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CLINICAL TRIALS AND OBSERVATIONS
Recombinant versus plasma-derived factor VIII products and the development
of inhibitors in previously untreated patients with severe hemophilia A:
the CANAL cohort study
Samantha C. Gouw,1,2 Johanna G. van der Bom,3 Günter Auerswald,4 Carmen Escuriola Ettinghausen,5 Ulf Tedgård,6
and H. Marijke van den Berg,1 for the CANAL Study group
1Van Creveldkliniek, University Medical Center Utrecht, the Netherlands; 2Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center
Utrecht, Utrecht, the Netherlands; 3Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands; 4Prof Hess-Kinderklinik,
Zentrum fur Kinderheilkunde und Jugendmedizin, Bremen, Germany; 5Centre of Pediatrics III, Department of Hematology, Oncology and Haemostaseology,
Johann-Wolfgang-Goethe University Hospital, Frankfurt AM Main, Germany; 6Department of Pediatrics, University of Lund, University Hospital, Malmö, Sweden
It has been suggested that plasma-derived factor VIII products induce fewer
inhibitors than recombinant factor VIII
products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the
risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The
outcome was clinically relevant inhibitor
development, defined as the occurrence
of at least 2 positive inhibitor titers with
decreased recovery. The risk of inhibitor
development was not clearly lower in
plasma-derived compared with recombinant factor VIII products (relative risk [RR],
0.8; 95% confidence interval [CI], 0.5-1.3).
Among high-titer inhibitors, the possible
reduction in risk was even less pronounced
(RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von
Willebrand factor (VWF) carried the same
risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.61.6). Switching between factor VIII products
did not increase the risk for inhibitors (RR,
1.1; CI, 0.6-1.8). In conclusion, our findings
support neither the notion that plasmaderived factor VIII products with considerable concentrations of VWF confer a lower
risk to develop inhibitory antibodies than
recombinant factor VIII products, nor that
switching between factor VIII product brands
increases inhibitor risks in previously untreated patients with severe hemophilia A.
(Blood. 2007;109:4693-4697)
© 2007 by The American Society of Hematology
Introduction
At present, the main concern in the treatment of children with
severe hemophilia A is the development of inhibitory antibodies
that neutralize infused factor VIII, occurring in 10% to 30% of
patients.1 Several patient-related factors have been associated with
the risk of developing inhibitors, such as factor VIII gene mutation,2-4 other genetic factors,5-8 family history of inhibitors,9-11 and
ethnicity.11,12 In addition to these determinants, a number of
treatment-related factors have been suggested to affect the risk of
inhibitor development, such as prophylaxis,13,14 age at first exposure,15,16 and intensity of treatment.17 One of the most intensively
discussed potential risk factors is the factor VIII product type.
Indications for a potential role of the factor VIII product type in
inhibitor development arose when prospective registration studies
of recombinant factor VIII products among previously untreated
hemophilia A patients reported inhibitor incidences between 29%
and 32%.18-23 These incidences were considerably higher than the
previously observed 0% to 12% in patients treated with single
plasma-derived products.1,24 However, methodologic differences
between studies rendered comparisons inconclusive.25 More convincing were the findings of a recent comparative study in which
the inhibitor risk in patients treated with full-length recombinant
factor VIII was again higher than the risk in patients treated with a
high-purity plasma-derived factor VIII product containing von
Willebrand factor (VWF).26 Yet, it remains unclear whether it is
just the latter high-purity plasma-derived factor VIII product that
carries a lower risk for inhibitors, or whether other plasma-derived
products have the same effect. And, it is also unclear whether the
VWF content of a factor VIII product brand indeed decreases the
risk for inhibitors.
In addition, it has been suggested that switching between factor
VIII products might trigger the development of inhibitors, because
of observations of low inhibitor risks in patients treated with only
one brand of plasma-derived factor VIII.24
We, therefore, set out to describe inhibitor risks according to
different factor VIII product types and to examine whether
switching between factor VIII products affected the risk of
inhibitor development in a multicenter cohort of previously untreated patients with severe hemophilia A.
Submitted November 9, 2006; accepted January 2, 2007. Prepublished online
as Blood First Edition Paper, January 11, 2007; DOI 10.1182/blood-2006-11056317.
Supplemental Appendix link at the top of the online article.
The online version of this article contains a data supplement. that lists the
members of the CANAL Study group, available on the Blood website; see the
BLOOD, 1 JUNE 2007 䡠 VOLUME 109, NUMBER 11
Patients and methods
Eligible for inclusion were all 376 patients with severe hemophilia A
(residual factor VIII activity of ⬍ 0.02 IU/mL) born between 1990 and
2000, who were treated in one of the participating hemophilia treatment
centers (13 European and 1 Canadian center) from their first clotting factor
administration onwards. Ten patients were excluded for various reasons; 1
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
© 2007 by The American Society of Hematology
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BLOOD, 1 JUNE 2007 䡠 VOLUME 109, NUMBER 11
GOUW et al
because of an unknown baseline factor VIII activity level, 1 because he was
treated with DDAVP (desmopressin), 6 because they were lost to follow-up
before they received treatment with factor VIII on a total of 50 exposure
days, and 2 because they were treated with a particular immunogenic factor
VIII product.27 In 322 (87%) patients, data on treatment with factor VIII up to 50
exposure days were available. Of these patients, 6 were excluded because they
were treated with an unknown type of factor VIII product on one or more
exposure days. This left 316 (84%) patients in the present analyses.
We collected data from the medical records and patients’ infusion
logbooks using standardized case report forms. Data were collected on
patient characteristics, including factor VIII gene mutation, and on all
clotting factor infusions up to 50 “exposure days” or until inhibitor
development, including dates of infusion, doses and brand name of factor
VIII product, reasons of treatment, types of bleeds, and surgery. We also
collected details on all performed inhibitor tests and recovery measurements, including dates, infused doses of clotting factor, preinfusion and
postinfusion factor VIII activity levels, and time between infusion of
clotting factor and blood sampling for postinfusion factor VIII activity
level. An “exposure day” was defined as a calendar day during which one or
more infusions of factor VIII were given.
duration between exposure days, dose of factor VIII (as a measure of treatment
intensity), and regular prophylaxis. Factor VIII gene mutation type was categorized as high-risk (large deletions, nonsense mutations, intron 1 and 22
inversions) and low-risk (small deletions/insertions, missense mutations, splice
site mutations) factor VIII gene mutation types. The period of 5 exposure days
prior to the day at which the inhibitor occurred was felt to be the most important
period for treatment intensity. Therefore, “duration between exposure days” was
defined as the time period between the current exposure day and the fifth
exposure day prior to this exposure day; this was extrapolated to 5 exposure days
in cases with fewer than 5 exposures. This “duration between exposure days” was
calculated for all exposure days of all patients. Similarly, dose of factor VIII
product was defined as the mean dose of factor VIII product per kilogram body
weight of the last 5 exposure days prior to each exposure day (or in the first 4
exposure days, mean dose of all previous days). We defined regular prophylaxis
as regular factor VIII infusions at least once a week aimed at preventing bleeds.
Missing values were imputed using multiple linear regression methods.31 Family history of inhibitors was not imputed because 57% of the
patients did not have relatives with hemophilia, providing insufficient data
to impute this variable.
Definition of inhibitor development
We defined inhibitor development in 2 ways. First, the development of “all
clinically relevant inhibitors” was defined as the occurrence of at least 2
positive inhibitor titers combined with a decreased factor VIII recovery
within the first 50 exposure days. Second, the development of “high-titer
inhibitors” occurred when the peak inhibitor titer was at least 5 Bethesda
units per milliliter. A positive inhibitor titer was defined according to the
used inhibitor assay and cut-off level of each center’s laboratory. We
considered the factor VIII recovery to be decreased when it was less than
66% of expected. The expected level of factor VIII activity was calculated
according to Lee et al.28 Fifteen patients with marginally positive inhibitor
titers (median titer, 0.7 BU/mL; range, 0.2 to 1.5 BU/mL) on only one
occasion with normal factor VIII recoveries did not meet the definition of a
clinically relevant inhibitor.
Data analyses
For each patient, follow-up time accrued from the first exposure day and ended at
the 50th exposure day, or at the time of inhibitor development. To examine
whether the factor VIII product type and switching between factor VIII products
were associated with inhibitor development, we used pooled logistic regression29
with inhibitor development as the dependent variable and exposure day as time
increment. Observations over all exposure days of all patients were pooled into a
single sample, and a logistic regression model was used to relate the risk factors to
the occurrence of inhibitors. The odds ratios can be interpreted as incidence rate
ratios, given the low incidence of inhibitors within strata of exposure days. This
method accounts for varying risks according to the cumulative number of
exposure days, and is equivalent to Cox regression with exposure days as
time-variable and time-dependent covariates.29
First, we compared the inhibitor risk between recombinant and plasmaderived factor VIII products.
Second, in order to investigate whether the von Willebrand factor
(VWF) content was associated with the risk of inhibitor development, we
categorized factor VIII products into those containing no VWF (all 4
recombinant factor VIII products), products containing less than 0.01 IU
VWF antigen per IU factor VIII antigen (monoclonal antibody–purified
plasma-derived products), and products containing more than 0.01 IU VWF
per IU factor VIII antigen (other plasma-derived products).30
Third, we compared the risks of inhibitor development according to the
different brands of recombinant factor VIII products, with the risk in the
recombinant factor VIII product that was used most frequently in this study
population as the reference.
Fourth, we investigated the effect of switching of factor VIII products,
occurring at infusion of any new brand of factor VIII product, by comparing
the risk of inhibitor development after switching to a new brand of factor
VIII to the risk of inhibitor development among patients who had not (yet)
switched from one product to another.
In the multivariate analyses, we adjusted all associations for baseline factor
VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure,
Results
Patient characteristics
Table 1 presents the characteristics of the 316 patients included in
the study according to the first used product type. Patients receiving
plasma-derived products tended to be born and treated in an earlier
calendar time period and switched to another product type more
often than patients on recombinant factor VIII products. Since
patients from many different countries were included, a wide
variety of plasma-derived factor VIII concentrates was used
(Supplemental Appendix). Patients received factor VIII products
on a total of 12 918 exposure days, of which 8493 (66%) exposure
days were on recombinant factor VIII products. Eighty-two patients (26%) developed clinically relevant inhibitors. High-titer
inhibitors developed in 66 patients and low-titer inhibitors, in 16
patients. Patients developed inhibitors after a median of 14
exposure days (interquartile range [IQR], 8-19 days) and at a
median age of 15 months (IQR, 10-22 months).
Factor VIII product type and inhibitor development
Table 2 presents crude and adjusted relative risks of inhibitor
development (all clinically relevant inhibitors and high-titer inhibitors) according to recombinant and plasma-derived factor VIII
product types.
The risk of inhibitor development was not clearly lower in
plasma-derived compared with recombinant factor VIII products
(relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3).
Among high-titer inhibitors, the possible reduction in risk was even
less pronounced (RR, 0.9; CI, 0.5-1.5).
Compared to recombinant factor VIII products, the inhibitor
risk was similar in patients on plasma-derived products containing
considerable quantities of VWF (RR, 1.0; CI, 0.6-1.6), and it was
70% decreased in patients receiving plasma-derived products
containing small quantities of VWF (RR, 0.3; CI, 0.1-1.1). These
findings did not change after adjustment for potentially confounding factors (Table 2).
Additionally, we compared the risks of inhibitor development in
patients receiving B-domain–deleted recombinant factor VIII products
with the risk in patients receiving a full-length recombinant factor VIII
product (Kogenate). The risk to develop inhibitors in patients receiving
B-domain–deleted recombinant factor VIII (Refacto) appeared to be
somewhat, but not statistically significantly, higher (RR, 1.4; CI,
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BLOOD, 1 JUNE 2007 䡠 VOLUME 109, NUMBER 11
FVIII PRODUCT TYPE AND INHIBITORS IN HEMOPHILIA
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Table 1. Patient and treatment characteristics according to used factor VIII product type at first treatment
Plasma-derived factor VIII product
Recombinant factor
VIII product
No. of patients
Low VWF content*
181
High VWF content*
33
Total
102
53 (29)
No. of high-titer inhibitors (%)
43 (24)
4 (12)
19 (19)
66 (21)
5 (3)
14 (42)
35 (34)
54 (17)
No. of switched product type (%)
Median date of birth (IQR)
5 (15)
316
No. of inhibitors (%)
Jul 1996 (Dec
24 (24)
Jan 1992 (Dec
1994-Apr 1998)
Mar 1993 (Feb
1990-Jun 1993)
82 (26)
Jun 1995 (Aug
1991-Dec 1995)
1992-May 1997)
Baseline factor VIII activity level less than 0.01 IU/mL, no. (%)
165 (91)
32 (97)
91 (89)
White, no. (%)
163 (90)
29 (88)
89 (87)
281 (89)
78 (43)
18 (55)
45 (46)
141 (45)
Positive family history of hemophilia, no. (%)
Positive family history of inhibitors, no. (%)
High-risk mutation, no. (%)
Median age at first exposure, mo (IQR)
14 (19)
3 (19)
5 (11)
22 (16)
107 (66)
19 (66)
57 (70)
183 (68)
11 (7-14)
Start regular prophylaxis within first 50 exposure days, no. (%)
288 (91)
105 (58)
10 (5-15)
10 (6-15)
23 (70)
44 (43)
11 (6-15)
172 (54)
Median age at start of prophylaxis, mo (IQR)
21 (14-35)
20 (15-32)
18 (12-35)
20 (14-35)
Median cumulative no. of EDs at start of prophylaxis (IQR)
15 (6-28)
17 (10-26)
15 (7-29)
15 (7-27)
129 (71)
23 (70)
93 (91)
245 (78)
41 (23)
8 (24)
27 (26)
76 (24)
Peak treatment moment present, no. (%)†
Surgical procedure, no. (%)
VWF indicates von Willebrand factor antigen; ED, exposure day.
*Low VWF content was defined as less than 0.01 IU VWF antigen per IU factor VIII antigen; high VWF content was defined as more than 0.01 IU VWF antigen per IU factor
VIII antigen.
†Peak treatment moment was defined as an episode of treatment with factor VIII for a bleed or surgery on at least 3 consecutive days.
0.8-2.6). The risks of inhibitor development in patients receiving the
other recombinant products were similar (Table 2).
A total of 104 (33%) patients switched to another factor VIII
product brand. They changed products for the first time after a
median of 5 exposure days (IQR, 2-15 days; range, 2-48 days). Of
the patients who switched products, 66% switched to another
product only once. The reasons for switching were not known. To
illustrate the association of switching between factor VIII products
and the risk of inhibitor development, we plotted the cumulative
incidences of inhibitor development according to switching from
one product brand to any other brand (Figure 1), using a method
described by Kurtzke.32 The risk of developing inhibitors was not
increased after switching to another factor VIII product (adjusted
RR, 0.9; CI, 0.6-1.6) (Table 3).
at least 50 exposure days. Patients who had received plasmaderived factor VIII products had a not statistically significant
slightly lower risk to develop inhibitors than the patients who had
received recombinant factor VIII products. Patients who had
received product brands containing substantial amounts of von
Willebrand factor did not have fewer inhibitors than patients who
had received recombinant factor VIII products (containing no von
Willebrand factor). Patients who had received monoclonal antibody–
purified plasma-derived products containing very small amounts of
von Willebrand factor developed fewer inhibitors. However, the
number of patients receiving these products was low. Switching
between factor VIII product brands was not associated with an
increase in the risk for inhibitor development.
The absence of an evident difference in inhibitor incidences
between plasma-derived and recombinant factor VIII products was
at variance with a recent study by Goudemand et al.26 The latter
study found a more than doubled risk of inhibitors in a historic
cohort of patients treated with a full-length recombinant factor VIII
product, Recombinate or Kogenate (inhibitor risk, 31%; adjusted
relative risk for all inhibitors, 2.4 [CI, 1.0-5.8]) relative to a similar
Discussion
We performed a retrospective multicenter cohort study among 316
previously untreated patients with severe hemophilia A treated on
Table 2. Risk of inhibitor development according to type of factor VIII product
All clinically relevant inhibitor development
Crude
NED
RR (CI)
Recombinant
8493
1.0
Plasma-derived
4425
0.8 (0.5-1.3)
Recombinant
8493
1.0
High-titer inhibitor development*
Adjusted
P
RR (CI)
.34
0.7 (0.4-1.1)
Crude
P
RR (CI)
.14
0.9 (0.5-1.5)
1.0
Adjusted
P
RR (CI)
.72
0.8 (0.4-1.3)
1.0
1.0
P
1.0
1.0
.33
1.0
Plasma-derived
Low VWF content†
1272
0.3 (0.1-1.1)
.07
0.4 (0.1-1.1)
.08
0.3 (0.1-1.2)
.09
0.3 (0.1-1.3)
.11
High VWF content†
3153
1.0 (0.6-1.6)
.91
0.8 (0.5-1.4)
.45
1.1 (0.7-2.0)
.61
0.9 (0.5-1.6)
.79
Kogenate
4267
1.0
378
1.1 (0.2-4.5)
.94
1.2 (0.3-5.4)
.79
1.5 (0.3-6.5)
.60
1.6 (0.3-7.3)
.55
Recombinate
1639
1.1 (0.5-2.3)
.75
1.0 (0.5-2.1)
.99
1.4 (0.6-3.1)
.39
1.2 (0.5-2.7)
.70
Refacto
2209
1.4 (0.8-2.6)
.24
1.6 (0.9-3.2)
.14
1.5 (0.7-3.0)
.30
1.4 (0.6-3.1)
.38
Kogenate Bayer
1.0
1.0
1.0
Adjusted for baseline factor VIII activity level, ethnicity, factor VIII gene mutation type, age at first exposure, duration between exposure days, dose of factor VIII, and
regular prophylaxis.
NED indicates number of exposure days on the concerning product type; CI, 95% confidence interval; and RR, relative risk.
*High-titer inhibitor was defined as a clinically relevant inhibitor with inhibitor titers of at least 5 Bethesda units/mL at any time.
†Low VWF content was defined as less than 0.01 IU VWF antigen per IU factor VIII antigen; high VWF content was defined as more than 0.01 IU VWF antigen per IU factor
VIII antigen.
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BLOOD, 1 JUNE 2007 䡠 VOLUME 109, NUMBER 11
GOUW et al
Figure 1. Cumulative incidence of clinically relevant inhibitor development
according to switching products.
cohort of patients treated with a single plasma-derived factor VIII
product containing large amounts of von Willebrand factor (inhibitor risk, 11%). A possible explanation for the difference with our
findings is that the plasma-derived product studied by Goudemand
et al26 is less immunogenic than the plasma-derived products used
in our study. The patients in our study were treated with 23 different
kinds of plasma-derived products. Monoclonal antibody–purified
plasma-derived products containing very small amounts of von Willebrand factor induced fewer inhibitors in our patients. Yet, the number of
patients receiving these products was low. This finding needs to be
confirmed in future studies, in order to exclude a chance finding.
In accordance with our findings of no difference between the
risk of developing inhibitors between plasma-derived and recombinant products were previous observations that multitransfused
patients who switched from plasma-derived to recombinant factor
VIII products did not appear to develop more inhibitors than
similar patients receiving plasma-derived products, suggesting no
obvious immunogenicity of recombinant products.33-36
The present observations on the association of von Willebrand
factor and inhibitor development are at variance with several earlier
reports, in which lower inhibitor risks in plasma-derived products
have been ascribed to von Willebrand factor. Von Willebrand factor
has been hypothesized to modulate the immunogenicity of factor
VIII by masking B- and T-cell epitopes37 or by altering the whole
tertiary structure of factor VIII.38 Several clinical observations and
in vitro studies suggested that von Willebrand factor in factor VIII
concentrates protects factor VIII from circulating inhibitory antibodies by masking antibody epitopes on the C2 domain.37,39,40 Additionally, hemophilic mice treated with factor VIII products without von
Willebrand factor developed higher peak inhibitor titers than those
treated with factor VIII products that contained von Willebrand
factor.41 We showed that there is no decreasing trend in inhibitor
development with an increasing von Willebrand factor content.
The risk of developing inhibitors was not increased after
switching to another factor VIII product. This was in accordance
with the findings of Baglin and Beacham.42 In 73 patients with
hemophilia, the observed odds ratio for inhibitor development
following a change in product as opposed to no change was 0.4 (CI,
0.1-2.1). It should be noted, however, that the effect of switching
products may differ between previously untransfused patients and
multitransfused patients. As we did not study multitransfused
patients, our results cannot be generalized to this group.
A major strength of this study was that details on all first 50
exposure days were available, which enabled us to adjust associations for confounding factors. A well-known threat to the validity
of nonrandomized comparison studies is confounding by indication. In the present comparison, we do not expect such confounding, because the choice of a factor VIII product for a previously
untreated patient does not depend on the patient characteristics.
Nevertheless, time trends in the choice of products may have
confounded our findings. Patients treated with plasma-derived
products are predominantly treated earlier in the time period of our
study. In these earlier years, the use of prophylactic treatment was
less common. Therefore, we adjusted all our findings for prophylactic treatment and for other treatment-related factors.
We prevented selection bias by studying the association of factor
VIII product type and inhibitor development in an unselected cohort of
patients. Selection of patients treated with only one type of factor VIII
product would have biased the findings, because patients first treated
with plasma-derived products more frequently switched product type
than those who were first treated with recombinant products. Moreover,
inhibitor patients were less likely to switch products because they
developed an inhibitor after a few exposure days. As a consequence,
selection of patients who never switched product would lead to an
excess of inhibitor patients in the group of patients treated with
plasma-derived products. Therefore, we analyzed factor VIII product
type as a variable that could change on any exposure day, and we
adjusted our findings accordingly.
When categorizing the plasma-derived products according to
the von Willebrand factor content, we assumed that the stoichiometry of the factor VIII–von Willebrand factor complex was one
factor VIII molecule per one von Willebrand factor monomer.
However, it was reported to vary from 1:1 up to 1:50 according to
the technique used.43 Since we aimed to classify patients according
to high and low VWF, this classification seemed justified. Although
Recombinate was reported to contain trace amounts of von
Willebrand factor,44 it was grouped in the products containing no
von Willebrand factor because other investigators did not detect
any measurable von Willebrand factor.41,45
In conclusion, some, but not all, plasma-derived factor VIII products
may confer a lower risk to develop inhibitors than recombinant factor
VIII products in previously untreated patients with severe hemophilia.
According to our data, it seems unlikely that the von Willebrand factor
content of a product decreases inhibitor risks. Switching between
products does not seem to affect inhibitor risk.
Acknowledgments
This study was supported in part by an unrestricted educational
grant of Novo Nordisk to the CANAL Study Group members, who
are listed in Document S1 (available on the Blood website; see the
Supplemental Document link at the top of the online article).
The authors would like to thank J. Over, PhD, Department of
Product and Process Development, CLB, Sanquin Blood Supply
Foundation, the Netherlands, for his expert advice on factor VIII
products and S. le Cessie, PhD, department of medical statistics
Table 3. Switching product types
After switching factor VIII
product types
RR (95% CI)
P
Crude
1.1 (0.6-1.8)
.83
Adjusted
0.9 (0.6-1.6)
.82
Crude
1.0 (0.5-1.7)
.92
Adjusted
0.9 (0.5-1.6)
.68
Clinically relevant inhibitor
High-titer inhibitor*
Values are relative risk (RR) (95% confidence interval). Data adjusted for
baseline factor VIII activity level, ethnicity, factor VIII mutation type, age at first
exposure, duration between ED, mean dose of factor VIII, and prophylaxis.
*High-titer inhibitor was defined as a clinically relevant inhibitor with inhibitor titers
of at least 5 Bethesda Units/mL at any time.
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BLOOD, 1 JUNE 2007 䡠 VOLUME 109, NUMBER 11
FVIII PRODUCT TYPE AND INHIBITORS IN HEMOPHILIA
and clinical epidemiology, Leiden University Medical Center, the
Netherlands, for her statistical advice.
Authorship
Contribution: All authors participated in designing the research;
S.C.G., G.A., C.E.E., U.T., and all CANAL Study participants
collected patient data; S.C.G. and J.G.B. analyzed data; S.C.G.,
J.G.B., and H.M.B. wrote the paper; all authors critically reviewed
the final version of the paper.
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Conflict-of-interest disclosure: S.C.G., H.M.v.d.B., and J.B.v.d.B.
have received unrestricted research/educational funding for various
projects at the Van Creveldkliniek from the following companies: Bayer,
Baxter, ZLB Behring, Novo Nordisk, and Wyeth.
A complete list of the members of the CANAL study group is
available as an online supplement on the Blood website; see the
Supplemental Materials link at the top of the online article.
Correspondence: Johanna G. van der Bom, Department of
Clinical Epidemiology, PO Box 9600, 2300 RC Leiden, the
Netherlands; e-mail: [email protected].
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2007 109: 4693-4697
doi:10.1182/blood-2006-11-056317 originally published
online January 11, 2007
Recombinant versus plasma-derived factor VIII products and the
development of inhibitors in previously untreated patients with severe
hemophilia A: the CANAL cohort study
Samantha C. Gouw, Johanna G. van der Bom, Günter Auerswald, Carmen Escuriola Ettinghausen,
Ulf Tedgård and H. Marijke van den Berg
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