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The
occurrence of inhibitors of anti-hemophilic factors during treatment remains
the main complication in the management of hemophilia. In Cameroon, there are
over 160 people diagnosed with hemophilia, usually receiving “on-demand”
treatment, with restricted access to primary prophylaxis. Thus, such
prophylaxis is poorly assessed in Africa.
Objective: To determine the frequency of inhibitors in
patients with hemophilia A during primary prophylaxis.
Method: A cohort of 5 patients undertaking primary
prophylactic treatment of hemophilia A was followed from January to December
2018. The screening for inhibitors using the APTT to test 50:50 plasma patients
mixed with normal plasma was performed every 5 cumulative exposure days. We
performed the titration of inhibitors using the Bethesda Nijmegen method on all
positive samples.
Results: Out of the five patients included in our
cohort, four patients were tested positive at least once during treatment. Two
patients had developed high responder inhibitors before prophylaxis and had a
bleeding frequency of 2.5 to 3 per month of which 40 to 80% were hemarthrosis.
The other two patients developed low responder inhibitors during treatment with
a bleeding frequency of 1 per month, of which 19-20% had hemarthrosis. The only
patient who did not develop inhibitors was never subjected to hemarthrosis.
Conclusion: The primary prophylactic treatment may be
effective in improving the quality of life of patients and may be responsible
for the appearance of low responder inhibitors with minimal influence on
treatment in Cameroon.
Keywords: Hemophilia, Primary prophylaxis,
Inhibitors of anti-hemophilic factors
INTRODUCTION
Hemophilia affects nearly 400,000 people
worldwide and although the management of this pathology has improved
significantly since the advent of anti-hemophilic factor concentrate
substitution therapy, it is still a real challenge in Africa given the
relatively high cost and low availability of replacement factors [1]. The
primary prophylactic treatment that prevents the risk of bleeding and
especially the occurrence of arthropathy is recommended by the World Federation
of Hemophilia but has been very little experienced in Sub-Saharan Africa. Yet
it would be an ideal tool for improving the quality of life of hemophiliac
patients. Although it has been shown that the use of low doses of
anti-hemophilic factor (AHF) in the management of this pathology gives
satisfactory results [2]. The fact remains that the most frequent and most
feared complication is the appearance of AHF inhibitors which neutralize the
procoagulant activity of the injected factors [3]. It develops mainly during
the treatment of hemophilia A, in 20 to 30% of the treated patients and
generally appears during the first 50 cumulative exposure days (CED) [3]. As
part of a pilot study at the Hemophilia Treatment Center at the Yaoundé
University Teaching Hospital, concerning the primary prophylactic treatment of
hemophilia A patients on long-acting factor concentrates, this study was
carried out to examine the occurrence of AHF inhibitors. Furthermore, the study
intended to describe the types of bleeding that occurred during primary
prophylaxis and to identify the profile of patients who developed these
inhibitors.
MATERIALS AND
METHODS
We conducted a prospective cohort study that
included hemophilia patients on primary prophylaxis with long-acting AHF
concentrates. The study took place at the Yaoundé University Teaching Hospital from
January 2018 to December 2018. The participants were recruited through the
information contained in their medical records (including telephone contacts)
stored at the Yaounde Hemophilia Treatment Center. Children with hemophilia who
were younger than 7 years old, with less than 2 documented histories of joint
bleeding, not having clinical arthropathy were included in the study.
Furthermore, they have to live in Yaoundé and with parental commitment to
regularly bring the children to the hospital, at least once a week, for
prophylaxis and follow-up. The parents of those who met the clinical criteria
were contacted and following their consent. Patients who dropped out were
automatically excluded. Prophylaxis consisted in injection of 10-20 UI/kg of
AHF twice a week at regular interval at the Hemophilia Treatment Center.
For each patient included in the cohort
study, screening and titration of AHF inhibitors was done from the 10th
CED and every 5 CED until the 50th CED or until the appearance of
the inhibitors. Blood samples were collected from all patients into tubes
containing sodium citrate (0.109 M) and centrifuged at 1700 g for at least 10
min [4]. The Start 4 semi-automatic coagulometer and STA reagents (Diagnostica
Stago, Paris, France) were used to perform the analysis on the patient plasmas.
Inhibitor screening was done using an Activated Partial Thromboplastin Time
(APTT) assay and the Rosner index was determined, based on the formula [5]:
100 × [(APTT mixture - control
APTT)/sick APTT]
All patients with a Rosner score greater than
or equal to 12% were considered positive for inhibitors.
Inhibition titration by the Bethesda Nijmegen
method was performed in all patients who screened positive. The source of
factor VIII was a plasma pool of 20 normal individuals with no history of
hemostatic disorder. This plasma pool was buffered with 1 M Hydroxy Ethyl
Piperazine Ethan Sulfonic: HEPES Buffer (SIGMA Aldrich, St. Louis USA) to
improve the stability of Factor VIII (FVIII) during incubation [6,7]. The
residual FVIII level of this mixture was then measured by comparing the value
of its APTT with that of the standard sample. Based on the FVIII level
obtained, the inhibitor titer of the sample was determined, as defined by a
Bethesda Unit (BU) which is the amount of inhibitor that neutralizes 50 % of
the activity of an International Unit (IU) of FVIII in two hours of incubation
at 37°C [4,7]. The sensitivity threshold for this technique was 0.6 Bethesda
units per milliliter (BU/mL). A patient was classified as a low responder when
his inhibitor titer was less than 5 BU/mL and a high responder when the titer
was greater or equal to 5 BU/mL [4,8]. The CS-Pro Version 7.00 and Microsoft
Excel 2013 software were used to analyze the data obtained.
RESULTS
Our cohort consisted of 5 hemophiliac A
patients, of which 2 had moderate hemophilia and 3 had severe disease. The age
of the patients ranged between 1 and 7 years. Patients 2 and 4 were cousins (Table 1). The age of discovery of the
disorder ranged from one to 18 months and the circumstances of discovery of the
pathology were gum bleeds or bleeding during circumcision. All the patients
were already taking anti-hemophilic drugs prior to the implementation of the
prophylaxis scheme, with a maximum of 22 CED. The two cousins included in our
study previously had inhibitors at the time of first screening, although they
had less than 10 CED when prophylaxis was initiated (Table 1).
DISCUSSION AND CONCLUSION
Our study revealed that four of the five
patients in this study had a positive Bethesda Nijmegen test at least once
during prophylaxis among which two were high responders.
This is the first study in Central Africa
that reports appearance of inhibitors in hemophiliac patients during primary
prophylaxis. Few studies have reported the frequency of inhibitors in
hemophiliac patients under prophylaxis in Africa. Kraiem et al. [10] in Tunisia
found only 5% of positive patients for inhibitors in a cohort of 32 patients in
2012. Similarly, Balogog et al. [11] in Cameroon had found a prevalence of
inhibitors of 19% in a population of 42 hemophilia patients of whom 38 were
diagnosed hemophilia A. These are different from the results we obtained
probably because of the small size of our sample. In addition, according to
data from a Swedish registry that included 460 pairs of hemophilia A or
hemophilia B brothers, the existence of a family history significantly
increases the risk of inhibitors [12]. It is also described that the risk of
inhibitors is higher in black subjects and in families with antecedent of
antibodies compared to the others [12]. This could explain the consanguinity found
between the two high responding patients to AHF inhibitors in this study. In
contrast to high responders, inhibitors in low responders appeared relatively
late in prophylaxis and resolved spontaneously. This better reflects the
characteristics of transient inhibitors, which are defined as “low-titer
inhibitors, sometimes exceeding 5 BU and “spontaneously disappearing” after a
certain time, without modification of the therapeutic regimen” [3,7].
The higher frequency of bleeding in high
responders compared to others shows the impact of AHF inhibitors on the health
and well-being of patients by rendering the treatment in place completely
ineffective. Unfortunately, in our context, we do not have by-pass products
whose effectiveness has however been demonstrated in such cases [7,13,14]. Low
responder patients had a predominance of hematomas compared with joint bleeds
during prophylaxis. Thus showing the action, although reduced but presents, of
low responder inhibitors on the primary prophylactic treatment put in place.
This is especially true since the only patient who had never developed
inhibitors throughout the study, was not subject of joint bleeding.
The study population consisted exclusively of
moderate and severe hemophilia A patients, who met the set eligibility
criteria. Hemophilia A occurs more frequently worldwide, and would explain why
they were predominant in this study. A relationship was found between two
patients included in our cohort, coincidentally and despite the
small size of our sample. This is not surprising given the hereditary nature of
the pathology because in about two-thirds of cases, patients have a family
history of hemorrhagic disease [3].
Among the secondary findings, we noted that
the age of discovery of the pathology was relatively low in our study
population (less than 18 months). This may be due to the rapid management of
patients during the first year of their life, which will have made it possible
to prevent bleeding episodes and thus preserve their joint function. This is
also the reason why all had already received AHF. Circumcision and gum bleeding
were the most common circumstances of discovery of pathology in our cohort.
This is close to the results of the 2001 French cohort showing that the
hemorrhagic event represents the first diagnostic circumstance for hemophilia,
accounting for 59.9% of cases [9]. The two cousins included in our study
already had inhibitors despite having less than 10 CED. This makes us think
that genetic factors including the abnormality of the FVIII gene would have
predisposed these patients to a rapid development of inhibitors. In-depth
genetic testing would provide more insight for our 2 patients. The results of
the AFSSaPS report (Agence Française de Sécurité Sanitaire des Produits de
Santé) on the development of inhibitors and the management of hemophilia
patients supports this hypothesis. According to this report, the type of
abnormality affecting the FVIII gene significantly modifies the risk of
inhibitors up to 90% of the most deleterious abnormality cases [8]. In
addition, the early establishment of prophylaxis in children at the first
exposure could have an effect comparable to that of the Immune Tolerance
Induction (ITI) treatment and induce the disappearance of early-onset AHF
inhibitors.
We recognize that the main limit of this
study is the sample size. This is a pilot study that can be considered as the
first description of inhibitors appearance in western African hemophiliac
patients. However, it indicates that exposition to regular AHF during primary
prophylaxis may increase the frequency of inhibitors. Primary prophylaxis in
Africa needs to be better assessed to find the best strategy that will balanced
the benefit in terms of reduction in frequency of bleeding with the risk of
inhibitor appearance.
ACKNOWLEDGEMENT
The authors of this article declared that they
had no interests which might be perceived as posing a conflict or bias. A
special thanks to the staff at the Hematology and Blood Transfusion unit of the
Yaoundé University Teaching Hospital. Our deepest gratitude to all the patients
and parents who participated in this study. Also acknowledge the WFH who
provided the clotting factors.
1.
World Federation of Hemophilia (2016)
Report on the annual global survey 2015. Montreal: World Federation of
Hemophilia.
2.
Diop S (2017) Low dose prophylaxis in
hemophilia. In: WFH Regional Medical Workshop on Hemophilia Care: Dakar.
3.
World Federation of Hemophilia (2012)
Guidelines for the management of hemophilia. 2nd Edn. Montreal:
Hemophilia.
4.
Kitchen S, McCraw A, Echenagucia M
(2010) Diagnosis of hemophilia and other bleeding disorders: A laboratory
manual. 2nd Edn. Montreal: World Federation of Hemophilia.
5.
Delisle V, Ternisien C, Butterman P,
Zandecki M (2000) A rare pathology but with a very high risk of hemorrhage:
Hemophilia A acquired. Ann Biol Clin 6: 741-744.
6.
High Authority of Health (2011)
Technological evaluation report: Research and titration of an inhibitor against
anti-hemophilic factors. Paris: HAS.
7.
Carcao M, Goudemand J (2018) Inhibitors
in hemophilia: A primer. 5th Edn. Montreal: World Federation of
Hemophilia.
8.
French Agency for Sanitary Safety of
Health Products (2006) Development of inhibitors and management in haemophiliac
patients treated with factor VIII or IX of plasma or recombinant origin. Paris:
AFSSaPS.
9.
World Federation of Hemophilia (2008)
Guidelines for the management of hemophilia. Montreal: Hemophilia.
10.
Kraiem I, Hadhri S, El OH, Sassi R,
Chaabani W, et al. (2012) Frequency of specific coagulation inhibitors and
antiphospholipid antibodies in Tunisian hemophiliacs. Ann Biol Clin 70:
659-665.
11.
Balogog PN, Tagny CT, Ndoumba A, Mbanya
D (2014) FVIII and FIX inhibitors in people living with hemophilia in Cameroon,
Africa: A preliminary study. Int J Lab Hematol 36: 566-570.
12.
Astermark J, Berntorp E, White GC,
Kroner BL (2001) The Malmo International Brother Study (MIBS): Further support
for genetic predisposition to inhibitor development in hemophilia patients.
Hemophilia.
13.
Canadian Hemophilia Society (2003) All
about inhibitors. Accessed 18 November 2017; Available from: http://www.hemophilia.ca/en/documentation/improved-documents/inhibitors
14.
High Authority of Health (2017)
Recommendation concerning the exemption of Eptacog alfa active as part of a
temporary recommendation for use. Paris: HAS.
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