HAEMOSTASIS AND THROMBOSIS
Acquired hemophilia A
Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Azienda Ospedaliera di Verona, Verona, Italy
(Received 19 September 2005; accepted 25 November 2005)
Acquired hemophilia A is a rare but severe autoimmune bleeding disorder, resulting from the presence of autoantibodies
directed against clotting factor VIII. The etiology of the disorder remains obscure, although approximately half of all cases are
associated with other underlying conditions. A prompt diagnosis and appropriate management enable effective control of this
acquired hemorrhagic disorder: the aims of therapy are to terminate the acute bleeding episode and eliminate or reduce the
inhibitor. The recent availability of bypassing agents, first activated prothrombin complex concentrates and then recombinant
activated factor VII, has significantly reduced mortality during the acute phase of the disease in patients with high titer
inhibitors. On another front, immunosuppressive therapy (corticosteroids and cytotoxic agents, alone or in various
combinations) has resulted in long-term inhibitor suppression in up to 70% of the cases. Moreover, new therapeutic strategies
(anti-CD20 monoclonal antibody and immune tolerance protocols) are very promising and mayfurther improvethe prognosis
of acquired hemophilia A.
Keywords: Acquired, hemophilia, factor VIII, bleeding, treatment
Acquired hemophilia A is an uncommon but poten-
tially life-threatening hemorrhagic disorder caused by
the development of autoantibodies (mostly IgG)
directed against the coagulation factor VIII (FVIII)
[1–7]. The incidence of acquired hemophilia A has
per year, but this figure may be an underestimate given
the difficulty in making the diagnosis. The clinical
picture is dominated by severe hemorrhage in the
rate of up to 22% [8–13]; most of these deaths occur
within the first few weeks after presentation. However,
the reduction in mortality rate observed in the most
the management of acute bleeding during the last few
years (first porcine factor VIII and prothrombin
complex concentrates [PCC] and then recombinant
activated factor VII [rFVIIa]) [14,15]. Nevertheless,
underestimated due to the high median age at the
time of diagnosis (60–70 years old).
The age distribution of autoantibodies is typically
biphasic with a small peak between 20 and 30 years
(postpartum inhibitors) and a major peak in patients
aged 68–80 years [1,3]. Factor VIII inhibitors are
distributed equally by sex, although females pre-
dominate in the younger age group because of the
association with pregnancy while males constitute the
majority of patients over the age of 60 . However,
it is difficult to draw any firm conclusions as regards
epidemiology, clinical aspects and therapy of this
disease from literature data, since most of the reports
are anecdotal and describe only a few cases.
In this review, we briefly report present knowledge
about acquired hemophilia A, analyzing its epidemio-
logy, pathogenesis, diagnostic and clinicalfeatures.We
ISSN 1024-5332 print/ISSN 1607-8454 online q 2006 Taylor & Francis
Correspondence: M. Franchini, Servizio di Immunoematologia e Trasfusione, Centro Emofilia, Ospedale Policlinico, Piazzale L.Scuro,
10, 37134 Verona, Italy. Tel: 39 45 8073610. Fax: 39 45 8073612. E-mail: firstname.lastname@example.org
Hematology, April 2006; 11(2): 119–125
also describe the main characteristics of the disorder
according to its association with different conditions
and the most important advances in the treatment
of bleeding episodesand
Source of materials
This review presents information from studies so far
published in the medical literature on acquired
hemophilia A. MedLine reports were searched via
PubMed using the following terms without time limits:
“acquired hemophilia A”, “acquired hemophilia and
factor VIII”, “acquired hemophilia and coagulation
factors”, “acquired inhibitors”, “acquired factor VIII
inhibitors”, “acquired inhibitors and coagulation fac-
tors”, “autoantibodies and coagulation factors”, “anti-
factor VIII antibodies”, “factor VIII autoantibodies”,
“autoimmune factor VIII inhibitors”, “hemophilia and
inhibitors”, “hemophilia and autoantibodies”, “spon-
searched for alone and in combination with “idio-
pathic”, “elderly”, “postpartum”, “pregnancy”, “auto-
sus”, “rheumatoid arthritis”, “thyroid”, “malignant
disease”, “cancer”, “carcinoma”, “neoplasm”, “solid
tumor”, “hematologic diseases”, “lymphoproliferative
“allergy”, “vaccine”, “dermatologic diseases”, “neuro-
logic diseases”, “infection”, “hepatitis”, “surgery”,
“therapy”, “treatment”, “desmopressin”, “porcine
factor VIII”, “prothrombin complex concentrates”,
“plasmapheresis”, “extracorporeal immunoadsorp-
oids”, “immunosuppression”, “cyclophosphamide”,
“immunoglobulins”, “azathioprine”, “cyclosporin”,
“rituximab”, and “immune tolerance induction”.
Table I lists several conditions and diseases associated
with the development of factor VIII inhibitors.
In approximately 50% of cases FVIII autoantibodies
occur in patients, usually elderly, lacking relevant
concomitant diseases , whereas in nearly 10% of
cases the autoantibody against FVIII appears during
the postpartum period, usually in primiparas within 3
months of delivery [17–24]. Autoimmune diseases
associated with the development of factor VIII
inhibitors include systemic lupus erythematosus
[25,26], rheumatoid arthritis [27,28], Sjo ¨gren’s
syndrome [29,30], autoimmune hemolytic anemia
, myasthenia gravis , Graves’ disease  and
autoimmune hypothyroidism . However, many
other conditions associated with acquired hemophilia
A are characterized by immune dysregulation such as
inflammatory bowel diseases (ulcerative colitis) ,
dermatologic disorders (psoriasis, pemphigus) ,
respiratory diseases (asthma, chronic obstructive
pulmonary disease) , diabetes , acute hepatitis
C infection , and allergic reactions to medications
(penicillin and its derivatives, sulfa antibiotics,
[1,3,34]. Acquired hemophilia A is also seen after
treatment with drugs interfering with the immune
system, such as interferon-alpha and fludarabine
[35–38]. Nearly 10% of patients with acquired
hemophilia A have an underlying malignancy, either
solid or hematologic [39–48]. The solid tumors most
frequently involved are prostate and lung cancer,
though a wide variety of cancers have been described
(colon, pancreas, stomach, bile duct, head and neck,
cervix, breast, melanoma and kidney) [39–46]. The
relationship between factor VIII inhibitor and altered
immune status is further confirmed by the fact that
lymphoproliferative disorders (chronic lymphocytic
myeloma and Waldenstro ¨m’s macroglobulinemia)
are the most frequent hematologic malignancies
Table I.Conditions associated with acquired hemophilia A.
Autoimmune disorders Systemic lupus erythematosus, rheumatoid arthritis, Sjo ¨gren’s syndrome,
autoimmune hemolytic anemia, myasthenia gravis, Graves’ disease,
Asthma, chronic obstructive pulmonary disease
Penicillin and its derivatives, sulfamides, phenytoin, chloramphenicol,
methyldopa, interferon-alpha, fludarabine
Prostate, lung, colon, pancreas, stomach, bile duct, head, neck, cervix,
breast, melanoma, kidney
Chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, multiple myeloma,
Waldenstro ¨m’s macroglobulinemia, myelodysplastic syndrome,
Inflammatory bowel disease
Allergic drug reactions
Acute hepatitis C infection
associated with the development of inhibitors [47,48].
Other hematologic diseases include myelodysplastic
syndrome, myelofibrosis and erythroleukemia .
Diagnosis of acquired hemophilia A
The diagnosis of acquired hemophilia A is often
difficult, since the patient does not have a personal or
family history of bleeding episodes. Thus, the patient
may be seen by several specialists and subjected to
dangerous invasive investigations and interventions
before the correct diagnosis is made. To complicate
the diagnosis further, the clinical picture of acquired
hemophilia A differs from that of “classical” heredi-
tary hemophilia A. In fact, more than 80% of patients
with FVIII autoantibodies hemorrhage into the skin,
muscles or soft tissues and mucous membranes
(e.g. epistaxis, gastrointestinal and urological bleeds
and retroperitoneal hematomas), whereas joint bleeds,
typical of congenital factor VIII deficiency, are
unusual. Not rarely the hemorrhages in acquired
hemophilia A are serious or life-threatening, such as in
the case of rapidly progressive retroperitoneal hemato-
mas, compartment syndrome due to intramuscular
bleeds or cerebral hemorrhage . Other mani-
festations include prolonged postpartum bleeding
and excessive bleeding following trauma or surgery.
However, some patients with low titer inhibitors
remain clinically asymptomatic and are diagnosed
during routine blood examinations (e.g. prior to
The diagnosis of acquired hemophilia A is based on
the demonstration of an isolated prolongation of the
activated partial thromboplastin time (APTT), not
corrected by incubating the patient’s plasma with
equal volumes of normal plasma (mixing study),
associated with a normal prothrombin time (PT),
reduced factor VIII levels and formal evidence of a
factor VIII inhibitor in a patient with no previous
personal or family history of bleeding . The APTT
of the mixture of the patient’s plasma with normal
plasma must be measured before and after incubation
at 378C for 2h, because inactivation of FVIII is related
to both time and temperature. Furthermore, the
presence of heparin and lupus anticoagulant must be
excluded. The presence of heparin is suggested by a
prolonged thrombin time in association with a normal
reptilase time. APTT values of the mixing test
(patient’s plasma/normal plasma) that are similar at
time 0 and after incubation are indicative of lupus
anticoagulant (the diagnosis is then confirmed by
specific tests: dilute Russell’s viper venom time, kaolin
clotting time) [49,50]. The diagnosis of an inhibitor is
confirmed by specific assays of the factor and the
inhibitor using the Nijmegen modification of the
Bethseda assay . Since porcine FVIII concentrate
is not currently available, the search for inhibitors of
porcine FVIII is not recommended.
The IgG autoantibodies directed against clotting
factor VIII that develop in patients with acquired
hemophilia A are predominantly of IgG1and IgG4
subclasses . The FVIII autoantibody epitope
specificity is shown for the A2 and C2 domains of
the FVIII protein . Inhibitor antibodies may exert
the effect by interfering with thrombin cleavage of
FVIII or with the interaction of FVIII with activated
factor IX, factor X or phospholipid and von Will-
ebrand factor (VWF). The inactivation of FVIII
resulting from this interaction is, however, very
different between autoantibodies and alloantibodies.
In fact, whereas alloantibodies inactivate FVIII
activity completely (type I kinetics), autoantibodies
usually have more complex, exponential kinetics (type
II kinetics) undergoing an initial rapid inactivation,
followed by a slower inactivation or a period of
equilibrium in which some residual FVIII can still be
assayed in the patient’s plasma . Thus, the
Bethesda assay, which quantifies the in vitro inhibitor
titer, may underestimate the in vivo inhibitor potency
due to the complex, non-linear reaction kinetics and
complicate therapeutic choices and monitoring.
Treatment of acquired hemophilia A
The basic therapeutic strategy in patients with
acquired hemophilia A is to treat any bleeding
episodes and eradicate the autoantibody [54–58].
The treatment of bleeding episodes depends on the
level of inhibitor. Patients with a low titer of inhibitor
(,5 Bethesda Units [BU]/ml) can be treated with
concentrates of human FVIII, administered at large
enough doses to overwhelm the inhibitor so that
hemostatic levels of FVIII can be achieved .
Desmopressin, alone for the treatment of minor
bleeding episodes or in association with FVIII
concentrates, may also be effective in patients with a
low titer of inhibitor [59,60]. However, when the
inhibitor titer is high (.5BU/ml) the above men-
tioned drugs are ineffective. In the past heterologous
porcine factor VIII, which has a reduced cross-
reactivity with anti-human factor VIII antibodies [61–
63], was successfully used in such patients. However,
more recently, porcine factor has been substituted by
bypassing agents, which circumvent the site of activity
of inhibitors. Prothrombin complex concentrates
derived from plasma and containing activated vitamin
K-dependent coagulation factors are able to promote
hemostasis in the absence of factor VIII [64–66].
A major step towards the control of bleeding in
acquired hemophilia has been recently achieved with
the introduction of a new hemostatic agent, recombi-
nant activated factor VII (rFVIIa), which has been
shown to be clinically safe and effective as both first
and second line treatment for acute bleeding [67–75].
In a multicenter retrospective study, Hay and
colleagues  described the results of rFVIIa
Acquired hemophilia A
treatment of hemorrhages in 38 patients with acquired
bleedingepisodes inwhichrFVIIawas administeredas
salvage therapy, the response was good in 75%, partial
in 17% and poor in 8% of cases. The conclusion of the
analysis was that rFVIIa is a safe, useful and effective
treatment for bleeding in patients with acquired
hemophilia. Recently, Baudo and colleagues 
reported the data collected in the Italian Registry of
Acquired Hemophilia: bleeding was controlled in 90%
first-line therapy and in 1 case as salvage treatment),
thus suggesting the drug’s efficacy in this condition.
Treatment to eradicate the inhibitor is based on
immunosuppression which is aimed at neutralizing
the autoantibodies and inhibiting or eliminating the
cell clone responsible for their synthesis. The drugs
azathioprine, 6-mercaptopurine, cyclosporin, vin-
cristine and high-dose immunoglobulins, given
alone or in various combinations [76–84]. Pro-
spective, controlled clinical trials evaluating the
efficacy of the different therapeutic strategies have
not been performed, in part because of the
spontaneous remissions that can occur (particularly
in cases associated with pregnancy or drugs).
Extracorporeal removal of the autoantibody by
therapeutic plasmapheresis, or immunoadsorption
of immunoglobulins to staphylococcal protein A has
been employed in particular clinical situations such
as prior to factor concentrate treatment in patients
with a high titer of inhibitor and severe hemorrhage
or before surgery [85–88]. Features that are
prognostic of a better response to treatment are a
low level of inhibitor and a short interval between
the appearance of the inhibitor and the start of
immunosuppressive therapy . However, not all
patients require immunosuppression in order to
eradicate the autoantibody, since the inhibitor is
cleared naturally in up to one third of patients.
Thus, the appropriate treatment of patients with
acquired inhibitors to factor VIII essentially depends
on the natural history of any concomitant condition
and the clinical presentation of the coagulopathy.
Some patients, for instance those with postpartum
or drug-induced inhibitors, may require nothing
other than close observation (“watch and wait”),
since these inhibitors tend to disappear spon-
taneously within a few months after delivery or
drug discontinuation [1,3]. Idiopathic autoanti-
bodies, especially those at a low titer, may also
resolve spontaneously. Vice versa, the cases associ-
ated with an underlying autoimmune disease or a
often require a combination of immunosuppressive
therapy. However, given the risk of hemorrhage
eradication therapy must be attempted when there
are hemorrhagic symptoms or when the inhibitor
remains present even if the bleeding symptoms are
mild. Various prospective studies have shown that
steroid therapy is the treatment of first choice
[54,80]. In fact, a positive response is obtained
within 3 weeks in one-third of the cases and the
percentage of responses can increase to over 70% as
the treatment is continued. The inhibitor may recur
after withdrawal of prednisone. The dose used is 1–
2mg/kg/die for at least 3 weeks; thereafter the dose
is adjusted according to the therapeutic response.
Cyclophosphamide, in most cases associated with
prednisone, has been evaluated in various studies
and has been shown to produce a high rate of
complete and sustained remissions (above 50–70%,
on average), even in patients initially refractory to
[76,79,80]. It could be a first-line treatment, in
combination with corticosteroids, in selected cases,
or a second-line treatment for those patients in
whom initial treatment with corticosteroids fails to
produce a response. The dose of cyclophosphamide
used is 2mg/kg/die per os, for 3–6 weeks or until
complete remission, adjusting the dose according to
hematologic tolerance. High dose immunoglobulins
(HDIg), at a dose of 1g/kg/day for 2 days or
0.4g/kg/day for 5 days, have been shown to be
effective in reducing inhibitor titer or eliminating
the autoantibody in about 30% of cases [81,89,90]
and could be considered in those patients who do
not respond to standard immunosuppressive regi-
mens. There are reports of promising results from
the use of cyclosporin, 2-chloro-deoxyadenosine and
interferon alpha [82,83,91–95], but the data are
still insufficient. However, there is a growing body
of evidence on the efficacy and good tolerability of
anti-CD20 monoclonal antibody (rituximab), par-
ticularly in patients with low inhibitor
[96–98]. That said, there are many aspects of this
treatment that remain to be clarified, such as the
optimal dose, its mechanism of action, and its long-
induction (ITI) protocols have been proposed for
the eradication of autoantibodies against coagulation
factors [99–101]. Their efficacy and safety were
demonstrated by the Budapest protocol 
(human FVIII 30U/kg/die in the first week,
20U/kg/die in the second week and 15U/kg/die in
the third week combined with i.v. cyclophosph-
amide 200mg/die [total dose 2–3g] and i.v.
methylprednisolone [100mg/die in the first week
and then gradually tapered down over the sub-
sequent 2 weeks]). It was reported than more than
90% of the patients achieved a sustained complete
remission. Similar results were reported by Heidel-
berg’s group using the modified Malmo ¨ protocol
cyclophosphamide and corticosteroids) .
A prompt diagnosis and appropriate management are
The therapeutic strategy for this clinically severe
acquired hemorrhagic disorder is treat the acute bleed
and eliminate the inhibitor. While the new bypassing
agent rFVIIa has been shownto be safe and effective in
controlling acute bleeds in such patients, immuno-
suppressive therapy (corticosteroids and cytotoxic
agents, alone or in various combinations) has resulted
in long-term inhibitor suppression in up to 70% of the
cases. Moreover, the preliminary results of the new
therapeutic strategies (anti-CD20 monoclonal anti-
body and immune tolerance protocols) are very
encouraging and may further improve the prognosis
of patients with acquired hemophilia A.
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Acquired hemophilia A