Discussion
Previous investigations of adult hemophilia carriers, including an
investigation of the ATHNdataset, have shown that roughly one-fourth
meet criteria for having hemophilia.1,4 Our
investigation of pediatric carriers enrolled in the ATHNdataset showed
nearly half of pediatric carriers meet current criteria for having
hemophilia. There are several potential explanations for the high
proportion of pediatric carriers in this study having hemophilia. One is
that there could be ascertainment bias in the ATHNdataset. Pediatric
carriers with hemophilia (and more likely to have abnormal bleeding) may
be more likely to be seen at a HTC, thereby skewing the data. However,
of those reporting a BLS, the majority reported a normal BLS for age,
and the median BLS was 0. This suggests that recruitment of subjects
with a higher bleeding risk may not be skewing the data to a significant
extent. Also, similar ascertainment bias may exist in studies of adult
carriers. Pre-analytical or analytical errors are another possible
explanation. However, these specimens were handled by HTCs well versed
in handling blood specimens for hemophilia patients. Also, many of the
subjects in this study are seen at the same HTCs that also see adults.
Factor VIII is an acute phase response protein and if anything, the
stress of phlebotomy in a child might lead to falsely elevated factor
VIII activity levels. Pre-analytical and analytical issues are unlikely
to explain the high proportion of pediatric carriers with hemophilia
enrolled in the ATHNdataset compared to adult carriers with hemophilia
enrolled in the same database. It is known that factors VIII and IX
levels rise with age, and the mean factor activity level in child and
adolescent carriers was lower than that reported for
adults.2,8,9 This could explain the difference in
proportion of those reporting a factor activity below 40 IU/dL in adults
compared to pediatric carriers.
Of those reporting a BLS, a minority (9.7%) of pediatric carries with
factor activity levels >40 IU/dL in the ATHNdataset report
BLS that were abnormal for age. Abnormal bleeding with normal factor
activity levels is a consistent finding in multiple studies of adult
carriers as well and seems to be more prevalent than in
children.1-3 Again, it is possible that bias could
explain this finding. A very small, single institution study showed a
higher BLS for carriers that knew their carrier status prior to
obtaining their BLS compared to carriers that did
not.10 In addition, cultural difference in the
reporting of BLS in carriers have been
reported.1,11,12 It is possible that carriers with
normal factor activity levels do not truly have abnormal bleeding, and
the apparent abnormal BLS are due to methodologic/cultural issues used
to determine the BLS. However, this should not be assumed to be the
explanation. To date, studies demonstrating a strong correlation between
factor VIII and IX activity levels and bleeding risk have been done
exclusively in males. It is not unreasonable to propose that factors
VIII and/or IX have gender related hemostatic functions that are not
measured by aPTT based assays. Factor VIII, at least, is known to have a
non-hemostatic function that is not measured by an aPTT based
assay.13 The factor VIII:Von Willebrand complex is
important for bone homeostasis, and female carriers have recently been
shown to have higher rates of osteoporosis and fractures compared to an
unaffected population.13,14 In factor XI deficiency,
there is a no correlation between factor activity levels and clinical
bleeding.15 It has been proposed that this is due to
hemostatic effects of factor XI that are not measured by aPTT based
assays.16,17 As shown in table 3, moderate to weak
correlation between factor activity and clinical bleeding is seen in
other coagulation factor deficiencies.15,18 Additional
investigation into possible hemostatic functions of factor VIII and IX
outside those measured by aPTT based assays are needed.
Another finding of our study was that most pediatric females with
hemophilia that reported a BLS had a normal BLS for age. This is also
seen in adult carriers with hemophilia.1 However, an
overwhelming majority with hemophilia had factor activity levels between
16 IU/dL and 40 IU/dL, levels that are expected to have a lower risk of
abnormal bleeding.19 Alternatively, this could be
another example of the inadequacy of aPTT based factor assays in
predicting bleeding symptoms in this population.
Several guidelines recommend against testing potential carriers for
genetic diseases during childhood.20.21 A principal
reason for this stems from ethical concerns regarding the loss of the
child’s future autonomy. However, these guidelines have not met with
universal acceptance.22 A more recent policy statement
from British Medical Health allows for carrier testing so long as no
harm comes to the child.22 The American Academy of
Pediatrics and American College of Medical Genetics most recent
guideline also recommends against carrier testing unless a child is at
risk for childhood onset conditions.21 Our study
suggests that hemophilia carriers are at significant risk for having
hemophilia and/or abnormal bleeding. Because factor activity levels may
not be diagnostic of carrier status and may not be predictive of
bleeding risk, genetic testing of potential/obligate carriers seems
indicated.
This study has several strengths, even compared to other investigations
of adult carriers, including data submitted from multiple institutions,
genotyping of a significant proportion of subjects, standardized measure
of bleeding symptoms, and a sample size that is larger than most studies
involving adult hemophilia carriers.2,3,23 Even with
this large sample size, only a small number of pediatric carriers
reported an abnormal BLS for age. Thus, we could not make valid analysis
of other factors that might contribute to an abnormal BLS. Further
improvement of the study would have been inclusion of additional details
regarding clinical bleeding such as joint or menstrual bleeding.
However, this type of data is not consistently submitted by
participating HTCs and would lead to an underestimation of bleeding
symptoms.
Our investigation suffers from a weakness common to many previous
studies of hemophilia carriers, namely, they only investigate carriers
seen at a HTC. It is unknown to what degree carriers seen at a HTC are
representative of all hemophilia carriers, most of whom are not seen at
a HTC. The majority of subjects in this study did not submit a BLS, and
of those that did, nearly all were participants in the MLOFgenotype initiative. Despite this limitation, the sample size of
pediatric subjects that did submit a BLS was larger than most studies of
adult carriers that report BLS, thereby making this data of value.
We relied on the ISTH-BAT BLS to describe bleeding symptoms. Bleeding
scores remain the best objective measure of clinical bleeding and have
been validated for carriers.23 However, there are
limitations, which may be particularly relevant for pediatric hemophilia
carriers. For instance, a 2-year-old carrier with a single untreated
joint bleed and no other abnormal bleeding would get an ISTH-BAT BLS
score of 2. This would not flag as abnormal for age in this study, but
most clinicians would consider this abnormal bleeding. Unlike Von
Willebrand disease, investigations of carriers have noted a poor
correlation between factor activity levels and bleeding
symptoms.1, 24-26 It is unknown if this is due to the
inadequacies of the BLS, factor activity levels, or both.
The benefits of a large sample size can be offset by errors associated
with large databases, including enrollment, data collection and
submission, and query errors. We attempted to limit this by restricting
this investigation to continuous variables (factor activity and BLS) and
categorical variables that are audited by ATHN. This study was limited
to pediatric carriers residing in the United States who participated in
the ATHNdataset and may not be reflective of pediatric carriers residing
in other areas of the world.
Despite the limitations of this study, as one of the few investigations
of hemophilia carriers focusing exclusively on the pediatric population,
we believe it makes important contributions. Significant knowledge gaps
remain regarding clinical bleeding in this population and additional
investigation is needed. Also needed are investigations into the
potential hemostatic functions not measured by aPTT based assays. This
would have applicability beyond hemophilia carriers and include all
patients with coagulation factor deficiencies.
Acknowledgments : The authors would like to acknowledge ATHN and
all the participating hemophilia treatment centers including physicians,
nurse practitioners, nurses, and data managers for collecting and
submitting data.
Conflicts of Interest: The authors report no conflicts of
interest for this project.