC, Cohen JB. Cyclosporine controls

epidermolysis bullosa acquisita co-occurring
13. Kain S, Copeland TS, Leahy MF. Treatment
with acquired factor VIII deficiency.
of refractory autoimmune (acquired)
International Journal of Dermatology 2005;
haemophilia with anti-CD20 (rituximab).
British Journal of Haematology 2002;

23. Schwartz RS, Gabriel DA, Aledort LM,

Green D, Kessler CM. A prospective study
14. Wiestner A, Cho HJ, Asch AS, Michelis MA,
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Zeller JA, Peerschke EIB, Weksler BB,
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