SEMINAR

Seminar

Haemophilias A and B

Paula H B Bolton-Maggs, K John Pasi

The haemophilias are inherited disorders in which one of the coagulation factors is deficient. Although deficiencies of
factor VIII (haemophilia A) and factor IX (haemophilia B) are well recognised, von Willebrand’s disease is much more
common. Rare defects can occur in any of the coagulation factors. In the past, men with haemophilia were likely to die
in their youth. With advances in diagnosis, and especially with development of safe and effective treatment, affected
individuals can now look forward to a normal life expectancy. Complications of the disorder, particularly the
development of antibodies that make treatment ineffective, and of treatment, such as transfusion-transmitted
infections, have taken a severe toll on these patients. The future holds the realistic possibility of gene therapy.
However, we must not forget that haemophilia is a worldwide disorder that requires significant economic resources
not available for the majority.

The haemophilias are inherited bleeding disorders caused
by low concentrations of specific coagulation factors. The
most well known are deficiencies of factor VIII
(haemophilia A) and factor IX (haemophilia B), both of
which show X-linked inheritance. Factor XI deficiency
(originally called haemophilia C) is a less common and
in most cases mild bleeding disorder, autosomally
inherited and particularly common in Ashkenazi Jews. The
commonest inherited bleeding disorder is von Willebrand’s
disease, a defect in the quantity or quality of the von
Willebrand factor, present in perhaps as many as 1% of the
general population.1 This disorder is generally mild, but it
is an important cause of menorrhagia in affected kindreds.2
An important point to note is that the diagnosis is not
excluded by a normal coagulation screen. Congenital
deficiencies of other coagulation factors are rare. These
are autosomal recessive conditions that are therefore
more prevalent in communities where consanguinity is
common.3 This seminar focuses on recent advances in the
diagnosis and management of haemophilias A and B.
Haemophilias A and B are clinically indistinguishable
from each other. Diagnosis must be confirmed by specific
factor assay. The bleeding tendency is related to the
measured concentration of the factor and is classified as
mild, moderate, or severe (table 1).4 This classification
generally predicts bleeding risk, guides the optimum
management strategy, and predicts outcome. Although
most patients with severe haemophilia need regular
replacement therapy, a few rarely bleed and need only
occasional treatment. 15% of patients with severe
haemophilia in the UK had no record of treatment in a
year of observation.5 Coinheritance of thrombophilic
genes can modify clinical expression.6
Congenital deficiencies of coagulation factors are rare
disorders (table 2) requiring specialist management.
Haemophilia A occurs in all racial groups and can be
Lancet 2003; 361: 1801–09
found worldwide. In the UK, a national register has
been in operation since 1968; about 5000 individuals
with haemophilia A are registered.5 The prevalence of
haemophilia B is about a fifth that of haemophilia A.
Worldwide, there are estimated to be more than half a
million people with haemophilia (prevalence varying from
105 to 160 per million of the male population).7
Pathophysiology
Factor VIII is a complex plasma glycoprotein of
2351 aminoacids that is synthesised primarily by
hepatocytes, although kidney, sinusoidal endothelial
cells, and lymphatic tissues can also synthesise small
amounts of factor VIII.8 The protein contains a large B
domain of unknown function that is not required
for coagulant activity. It is one of the largest and
least stable coagulation factors, circulating in plasma
in a non-covalent complex with von Willebrand factor.
Factor VIII has a half-life of about 12 h in adults
(shorter in children). von Willebrand factor protects
factor VIII from premature proteolytic degradation and
concentrates it at sites of vascular injury.
Factor IX is a 415-aminoacid serine protease
synthesised in the liver and is the largest of the vitamin-
K-dependent proteins. Vitamin K is needed to
allow terminal gamma carboxylation of glutamic acid
residues to form the Gla domains, which are crucial
to normal function and biological activity. The
plasma concentration of factor IX is about 50 times
that of factor VIII, and factor IX has a half-life of
about 24 h.
Haemostasis and the role of factors VIII and IX
Bleeding occurs in haemophilia owing to failure of
secondary haemostasis. Primary haemostasis, formation of
the platelet plug, occurs normally but stabilisation of the
plug by fibrin is defective because inadequate amounts of
thrombin are generated.

Department of Haematology, Royal Liverpool Children’s Hospital, Search strategy

Liverpool (P H B Bolton-Maggs FRCPath) and Division of Haematology,
We searched PubMed with the keyword “haemophilia” followed
University of Leicester, Leicester Royal Infirmary, Leicester, UK
(K J Pasi FRCPath) by restrictions with subjects of the subtitles used in the
Seminar. As well as our personal archives, we searched
Correspondence to: Dr Paula Bolton-Maggs, Department of
abstracts of recent meetings of the World Federation of
Haematology, Royal Liverpool Children’s Hospital, Alder Hey,
Hemophilia and the International Society for Thrombosis and
Liverpool L12 2AP, UK
Haemostasis.
(e-mail: p.h.boltonmaggs@liv.ac.uk)

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For personal use. Only reproduce with permission from The Lancet Publishing Group.
 SEMINAR

Concentration of factor Classification Clinical

(VIIIC or IXC) Injury
<0·01 IU/mL Severe Spontaneous joint and IX IX
(<1% of normal) muscle bleeding; bleeding
after injuries, accidents,
IXa XIa
and surgery
VIIa VIIIa
0·01–0·05 IU/mL Moderate Bleeding into joints and
(1–5% of normal) muscles after minor
TF XI
TFPI Thrombin
injuries; excessive bleeding
activation
after surgery and dental
extractions
>0·05–0·40 IU/mL Mild Spontaneous bleeding X
(5–40% of normal) does not occur; bleeding Xa Va
after surgery, dental
extractions, and accidents Prothrombin Thrombin
Table 1: Classification of haemophilia4
Fibrinogen
Although the classic “waterfall” hypothesis of Fibrin
coagulation proposes two separate pathways, factors VIII
and IX are now known to be central to the process Figure 1: Schematic model of coagulation in vivo
of blood coagulation and for the adequate generation of Coagulation is initiated when tissue damage exposes tissue factor (TF).
thrombin (figure 1). After injury, activation of the Factor VII binds tissue factor and the complex then directly activates
factor X to factor Xa and some factor IX to factor IXa. In the presence of
complex of tissue factor and factor VII mediates factor Xa, tissue-factor pathway inhibitor (TFPI) inhibits further generation
generation of factor Xa. This production must be of factors Xa and IXa. After this inhibition, the amount of factor Xa
amplified by factor IX and factor VIII to allow coagulation produced is insufficient to maintain coagulation. Further generation of
to progress to completion. The revised scheme shows factor Xa, to allow haemostasis to progress to completion, can be
achieved only by the factor IX/VIII pathway. Sufficient thrombin has then
that in the absence of factor VIII or factor IX, bleeding been generated to activate factor VIII, and together with factor IXa
will ensue because the amplification and consolidating (generated by tissue-factor–factor-VIIa) further activation of factor X can
generation of factor Xa is insufficient to sustain proceed. Augmentation of factor IX activation occurs via thrombin
haemostasis. activation of the factor XI pathway.

Molecular genetics of haemophilia sense. Some 20–30% of cases of mild haemophilia B are
The genes for factors IX and VIII were cloned in 19829 due to a small number of founder mutations. About 7%
and 1984,10 respectively. This cloning has resulted in are short additions or deletions and about 3% gross gene
important advances in the molecular characterisation deletions or complex rearrangements. Substitutions in the
of the defects that cause the haemophilias and made promoter region of the factor IX gene classically result in
possible the production of recombinant clotting-factor the unusual factor IX Leiden phenotype.
concentrates for therapeutic use, the generation of
knockout animals to use as disease models of Haemophilia A: factor VIII gene mutations
haemophilia, and the production of wild-type and mutant The factor VIII gene spans 186 kb, consists of 26 exons,
proteins for structure–function analysis of proteins. and is on the long arm of the X chromosome at Xq28.
This gene is unusual since it has within intron 22 two
Haemophilia B: factor IX gene mutations additional genes F8A and F8B. Two further copies of F8A
The factor IX gene contains eight exons and measures exist outside (400 kb telomeric) the factor VIII gene. The
33·5 kb. It is located on the long arm of chromosome X at functions of the F8A and F8B genes are unknown.
Xq27. The factor IX gene is significantly smaller and less The most common genetic defect in haemophilia A,
complex than that for factor VIII. affecting about 45% of individuals with severe disease, is a
More than 2100 mutations in the factor IX gene are large inversion and translocation of exons 1–22 (together
recorded on an international database (www.kcl.ac.uk/ip/ with introns) away from exons 23–26, due to homologous
petergreen/haemBdatabase.html). Mutations have been recombination between the F8A gene in intron 22 and
described in all regions of the gene, the vast majority being one of the F8A copies lying away from the factor VIII
point mutations, with about two-thirds of these being mis- gene12,13 (figure 2). This mutation arises almost exclusively
in the male germline.14
Deficiency Estimated prevalence Gene on chromosome A haemophilia A mutation database has been compiled
of severe deficiency (per 106)* (http://europium.csc.mrc.ac.uk/usr/WWW/WebPages/mai
Factor VIII or 133 in 106 males† X n.dir/main.htm). Mutations, other than the intron
factor IX 22 inversion, are predominantly point mutations (about
Fibrinogen 1 4 85% mis-sense, 15% non-sense), with about 5% being
Prothrombin 0·5 11 large or small deletions and insertions. A similar inversion
Factor V 1 1
involving intron 1 of the factor VIII gene has also
Combined V
and VIII 1 18 been described in about 5% of patients with severe
Factor VII 2 13 haemophilia A.15 This rearrangement is the consequence
Factor X 10 13 of recombination between two repeated sequences (int1h-
Factor XI 1‡ 4 1, int1h-2), one within the factor VIII gene and one lying a
Factor XIII 0·5 6 (subunit A), distance away from the factor VIII gene, similar to the
1 (subunit B)
intron 22 inversion.
Modified from Peyvandi et al.3 *Factor concentration <10% of normal. †Data
from,7 combined factors VIII and IX, all severity. ‡Higher in Ashkenazi Jews,
among whom the estimated prevalence of severe deficiency is 1 in 190 and Inhibitor risk and molecular defect
8·1% of the population are heterozygotes.11 Inhibitor risk is associated with the type of mutation
Table 2: Prevalence of rare coagulation-factor deficiencies in present. In haemophilia A, patients with mutations
comparison with haemophilias A and B that severely truncate or prevent production of factor

1802 THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com

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Telomere Centromere
A A A Willebrand’s disease are mild; haemarthroses and muscle
1 22 23 26
Normal Factor VIII B VIIIC concentration is very low. There are several
A defective binding of factor VIIIC to von Willebrand factor
1 22 23 26
Intrachromosomal
recombination
A A
Severe haemophilia A
A A A B. The factor IXC concentration does not change
22 1 23 26
B (factor IX Leiden), in whom the concentration rises with
Figure 2: Schematic representation of one type of common
inversion of the factor VIII gene
The large intron IVS22 contains two nested genes F8A14 and F8B [B] with
two further telomeric copies of sequences homologous to F8A.
Orientation is indicated by the arrow. Owing to intrachromosomal
crossing-over between the homologous F8A sequences, a relocation and
inversion of exons 1–22 away from exons 23–26 occurs, resulting in
severe haemophilia A.
VIII (intron 22 inversion, large deletions, non-sense
mutations) have a much higher frequency (about 35%) of
inhibitor development than those carrying mis-sense
mutations and small deletions (about 5%) in whom some
protein may be produced. In haemophilia B, patients with
gene deletions or rearrangements have a risk of inhibitor
development of about 50%, whereas for frameshift,
premature stop, or splice-site mutations the risk is about
20%. For those with mis-sense mutations, the risk of
inhibitor development is almost zero.16
Diagnosis
Haemophilia is diagnosed either because of a known
family history (which is absent in a third of
haemophiliacs) or after presentation with bleeding. Most
children with severe haemophilia are born uneventfully by
vaginal delivery. The estimated risk of intracranial
haemorrhage in the neonatal period is 1–4%,17 and this
event is most likely within the first week. Some
researchers suggest prophylaxis at18 or before birth, but
this practice has not been widely adopted in Europe.
Bleeding is a particular risk after vacuum extraction.19
When the family history predicts the possibility of an
affected child, good communication between obstetrician,
paediatrician, and haematologist is essential. Most
children are free of symptoms until they learn to crawl or
walk. The hallmark of severe haemophilia is spontaneous
bleeding into joints and muscles, painful and destructive if
inadequately treated. Most children with severe
haemophilia experience their first bleed into a joint by age
4 years, but many bleed from other sites before this age.20
Affected toddlers bruise easily, and suspicion of non-
accidental injury may arise and complicate the early
management of a difficult and traumatic diagnosis.
Moderate haemophilia is diagnosed in most cases by the
age of 5 years, but mild haemophilia may be diagnosed
much later in life after trauma or surgery. The factor
VIIIC concentration does not change significantly with
age in haemophilia A.
Factor VIIIC deficiency due to haemophilia A must be
distinguished from von Willebrand’s disease by assays of
von Willebrand factor. The family history (autosomal
THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
SEMINAR
inheritance) and bleeding symptoms (menorrhagia,
easy bruising, and epistaxis) differ. Most cases of von
bleeds occur only in the most severe type 3 (uncommon)
in which von Willebrand factor is absent and the factor
subtypes of von Willebrand’s disease,21 including one with
(Normandy variant22). The amount of von Willebrand
factor present is normal, but binding is abnormal. This
diagnosis must be excluded in families with apparent
moderate or mild haemophilia A, particularly if some
female members have low factor VIIIC concentrations.23
A factor IX assay confirms the diagnosis of haemophilia
significantly with age in affected people except for those
with mutations in the promoter sequence of the gene
hormonal changes at puberty. Severe haemophilia B
becomes mild, and those with mild haemophilia B may
develop a normal concentration of factor IXC.
Identification of these families is important because of the
improved outlook.24–26
Haemophilias A and B are X-linked disorders; because
the mean factor concentration in carriers is about half
normal, a substantial proportion of female carriers have
low concentrations of factor VIIIC or IXC, which can
predispose to excessive bleeding, in effect mild
haemophilia. Factor concentrations should therefore be
measured in girls and women who are definite or possible
carriers. Factor VIIIC concentrations should be measured
on more than one occasion because the concentration
increases under stress. A reproducibly normal
concentration does not exclude carrier status, which can
then be identified only by mutation detection. Such
genetic testing is not advisable until the girl is old enough
to consent for herself (in most between 12 and 16 years).
Careful explanation is required for the women in the
family so that they do not assume, because their factor
concentration is normal, that they are not carriers. The
inheritance pattern is shown in figure 3. Rarely, females
have severe haemophilia. The genetic mechanisms for this
can be extreme lyonisation, Turner’s syndrome (XO), or
Carrier female
XX X X XY
Haemophilic male
X Y
X Y X Y X Y X X X X
X X X X X Y X Y X X X X X Y
III.v
III.vii
X Y
Figure 3: Inheritance of haemophilia
All the daughters of a haemophiliac will carry the abnormal X (X); none of
his sons will be affected. Individual III.v shows that haemophilia can occur
in an individual who at first sight appears remote from an affected
individual, and the importance of drawing an accurate pedigree and
ensuring that all potential female carriers are aware of their risk. III.vii has
a 1 in 2 chance that any son will have haemophilia.
1803
 SEMINAR
carriage of a mutation by both parents (father with
haemophilia and mother a carrier). Once haemophilia is
diagnosed in a family, it is very important for the clinician
to take a careful family history (including several
generations and ensuring accuracy in the family
relationships) and to construct an accurate pedigree as
preparation for counselling of other family members at
risk either of having the abnormality or of passing it on to
their descendants, issues interestingly covered in a recent
novel.27
Management
There is currently no cure for haemophilia A or B. The
mainstay of treatment is to raise the concentration of the
missing factor sufficiently to arrest spontaneous and
traumatic bleeds or to cover surgery. The factor VIIIC
concentration can be raised effectively in mild
haemophilia A and mild von Willebrand’s disease by use
of desmopressin, an analogue of antidiuretic hormone.28
Most people with severe haemophilia are on therapy at
home with intravenous infusion of the relevant missing
factor and are rarely admitted to hospital. The hallmark of
severe haemophilia A and B is repeated bleeds into joints
(as often as weekly) and muscles. Joint bleeds are
exquisitely painful, and blood is irritating to the synovial
lining. Early adequate treatment stops the bleeding and
limits the damage. Persistent or recurrent joint bleeding
results in synovial hypertrophy, predisposes to recurrent
bleeding (target joints) with progressive damage of the
cartilage and subchondral bone.26 In the long term,
inadequately treated individuals can become incapacitated
by progressive severe arthropathy with fixed flexion and
other deformities particularly of the large hinge joints
(knees, ankles, and elbows). Associated muscle wasting
can be profound, and at worst, the young adult becomes
immobile and confined to a wheelchair. Why joints and
muscles should be the main sites of bleeding in severe
haemophilia is not understood.
Muscle bleeds may threaten life or limb owing to
compression of blood vessels and nerves. Now that
effective therapy is available, the potential severity of these
bleeding disorders, in which death has resulted from very
trivial injuries such as a bitten tongue or cut finger, can
sometimes be forgotten.29 Any bleeding episode in a
person with severe haemophilia must be taken seriously
and treated promptly.
Effective treatment for haemophilia became available
quite recently but has had a profound impact on the
outlook for people with severe haemophilia. Jones wrote
in his account of the early history of haemophilia
treatment that his first patient with the disease had been
in hospital 27 times and had seen 17 different doctors
before he was 5 years old.30 Employment prospects were
bleak, and life expectancy short. Today a 5-year-old child
with severe haemophilia treated with prophylaxis may
never have experienced a bleed, will be in full-time normal
school, and will be encouraged to lead a normal life with
few restrictions. Plasma-derived factor VIII and IX
concentrates became widely available in the 1970s,
resulting in very effective treatment of bleeding episodes
and the development of self-infusion and home therapy
programmes. Effective therapy permitted surgery,
including major orthopaedic procedures with restoration
of joint function. Continued manufacturing advances
resulted in products of higher purity with fewer
contaminants. Viral inactivation steps were introduced in
1986 to eradicate transmission of HIV and hepatitis C
virus. Genetically engineered (recombinant) factor VIII
concentrates became available from 1992, and
1804
For personal use. Only reproduce with permission from The Lancet Publishing Group.
recombinant factor IX, unique in containing no animal or
human proteins, in 1999. The third-generation
recombinant factor VIII products will also be free of
animal and human proteins. Recombinant products are
the treatment of choice if available and affordable,
because they eliminate the risk of transmission of human
and animal infectious agents.
Treatment “on demand” or prophylaxis?
Bleeds can be treated as they occur (on demand) or
treatment can be given regularly to prevent bleeds
occurring (prophylaxis).
Prophylaxis
The aim of prophylaxis is to abolish spontaneous joint
bleeding. Patients with moderate haemophilia (baseline
factor concentrations above 1% of normal) generally have
few spontaneous joint bleeds and rarely suffer long-term
joint damage. Prophylaxis was pioneered in Sweden31 and
is now the recommended strategy for children with severe
haemophilia. Other groups have confirmed the benefit of
regular and adequate treatment (three times a week, or
alternate days, in haemophilia A, and twice a week in
haemophilia B). This approach prevents joint bleeds and
therefore their long-term consequences.32–38 Prophylaxis is
demanding for young children and their families, and
many questions remain. At what age should prophylaxis
begin? When can it be stopped? Prophylaxis is expensive
in the short term (cost of products) but is probably cost
saving in a lifetime if the adult has normal joints, normal
education without interruptions, and normal activity and
employment prospects—a very different scenario from
that for adults of earlier generations. There is limited
information on lifestyle and quality-of-life issues.39,40 Some
of these questions are being addressed in clinical trials.
Prophylaxis should begin by the age of 4 years, by which
time most affected children will have experienced their
first joint bleed.20 A stepwise start (infusions given weekly
into peripheral veins from the age of 12–18 months) is an
acceptable and realistic goal.41 Much depends on the
tolerance of the child and his family. Central venous lines
can be used, but they can cause complications42–46
particularly infection (25–30%), and haemophiliacs may
develop central venous thrombosis.47
Complications (panel)
Transfusion-transmitted infections
The benefits of replacement therapy came at a significant
cost. Two forms of hepatitis (B and C) have been
recognised since the late 1970s as complications of
plasma-derived concentrates made from large plasma
pools (up to 20 000 donations).48–51 Hepatitis B was
common, in most cases resulting in clearance of the virus
and immunity. Non-A, non-B hepatitis (hepatitis C),
initially thought to be of little importance, has serious late
complications.52,53 A small proportion of patients (around
Complications of haemophilia
Complications of the disorder
Recurrent joint bleeding leads to chronic arthropathy, pain, and
loss of function
● Crippling
● Death from haemorrhage
Complications related to treatment
Transfusion-transmitted infections (risk reduced with virally
inactivated concentrates; risk probably eliminated with
recombinant products)
Development of antibodies (inhibitors)
THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com

10%, and especially children) may clear the virus, but
most adults have chronic infection with slow progression
to cirrhosis of the liver and, in some, malignant disease.54
The risk of end-stage liver disease is higher in patients
coinfected with HIV, those with hepatitis B antigenaemia,
and older individuals.55 In some patients, hepatitis C virus
can now be cleared by use of a combination of interferon
and ribavirin.56 Some haemophiliacs have been cured of
both hepatitis and haemophilia by liver transplantation.57
Enveloped viruses (hepatitis B and C viruses and HIV)
are no longer transmitted by plasma-derived concentrates,
but the risks of transmission of non-enveloped viruses
(hepatitis A and parvovirus) have not been completely
eliminated.58 All people with coagulation disorders should
be vaccinated against hepatitis A and B. There is no
vaccine against parvovirus, and concern remains about the
possible impact of transmission by plasma-derived
products.59 This virus was thought to be of little clinical
consequence, but it has resulted in serious illness in one
immunocompetent adult with mild haemophilia A, and
transmission was also documented in a female carrier of
childbearing age.60 Parvovirus infection can have serious
consequences in the fetus, leading to severe anaemia and
hydrops fetalis. Wherever possible, plasma-derived
concentrates should have been subject to two viral
inactivation steps.
HIV infection in haemophilia was reported in 1981, and
in the UK more than 1200 individuals were infected by
blood-product infusions between 1979 and 1985 when
viral inactivation steps were introduced. More than half
these individuals have died. No new cases of HIV
infection from virally inactivated blood products have
been detected since 1986. Treatment of HIV infection has
become complex; combination drug therapy is highly
effective but use of some protease inhibitors has been
associated with an increased risk of bleeding, the cause of
which is not clear.61–63 Mortality statistics showed that the
commonest cause of death in haemophilia changed from
intracranial haemorrhage before the availability of
effective treatment to treatment-related deaths in the
1980s and 1990s, mainly related to HIV infection and
liver disease.64 Concern has more recently arisen that
variant Creutzfeldt-Jakob disease may be transmitted by
plasma-derived concentrates, but to date there is no
evidence of such transmission, and research shows that
protein-purification steps in manufacture are likely to
remove prions effectively.58
Inhibitor development
Development of antibodies (inhibitors) to infused factor is
a serious complication, occurring mainly in severe
haemophilia, and commoner in haemophilia A (30–50%
of patients) than in haemophilia B (1·5–3·0% of
patients).65 Factor VIII inhibitors may be either low-titre
(commonly transient) antibodies, overcome by increased
or continuing treatment with factor VIII concentrates, or
more serious high-titre, highly responding antibodies,
which preclude treatment with factor concentrates. There
is a higher frequency in black than white patients.66 The
risk of developing antibodies is highest within the first
20–100 treatments, irrespective of product, most cases
therefore becoming evident in young children. There is
some relation to genotype (inhibitors are more likely to
develop in patients with deletions). Young haemophiliacs
are therefore monitored regularly for inhibitor
development. The prevalence in haemophilia A in the UK
is 6%.64 Surveillance is closer now than previously;
transient low-level inhibitors are detected which perhaps
would not have been seen in the past.67
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SEMINAR
The management of patients (mostly small children)
with highly responding inhibitors is difficult. Acute
bleeding episodes may respond to plasma-
derived activated-prothrombin-complex concentrates—
a mixture of activated clotting factors that may be able
to bypass factor VIII activity. However, recombinant
activated factor VII is effective for acute joint bleeds
with the advantage of not being derived from pooled
plasma.68,69 Although expensive, use of this form early
is cost effective,70 not only for pain relief, but also
to reduce the risk of long-term joint damage with
its limitations on lifestyle, education, and employment
prospects. Major orthopaedic and other surgery
is possible with use of recombinant activated
factor VII.71,72
Highly responding inhibitors can be eradicated by
immune tolerance regimens, with regular infusion of
factor concentrates over long periods, in some cases
with additional immunosuppression and immuno-
adsorption.73 Successful treatment is associated with a
low inhibitor titre at the start, a low historical peak
inhibitor titre, an interval of less than 2 years between
inhibitor diagnosis and initiation of the immune
tolerance regimen, uninterrupted schedules, and
probably high-dose regimens.67,74 This approach is
expensive and demanding for the child and family, and
in many cases a central venous line is needed. Since
most inhibitors develop in small young children, and
because the long-term consequences of inhibitors in
terms of joint damage can be so severe, in the long term
investment in an immune tolerance regimen is cost
effective, and these regimens are effective in about
85% of cases in haemophilia A.75 An international
randomised controlled trial is under way to define the
optimum regimen. Inhibitors of factor IX are less
common, and the response to immune tolerance (up to
50% of cases) less good.75 Factor IX antibodies can be
associated with other features of allergy, particularly
anaphylaxis,76 and some patients on immune tolerance
have developed the nephrotic syndrome.77,78 Large gene
deletions (1–3% of patients) are associated with a high
risk of inhibitor development in factor IX deficiency
(50%), and these patients are at particular risk of
anaphylaxis.79,80 The best treatment for acute bleeds in
children with factor IX inhibitors is recombinant
activated factor VII.81
Gene therapy for haemophilia
Haemophilia is an ideal target for gene therapy because
only a small rise in factor concentrations to more than
1–2% of normal would achieve the goals of prophylaxis
without regular infusions of concentrate and would
deliver a substantial improvement in lifestyle for patients
with severe haemophilia.
The ultimate gene therapy for haemophilias A and
B would be direct correction of the molecular defect
in the mutated gene. Such direct gene modification
has been demonstrated,82,83 but for haemophilias A and
B this approach remains a long way in the future. Gene
therapy for haemophilia today, therefore, relies on
addition of normal factor VIII or IX genes. With
present technology, gene therapy can offer the
prospect of a true cure for haemophilia in animal
models, although this is not currently realisable in
human beings.
More than 25 patients with haemophilia have
now been treated in phase I gene-therapy protocols. No
study has conclusively shown that therapeutic
concentrations of factors VIII and IX can be reliably
1805
 SEMINAR

one patient to date. This patient experienced some

1·6 transient liver toxicity and thrombocytopenia at a
1·4 <13 years dose lower than might have been expected to cause
>19 years toxicity in primate models. Sustained concentrations
1·2 of factor VIII of about 0·01 IU/mL have been
1·0 observed over several months. Accrual to the study
Ratio

0·8 continues.
1·5 All human studies have been preceded by animal
0·6
trials that have generally shown greater rises in factor
0·4 VIII and IX than have been seen in the human trials;
0·2 thus, animal studies can be only a rough guide to human
0·3
response.
0
No haemophilia Haemophilia Haemophilia remains a prime target for gene therapy.
treatment centres treatment centres However, haemophilia is no longer a life-threatening
disease with current therapy that is both safe and
Figure 4: Relation of economic capacity and numbers of adult effective. A balance between the benefits and theoretical
haemophilia patients: effect of national haemophilia programmes risks must be taken into account when gene-based
Gross national product per person <$2000. approaches to therapy are being considered.91,92
Concerns about insertional mutagenesis and the safety
obtained, although none have highlighted significant of some viral vectors that randomly insert genes
safety concerns.84 through the genome have recently resurfaced since the
The first trial reported used intramuscular injection of development of a haematological malignant disorder
a factor-IX-containing recombinant adeno-associated in a child treated with a retroviral vector.93 Particular
virus in adult patients with severe haemophilia B. questions also remain as to whether gene therapy
Only very small increases in the concentration of and the production of ectopic factors VIII and IX
factor IX (rise of <0·02 IU/mL) have been observed, in will be a risk for inhibitor development or indeed
two of the eight patients enrolled, although there was whether this approach might promote tolerance in
a decrease in the amount of factor IX concentrate patients with inhibitors. The consequences of gene-
needed in three of the six participants.85,86 A similar transfer protocols on the natural history of HIV
study is under way with the same viral vector via and hepatitis C virus (with liver-directed therapies)
intrahepatic-artery infusion. remain unknown. Concerns have also arisen over the
For haemophilia A, three systems have been tried. transient appearance of the viral vector in the semen of a
The first involves ex-vivo addition of factor VIII gene to treated patient.
autologous fibroblasts and laparoscopic reimplantation.
Preclinical assessments showed the safety of the Organisation of haemophilia care and global
approach and durable expression of factor VIII perspectives
(0·05 IU/mL) for longer than a year in mice after a Bleeding disorders are rare and require specialist
single treatment.87 However, of six adult patients management. In the UK, a network of centres was
treated, four have repeatedly shown an improvement in initiated in 1968 and has been progressively developed
factor VIII concentration (0·5–3·5% rise), with two also since then with the definition of 22 comprehensive care
showing a decreased bleeding frequency and use of centres. These provide 24 h clinical and laboratory
factor VIII concentrate.88 No improvements lasted support plus specialist orthopaedic, dental, and
beyond 10 months. HIV services. There is an associated network of 80
The second protocol uses a murine leukaemia other haemophilia centres. The establishment and
retrovirus containing factor VIII, injected intravenously. maintenance of an associated national register of people
This is a development of the promising preclinical with bleeding disorders has resulted in a unique record
data in rabbits and haemophilic dogs.89 None of the and in several publications. The UK Haemophilia
13 patients enrolled have sustained concentrations of Centre Doctors Organisation works with patients’
factor VIII above 0·01 IU/mL.90 and other organisations (the Haemophilia Society
The third study, with a modified, “gutless”, and Haemophilia Alliance) to provide standardised and
adenovirus containing factor VIII gene, has recruited optimum care for patients across the UK
and continuous development of guidelines. All
Country Population % of patients Number of Factor VIII
people with bleeding disorders should be linked to such
(millions) diagnosed haemophilia use per head centres. Similar models exist elsewhere in more
treatment developed countries.
centres Haemophilia diagnosis is specialised, and
Australia 19 95 15 3·00 management is potentially expensive. Global surveys
USA 278 87 140 3·40 by the World Federation of Hemophilia (www.wfh.org)
Germany 82 82 6 5·50 document more than 100 000 people with haemophilia
Iran 63 82 10 0·50 in 89 countries. Most of these people do not have
Russia 146 81 4 0·10
Egypt 63 75 7 0·10
access to adequate treatment. Worldwide there are an
South Africa 42 52 10 0·60 estimated half million people with haemophilia, less
India 998 12 56 0·01 than a third of whom are diagnosed. The outlook
China 1227 5 ·· ·· for people with severe haemophilia differs substantially
Indonesia 207 4 8 0·01 between countries with a strong economy and
Bangladesh 128 2 ·· ··
those with major economic constraints. Replacement
Data from World Federation of Hemophilia Global Survey, 2002.7 therapy may not be easily provided, but a substantial
Table 3: Global comparisons in the provision of haemophilia effect on quality of life and life expectancy can be
centres and treatment made by development of national haemophilia

1806 THE LANCET • Vol 361 • May 24, 2003 • www.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

programmes and local blood transfusion services.7
Data from the World Federation of Hemophilia
show that survival into adulthood is greatly increased
not only by the development of treatment centres
(figure 4) but also by the use of replacement therapy.
Optimum survival is associated with a rate of use
of replacement therapy of at least 1 unit per head
(such as in the USA and Europe; table 3). In countries
with weaker economies (such as Iran, Russia, and
Egypt), many patients can be diagnosed but the rate
of use of factor replacement is lower (table 3). In
countries with major economic constraints (such as
India, China, and Bangladesh) most people with
haemophilia remain undiagnosed, and the ability to
give effective treatment is very low. Many people with
haemophilia in these countries probably die without
ever being diagnosed.7 There are several reasons:
haemophilia in these countries is not a government
priority, the medical infrastructures are inadequate, and
these factors are generally associated with poorly
developed blood-transfusion services.
The World Federation of Hemophilia has developed a
network of training centres and promotes twinning
between centres in more developed countries and
partners in less developed countries as an effective way
of sharing expertise.94 Twinning is a formal two-way
collaboration between two haemophilia treatment
centres, with the aim of helping emerging treatment
centres to improve haemophilia treatment and
diagnosis. The programme started in 1994, and there
are more than 30 partnerships at present. The
development of good laboratory diagnosis is paramount
and is aided by international training fellowships,
practical workshops in less developed countries, and
participation in international quality-assurance
schemes. Twinning partnerships between haemophilia
patients’ organisations are also very valuable for
sharing knowledge in areas such as advocacy
for patients, management, and fundraising. The World
Federation of Hemophilia is committed to developing
a Global Alliance for Progress to make significant
improvements in haemophilia care in some of the poorer
countries by assisting the implementation of national
haemophilia programmes. The objectives are to
introduce or improve national programmes in 30–40
countries, increase the number of people diagnosed
from 120 000 to 170 000, to ensure that these newly
identified patients have access to basic care, and to
ensure that those currently diagnosed but untreated
have access to basic care.7
Conflict of interest statement
KJP has received research grants from NovoNordisk, and has done
consultancy work for Wyeth Genetics Institute and Astra Zeneca. PBM
has received travel grants from Bayer, Wyeth, and Aventis, and has
done consultancy work for Baxter: these are companies that
manufacture coagulation factors.
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Uses of error
Continuity of neonatal care
Maureen Hack
Neonatal intensive care has resulted in the ability to sustain
life for extremely small and immature infants. An important
aspect of this care is the counselling of parents on the
appropriateness of initiation of such care in the delivery
room, and the withdrawal of care for some infants who have
a very poor prognosis.
In the late 1980’s, I took over the care of a three month
old African-American female infant who had been born
with a birthweight of 550 g at 24 weeks’ gestation. The
infant, who initially had respiratory distress syndrome,
developed severe chronic lung disease and was ventilator-
dependent with an increasing need for oxygen and
ventilator support. Throughout the first three months she
had repeated setbacks with episodes of infection, poor
nutrition, and subsequent poor growth.
The attending neonatologists rotate in the neonatal
intensive care unit on a monthly basis, and I had not
previously taken care of this infant. The infant’s pulmonary
status continued to deteriorate during the first two weeks of
my month as neonatal attending. I thought it appropriate to
initiate a care conference with the family, mid-month, to
discuss the very poor prognosis and the possibility of
discontinuing treatment. At this meeting I informed the
family of the very high probability of the infant dying during
the next few months and the ongoing suffering of this
ventilator-dependent child. The mother, who was single,
and her mother, participated in the discussion. The mother
was highly invested in the child and not only refused any
discontinuation of care, but also complained to the nurses
of a possible racial bias on my part in wanting to terminate
the life of her infant. I had been born and received my
medical degree in South Africa. The infant’s pulmonary
status continued to deteriorate and despite all medical and
technologic measures, she expired about six weeks later.
Rainbow Babies and Children’s Hospital, Case Western University, 11,100 Euclid Avenue, Cleveland, Ohio 44106, USA (M Hack MB)
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SEMINAR
90 Powell JS, Ragni MV, White GC, et al. Phase 1 trial of FVIII gene
transfer for severe hemophilia A using a retroviral construct
administered by peripheral intravenous injection. Thromb Haemost
2001; 86: OC2489.
91 Miller R, Fields PA, Goldspink G, Lee CA, Pasi KJ, Perry DJ.
Somatic gene therapy for haemophilia: some counselling issues for
today and tomorrow. Psychol Health Med 2002; 7: 163–73.
92 Dimicheck D, Miller FG, Fins JS. Gene therapy ethics and
haemophilia: an inevitable therapeutic future? Haemophilia 2003; 9:
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serious adverse event after successful gene therapy for X-linked
severe combined immunodefficiency. N Engl J Med 2003; 348:
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94 Giangrande PLF, Mariani G, Black C. The WFH Haemophilia
Centre twinning programme: 10 years of growth, 1993–2003.
Haemophilia 2003; 9: 240–44.
My “error” was both institutional and possibly
personal. The monthly rotation of the neonatal attending
in the intensive care unit in academic centres is scheduled
to provide physicians with the opportunity to partake in
other academic activities, including research, and to
provide respite after working in the neonatal intensive
care unit, which is both physically and emotionally
draining. This type of work schedule does not allow for
continuity of care for infants who develop chronic
sequellae of prematurity. I was thus unaware of the
family’s unrealistic investment in the life of their child.
Although I had left South Africa over twenty years
earlier, I still had a colonial accent and, to this family,
represented the racist apartheid regime.
My experience in North America has implications for
working with immigrant families of varying ethnicity and
religious and cultural backgrounds in other parts of the
world. Since many of these families are poor and at risk
for perinatal complications, their infants are hospitalised,
with greater frequency, in neonatal intensive care units. It
is extremely important to be aware of the varying cultural
and ethnic backgrounds of the families and their diverse
perceptions of neonatal intensive care and, in some cases,
their unrealistic expectations. Since my experience in the
1980s our neonatal department has initiated a system
whereby parents of infants with chronic conditions
identify a neonatologist for the total duration of hospital
stay. This primary physician may not actively participate
in the care throughout this period, but has the confidence
of the family and is available for care conferences and to
participate in critical decisions concerning their infant.
Since many of the infants are discharged home on
oxygen, we also provide continuity of such supportive
care in the follow-up clinic.
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