MILD HEMOPHILIA

T R E A T M E N T O F H E M O P H I L I A
DECEMBER 2006 • NO 41
MILD HEMOPHILIA
Sam Schulman
Department of Medicine
McMaster University
Hamilton, Ontario

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Published by the World Federation of Hemophilia (WFH)
© World Federation of Hemophilia, 2006
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
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Additional copies are also available from the WFH at:
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Montréal, Québec H3G 1T7
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Tel. : (514) 875-7944
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Internet: www.wfh.org
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

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Table of Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Life expectancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Laboratory diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2
Molecular basis for mild hemophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Hemophilia A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Hemophilia B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4
Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

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Mild Hemophilia
Sam Schulman
Introduction
World Federation of Hemophilia Annual Global
Survey 2004, the proportion of patients diagnosed
In this monograph I will discuss the mild forms of
with mild hemophilia (34 per cent) was close to the
hemophilia A and hemophilia B, from epidemiology
proportion with severe hemophilia (43 per cent) in
and molecular basis, via diagnosis, to the treatment
countries with a gross natural product (GNP) per
options available. The emphasis is on features that
capita of more than US $10,000. In countries with a
are characteristic of the mild form. Therefore, for
GNP below US $2,000 per capita, the proportion
example, treatment with factor concentrates will
with mild hemophilia (18 per cent) was clearly
only be briefly mentioned.
lower than that of the severe form (50 per cent).
Classification
In a Swedish survey of all patients with hemophilia,
it was observed that the proportion with known
The severity of hemophilia has been defined by a
mild hemophilia increased from 35 per cent in 1960
traditional classification into three forms:
to 54 per cent in 1980.[3] In this case the change was
due to increased awareness and family investigations
• Severe form – factor level <0.01 IU/mL (<1% of
rather than to a change in GNP.
normal);
• Moderate form – factor level 0.01 to 0.05 IU/mL
In the Canadian Hemophilia Registry of February 2006
(1 to 5% of normal); and
(data provided by Dr. Irwin Walker) the proportion
• Mild form – factor level >0.05 to 0.40 IU/mL
of patients with the mild form was 62.3 per cent for
(more than 5 to 40% of normal).
hemophilia A and 42.7 per cent for hemophilia B,
out of a total population of 3,284 patients.
This definition has been published by the subcommittee
on Factor VIII and Factor IX of the Scientific and
In small countries, the best example probably being
Standardization Committee of the International
Iceland, the distribution can be extremely skewed.[4]
Society on Thrombosis and Haemostasis.[1]
However, particularly the upper limit for mild
Life expectancy
hemophilia is vague and may in different publications
The course of the disease is obviously less dramatic
vary from 0.25 IU/mL (25%) up to 0.50 IU/mL
in mild compared to severe hemophilia, and the life
(50%), which is the lower limit of the normal range.
expectancy is thus very close to that of the normal
The wider the range for definition of mild hemophilia,
population. Whereas an impressive improvement in
the greater the proportion of females will be. For
life expectancy was described in Swedish patients
example, in one study, using the definition “5 to
with severe hemophilia in the period from 1960
50%” to define mild hemophilia, the proportion of
to1980 (57 years) compared to the period from 1831
females was 10 per cent.[2] Females, who are generally
to 1920 (11 years), no such comparison could be
carriers of hemophilia, have the same risk of bleeding
made for mild hemophilia due to lack of data from
as a male with mild hemophilia at the corresponding
the early period. However, during the period of
factor level.
1960-1980, life expectancy was 72 years for patients
with mild hemophilia, compared to 75.5 years in
Epidemiology
the normal population.[5] This positive picture was
tragically changed by the emerging transfusion-
The prevalence of hemophilia in general in countries
transmitted viral infections, which affected patients
where diagnostic tools are readily available is about
with all forms of hemophilia. In the United Kingdom,
1 in 10,000 people. The proportion of those with the
the death rate during the period from 1977 to 1984
mild form of hemophilia varies between countries,
of 4 per 1,000 with mild or moderate hemophilia
over time in the same country, and between the two
increased to 85 per 1,000 in HIV-seropositive
types of hemophilia. This variation to a considerable
patients in 1991-1992.[6]
extent depends on the resources available and the
awareness of hemophilia among physicians. In the

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2
Mild Hemophilia
Diagnosis
certain molecular defects, as described below (see
‘Molecular basis for mild hemophilia’).
The diagnosis of mild hemophilia is often made as
part of a family investigation, accounting for example
Differential diagnosis
for 64 per cent of cases at two centres in the United
States.[2] In the other cases in this study, the diagnosis
Mild hemophilia A has to be differentiated from
was made after one or several bleeding episodes
certain forms of von Willebrand disease (vWD).
and at a mean age of 5.5 years. In a recent French
The latter is often also characterized by a reduced
study, the diagnosis of mild hemophilia was made
FVIII level, but in addition there may be a prolonged
at an average age of 2.4 years.[7] However, from
bleeding time, a prolonged closure time in the PFA-
time to time elderly persons will be diagnosed with
100 instrument, and of course a reduction of the
mild hemophilia, as a result of an investigation trig-
von Willebrand factor (vWF) level in plasma, which
gered by bleeding complications after surgery or
can be measured as antigen, ristocetin co-factor, col-
tooth extraction.
lagen binding activity, FVIII binding capacity, mul-
Bleeding is rarely spontaneous in these patients. In
timer formation, etc. The most challenging differential
fact, in the above-mentioned U.S. investigation, 92
diagnosis is the von Willebrand Normandy variant
per cent of bleeding events were precipitated by
(vWD type 2N).[11] As in mild hemophilia A, the
trauma.[2] The type of bleeding was less often in
FVIII level is typically between 5% and 30% without
the joint (30 per cent) than in soft tissues (53 per cent).
a prolonged bleeding time or reduced plasma vWF
level and the clinical picture may be similar.
Laboratory diagnosis
The differences between the two entities are shown
below:
Patients investigated for a bleeding diathesis are
typically first screened for platelet count, bleeding
Mild hemophilia A
von Willebrand
time, activated partial thromboplastin time (aPTT),
disease type 2N
and prothrombin time. Only the aPTT may be
abnormally prolonged, but this depends of the sen-
X-linked inheritance
Autosomal recessive
sitivity of the reagent and on the deficient factor
inheritance
level. Standardization of the method is crucial to
Mutation in FVIII gene
Mutation in vWF gene*
obtain reliable and reproducible results.[8] Many
Capacity of vWF to bind
Capacity of vWF to bind
hemophilia treatment centre laboratories missed the
FVIII: normal
FVIII: reduced
diagnosis of mild hemophilia using aPTT.[9]
Response to DDAVP:
Response to DDAVP:
shorter effect
A factor assay must therefore be performed if there
good
is clinical suspicion, even in the absence of a pro-
Response to FVIII concen-
longed aPTT. Unfortunately, even with a routine
Response to FVIII concen-
trate: Good only if vWF
present in concentrate
factor VIII (FVIII) assay, the resulting clinical diag-
trate: good
nosis can vary. In a study in the United Kingdom
*The mutation results in amino acid substitution in the
with plasma samples from three untreated patients
N-terminal part of the vWF molecule, where the FVIII
with hemophilia A, distributed to a large number of
binding site is located.
centres, one sample with a median level of 5.8%
yielded a range from 1.5% to 36%.[10] The most
Obviously, a similar problem can occur if the defect
accurate results were obtained from comprehensive
is at the other side of the binding, i.e., on the FVIII
care centres. It is thus important for every diagnostic
molecule at its vWF-binding site in the C1 domain.
laboratory to participate in a quality assurance pro-
In the following table are such variants shown
gram for the assays of factor VIII and IX, and also
according to the mutation and the resulting effect
to react and improve their performance if the result
on the binding to vWF:
is far from the expected number. The WFH plays an
active part in this respect with support for partici-
Mutation in
Reduction of
pation in such a quality assurance scheme for centres
FVIII gene
affinity for vWF
participating in a WFH-sponsored project, the
International External Quality Assessment (IEQAS)
Ile2098Ser
8-fold
scheme.
Ser2119Tyr
80-fold
Arg2150His
3-fold
There are additional difficulties in the diagnosis of
mild hemophilia using a factor assay in the case of

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Mild Hemophilia
3
These patients also have reduced secretion of func-
In certain geographical regions one mutation can
tional FVIII and thus by definition they have hemo-
dominate among patients with mild hemophilia
philia A.
due to a common founder effect. Such an effect has
been described in Iceland.[4] Also, in Northern
Another differential diagnosis is combined deficiency
Italy, 32 per cent of the patients have a duplication
of factor V (FV) and FVIII. Again, the FVIII levels
of exon 13 in the FVIII gene, which results in no
are as in mild hemophilia A, but the inheritance is
activity of the molecule and should result in severe
autosomal. The defect is neither in the FV gene nor
hemophilia. However, due to a phenomenon called
in the FVIII gene, but in one of the “chaperone”
“exon skipping,” one of the exon 13 twins is some-
proteins required for the post-translational processing
times not read (alternative splicing) resulting in a
and cellular secretion of these two structurally similar
few normal FVIII molecules and thus a phenotype
coagulation factors. The diagnosis is verified by
of mild hemophilia.[16]
also measuring the FV level. Typically, both the FV
and FVIII levels are in the 5 to 50% range.
Hemophilia B
Mild hemophilia B must be differentiated from con-
It has been estimated that in 97 per cent of patients
ditions characterized by combined deficiency of the
with mild hemophilia B, the underlying defect is a
vitamin K dependent factors (in addition to FIX also
missense mutation.[17] These mutations can cause
factors VII, X, and prothrombin [II]). This can be
reduced interaction with FVII-tissue factor and
acquired due to vitamin K deficiency, liver disease,
therefore reduced activation of FIX[18], decreased
or the use of vitamin K antagonist drugs such as
activity due to reduced affinity for FVIII[19], or
warfarin; or it can be congenital due to a mutation in
reduced activity if the amino acid substitution is in
the gene for γ-glutamyl-carboxylase or for vitamin K
the catalytic domain[20], a common mutation in the
epoxide reductase.
Amish population. Mutations in the carboxyterminal
portion of FIX (residues 403-415) result in impaired
Molecular basis for mild hemophilia
secretion of the factor from the hepatocyte[21], but
the secreted molecules have normal function.
Hemophilia A
The most spectacular type of mutation in the FIX
In a study of 101 patients with mild or moderate
gene results in low FIX levels until puberty, and
hemophilia A, most of whom were unrelated,
thereafter a rise by 5% per year up to a maximum
Schwaab et al described that underlying missense
of about 60%. This was first described in 1982 by a
mutations accounted for 86 per cent of the patients.[12]
Dutch group and is called hemophilia B Leyden.[22]
A minority of the patients have a much more pro-
It should be noted that even in the normal child there
nounced defect in FVIII activity than the amount of
is an increase of the FIX activity in parallel with the
circulating FVIII antigen and this is called Cross
maturation of the liver, but here the baseline is about
Reacting Material (CRM) positive. One explanation
50% and a major rise occurs already during the first
for this phenomenon was found in patients with
five years of life with a second rise during puberty.
mutations causing a change in the electrical charge
of the A2 domain of the FVIII molecule. This was
Figure 1
responsible for a more rapid degradation of active
Increase of the factor IX level with age in the normal
FVIII[13], so that although normal amounts of FVIII
population and in patients with hemophilia B Leyden.
are produced and secreted, the activity is diminished.
This mutation also appeared to be associated with
discrepancies in the one-stage and two-stage clotting
120
assays used for measuring FVIII. A few identified
100
mutations and the effect on the assays are listed below:
80
Normal
60
Hemophilia B
Mutation
FVIII
One-stage Two-stage
40
Leyden
domain
clot
clot
20
0
Ala284Glu14
A2
38%
10%
0 5 10 15 20 25 30 35 40
Ser289Leu14
A2
33%
9%
Arg531His13
A2
36%
19%
The point mutations associated with hemophilia B
Arg698Leu14
A2
30%
6%
Leyden have been identified in the promoter region
Arg698Trp14
A2
28-35%
10-15%
at nucleotide -20, -6, and –5, and in exon 1 at nucleotide
His1954Leu15
A3
106%
18%
+8 and +13. The promoter region of FIX contains a
Leu1932Phe14
A3
19%
7%

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4
Mild Hemophilia
binding site for hepatocyte nuclear factor 4 (HNF-4),
phenomenon known as tachyphylaxis. Since the
a transcription factor in the steroid hormone receptor
rise of FVIII is quite variable between patients (but
superfamily.[23] In hemophilia B Leyden the binding
reproducible from time to time), a test should be
of HNF-4 to this promoter region is impaired and
done in each patient to evaluate the response. In a
thereby also the transactivation of FIX. This is partly
population of 62 patients with mild hemophilia, 47
overcome by the increasing level of testosterone in
per cent responded to DDAVP with a doubling of
puberty.
the factor VIII level and a peak level above 30%.[25]
Predictors for a good response were a higher base-
Treatment
line level and older age.
Intranasal administration is also possible but requires
The use of factor concentrates is vital in patients
higher doses.
with the mild form of hemophilia in cases of major
surgery or trauma. The principles are the same as
DDAVP may be useful in patients with mild hemo-
for patients with severe hemophilia with identical
philia A and an inhibitor[26], since the antibodies
target levels and need for frequent bolus doses, at
may not inhibit the endogenous FVIII or not to the
least initially. The dose required to reach this target
same extent as exogenous FVIII.
level, whether given as bolus doses or as continuous
infusion, obviously decreases with increasing baseline
Hemophilia B
level of the deficient factor. However, for patients
A small but certain benefit of DDAVP has also been
with mild hemophilia, there are additional treatment
reported in patients with mild hemophilia B. Although
options. For minor procedures in patients with factor
the FIX level did not increase much (1.4 times), there
levels in the upper range of “mild hemophilia”
was a shortening of the aPTT and dental surgery
(approximately 20% factor level) treatment with an
could be performed with good result.[27] This is
inhibitor of fibrinolysis may be sufficient. This
probably a result of compensation from higher levels
approach, for example using tranexamic acid (20
of FVIII and vWF. It should be emphasized that this
mg/kg orally or 10 mg/kg intravenously every
effect of DDAVP is by no means as well document-
eight hours), should be used for any surgery involv-
ed as that in hemophilia A and it is of a much
ing mucosal membranes. For dental extractions,
smaller magnitude in hemophilia B.
mouth rinse (“swish and swallow”) with tranexamic
acid is efficient and safe (see WFH Treatment of
In patients with hemophilia B Leyden, attempts
Hemophilia Monograph No. 40, Guidelines for
have been made to anticipate the effect of puberty
Dental Treatment of Patients with Inherited Bleeding
by using anabolic steroids[28], but this is not a rec-
Disorders).
ommendable alternative due to many side effects.
Hemophilia A
Follow-up
In mild hemophilia A, an important alternative to
Patients with mild forms of hemophilia should not
factor concentrates is desmopressin (DDAVP).
be left without follow-up after the diagnosis has
Thirty years ago, Dr. Pier Mannucci discovered that
been established. Although the intervals between
DDAVP elevates the FVIII level about three-fold
visits can be longer than with the severe form, a
over baseline and is a useful strategy to provide
review of the patient every two to three years is
hemostasis during surgical procedures in these
vital. At this visit a bleeding history is taken; physical
patients.[24] The consequent and consistent use of this
exam (especially to identify arthropathy) is performed;
alternative mode of treatment saved many Italian
laboratory tests to identify complications of previous
patients with mild hemophilia A from transfusion-
transfusions (viral markers, factor inhibitor) are done;
transmitted viral infections in the late 1970s and
and information is given to the patient and/or his
early 1980s.
parents. This information should include signs and
symptoms typical for routine and dangerous types
The dose (0.3 µg/kg) is preferably given subcuta-
of hemorrhage, as well as appropriate response and
neously one hour before the procedure and may
treatment intervention. Self-injection of DDAVP is
have to be repeated every eight to 24 hours,
useful to teach patients with mild hemophilia A
depending on the extent of the surgery. However,
who bleed at least once per year.
repeated doses may cause fluid retention with
hyponatremia, and in sensitive subjects (children
and women at the time of delivery) seizures. The
effect may also decrease after several doses — a

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Mild Hemophilia
5
Inhibitors
and updated by regular visits, and to implement
appropriate diagnostic tools and treatment modalities.
Inhibitors occur also in mild hemophilia, most typically
after intensive exposure to factor concentrates.[29]
References
A suspicion was raised that continuous infusion of
factor concentrates may be more risky in this
1.
White GC 2nd, Rosendaal F, Aledort LM, et al.
respect than bolus injections.[29] However, this
Definitions in hemophilia. Recommendation of
remains to be proven.
the scientific subcommittee on factor VIII and
The cumulative incidence of inhibitors in patients
factor IX of the scientific and standardization
with mild hemophilia A has been reported to be 3
committee of the International Society on
to 13 per cent by the age of 33 in some populations.
Thrombosis and Haemostasis. Thromb Haemost.
These patients often have missense mutations with
2001; 85:560.
conformational changes at the site of an antigenic
2.
Venkateswaran L, Wilimas JA, Jones DJ, et al.
epitope on the surface of the molecule. The most
Mild hemophilia in children: prevalence, com-
common mutations that generate an inhibitor are
plications, and treatment. J Pediatr Hematol
Arg593Cys and Trp2229Cys. Patients with these
Oncol 1998; 20:32-35.
mutations have a 40 per cent risk of developing an
3.
Larsson SA, Nilsson IM, Blombäck M. Current
inhibitor.[30] In 60 per cent of these patients, tolerance
status of Swedish hemophiliacs: A demographic
occurs spontaneously about nine months after
survey. Acta Med Scand 1982; 212:195-200.
appearance of the inhibitor, but in the meantime
4.
Jensson O, Stenbjerg Bernvil S, Jonsdottir S, et
the inhibitor can cause severe bleeding and even
al. Mild haemophilia A in Iceland: clinical
deaths. Inhibitors in patients with mild hemophilia B
genetic studies of three families with the same
are extremely uncommon.
mutation. J Intern Med 1994; 235:443-450.
Conclusion
5.
Larsson SA. Hemophilia in Sweden: Studies on
demography of hemophilia and surgery in
Mild hemophilia is a neglected diagnosis. Patients
hemophilia and von Willebrand’s disease. Acta
with mild forms of hemophilia have generally not
Med Scand Suppl 1984; 684:1-72.
received the same degree of medical attention as
6.
Darby SC, Ewart DW, Giangrande PL, et al.
those with severe forms. Although justified to a cer-
Mortality before and after HIV infection in the
tain extent, this has not infrequently resulted in
complete UK population of haemophiliacs. UK
serious neglect. One of the first reports was in 1964
Haemophilia Centre Directors’ Organisation.
of an 18-year-old male with a delayed diagnosis
Nature 1995; 377:79-82.
after trauma-induced hemarthrosis, eventually
7.
Chambost H, Gaboulaud V, Coatmelec B, et al.
resulting in infection, osteomyelitis, and life-threat-
What factors influence the age at diagnosis of
ening sepsis, necessitating amputation of the leg at
hemophilia? Results of the French hemophilia
the hip joint.[31]
cohort. J Pediatr 2002; 141:548-552.
A review of all Swedish patients with hemophilia
8.
Ingram GI, O’Brien PF, North WR. The
in 1982 demonstrated the ironic situation that the
ICTH/WFH study of the partial thromboplastin
mortality in bleeding in the central nervous system
time in mild haemophilia. Scand J Haematol
was higher in mild than in severe hemophilia.[32]
Suppl 1980; 37:64-72.
Recently, in a Belgian-French study, intracranial
9.
Preston FE. Laboratory diagnosis of hereditary
hemorrhages were identified in 83 patients with
bleeding disorders: external quality assessment.
severe hemophilia, with fatal outcome in 17 (20 per
Haemophilia 1998; 4 Suppl 2:12-18.
cent); and in 40 patients with mild hemophilia, with
fatal outcome in 10 (25 per cent).
10. Preston FE, Kitchen S, Jennings I, et al.
SSC/ISTH classification of hemophilia A: can
Carriers of hemophilia with factor levels in the range
hemophilia center laboratories achieve the new
of mild hemophilia should receive the diagnosis of
criteria? J Thromb Haemost 2004; 2:271-274.
“mild hemophilia,” since there is a widespread con-
11. Mazurier C, Goudemand J, Hilbert L, et al.
cept that males have the disease and females are
Type 2N von Willebrand disease: clinical man-
“only” carriers.
ifestations, pathophysiology, laboratory diagnosis
It is of utmost importance to disseminate knowledge
and molecular biology. Best Pract Res Clin
about mild hemophilia, to keep patients informed
Haematol 2001; 14:337-347.

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6
Mild Hemophilia
12. Schwaab R, Oldenburg J, Schwaab U, et al.
23. Reitsma PH, Bertina RM, Ploos van Amstel JK,
Characterization of mutations within the factor
et al. The putative factor IX gene promoter in
VIII gene of 73 unrelated mild and moderate
hemophilia B Leyden. Blood. 1988; 72:1074-1076.
haemophiliacs. Br J Haematol 1995; 91:458-464.
24. Mannucci PM, Ruggeri ZM, Pareti FI, et al. 1-
13. Pipe SW, Eickhorst AN, McKinley SH, et al.
Deamino-8-d-arginine vasopressin: a new
Mild hemophilia A caused by increased rate of
pharmacological approach to the management
factor VIII A2 subunit dissociation: evidence
of haemophilia and von Willebrand’s diseases.
for nonproteolytic inactivation of factor VIIIa
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