Keywords
haemophilia A - parents - counselling
Schlüsselwörter
Hämophilie A - Eltern - Beratung
Introduction
This review will inform about the key steps we take when preparing for counselling
of parents of a newly diagnosed boy with haemophilia A (HA) and we structured this
review similar to the prioritisation of items in our counselling proceeding. First,
the basic knowledge of the medical background of HA needs to be present at the centre
to successfully provide the required information to the family. The first section
lists all critical and necessary medical background information. Second, before counselling,
we always remember the stressful situation of the family. Relevant information is
reflected in the second section together with a reference towards guidelines and regulations.
Third, controversially leading discussions in haemophilia need to be highlighted and
explained to the family as detailed as necessary and as precisely as possible to come
to well-informed and balanced decisions, summarized in the next two following sections.
Finally, the main aspects of our counselling procedure are again put together in the
conclusion and listed in [Table 1]; both the content in the different sections and [Table 1] complement each other. Due to the complexity of HA, its potential complications,
the scientific background and ongoing discussions especially regarding treatment options,
in our opinion, we feel it is of advantage to conduct the counselling at specialized
haemophilia centres (e.g. European haemophilia treatment centres, EHTCs, or European
haemophilia comprehensive care centres, EHCCCs).
Table1
Counselling checklist
|
Topic
|
Details
|
|
Haemophilia A (HA) – general aspects
|
|
What is HA?
|
The function of FVIII and the consequences of impairment of function[1]
[6]
[10]
|
|
Incidence
|
Incidence of HA[1]
|
|
Clinical picture, manifestation(s)
|
First bleeds, chronic/usual bleeds[1]
[4]
[8]
|
|
Bleeding-associated risks
|
Short-term risks (e.g. ICH), long-term risks (e.g. arthropathy) and how to prevent
them,[1]
[4]
[8]
[9]
[23] consequences for the quality of life[5] and risk of detrimental social impact (e.g. risk for unemployment) if not treated
adequately[7]
|
|
Severity
|
Bleeding frequency often depending on the remaining clotting factor level in plasma[1]
[6]
[10]
[32]
|
|
Treatment – individualisation
|
Advantages of pharmacokinetic approaches guided by frequency of bleeds[33]; consider the suitability of prolonged half-life FVIII concentrates[33]
|
|
Inheritance
|
Carrier status, 30% spontaneous mutations[1]
[15]
[16]
[17]
[18]
|
|
Diagnosis
|
Benefits of early diagnosis and careful taking of history/family history, laboratory
assays, genetic analysis and prediction of inhibitor risk[1]
[6]
[11]
[12]
[13]
[14]
[19]
[20]
[21]
[26]
[33]
|
|
Laboratory, assays
|
Variability of assays[19]
[20] (if diverging results in different centres) and consequences for monitoring
|
|
Genetics
|
Investigation of genetic mutation, mutation-associated risks,[21] genetic family counselling,[33]
[34] prenatal options[33]
|
|
The manifestation of bleeds, differentiation of bleeds, trauma-induced
|
Differentiation of bleeds (severe/not severe/occult) and first-aid measures in case
of bleeds[1]
[4]
[8]
[9]
[10]
[23]
[32]
Provide mobile number of on-call physician 24/7[34]
|
|
Treatment – education/information
|
Home therapy, self-administration of FVIII concentrates, documentation of product
use, details of the product (German Transfusion Act) and bleeds[32]
[33]
[34]
[35]
The benefit of treatment with FVIII concentrates; prophylaxis vs. on-demand treatment[24]
[25]
Inhibitor risk,[26] ITT, the burden for the family[27]
New products, extended half-life FVIII, Emicizumab, clinical trials need to be discussed
in detail (‘challenges associated’)
Subcutaneous vaccinations[36]
Treatment beside factor substitution (e.g. physical therapy, pain management)[32]
[34]
[36]
|
|
Counselling of parents of a boy newly diagnosed with HA
|
|
Psychosocial burden
|
The burden of the disease, provide contact details of the centre, psychologist, social
worker and communicate carefully[31]
|
|
Guidelines, recommendations
|
Refer to existing guidelines and recommendations[32]
[33]
[34]
[35]
|
|
Team introduction
|
Introduce yourself, haemophilia nurse, other physicians/nurses of the haemophilia
team, physical therapist, social worker (e.g. supporting necessity or possibility
of a handicapped ID application if indicated), psychologist[32]
[33]
[34]
|
|
Benefits of European haemophilia comprehensive care centres (EHCCCs)[34]
|
Co-ordination of delivery of haemophilia services (hospital/community/affiliated European
haemophilia treatment centres, EHTCs)[34]
24-hour advisory service for patients, families, hospital doctors, general practitioners
and affiliated EHTCs' health care professionals[34]
Specialist care for patients with inhibitors, including surgery[34]
Diagnostic and reference laboratory service with a full repertoire of tests for the
diagnosis and monitoring of inherited disorders of haemostasis[34]
24-hour laboratory service for clotting factor assays and inhibitor screens[34]
Access to orthopaedic and/or rheumatological service with provision of surgery[34]
Access to physical therapy service[34]
Access to a specialized obstetric and gynaecological service for the management of
haemophilia carriers and women with von Willebrand disease and other hereditary bleeding
disorders[34]
Access to paediatric facilities if children are treated[34]
Access to a genetic diagnosis service providing also carrier detection and antenatal
diagnosis[34]
Access to dental service[34]
Access to hepatology and infectious disease service for patients with HIV and/or viral
hepatitis[34]
Professional psychological support[34]
Access to the social worker and welfare advice[34]
Collating of data (e.g. product usage, patient demographics)[34]
Participation in research, including clinical trials[34]
|
|
Challenges associated with counselling – choice of factor concentrate
|
|
Virus safety of clotting factor concentrates
|
Refer to challenges with virus safety in the past and differences between plasma-derived
(pd) and recombinant (r) products regarding theoretical risk of transmission of unknown
viruses[37]
[38]
Today's products are considered to be safe[38]
|
|
Inhibitors
|
Explain inhibitors and risks for inhibitor development[21]
[26]
[27]
[38]
Pd vs. rFVIII; scientific, product-related inhibitor discussion, MASAC[39] statement, SIPPET[29]
Explain the hypothesis behind the use of pd-high VWF clotting factor concentrates
in PUPs[40]
|
|
Challenges associated with counselling – new treatment options
|
|
New treatment options
|
Inform about anti-TFPI, Fitusiran and gene-therapy clinical trials[41]
Discuss Emicizumab's use in paediatrics (no data for patients <1 year of age in SmPC,[28] haemostatic system of this patient group not fully developed,[28]
[47] monitoring is challenging)[28]
[42]
[43]
[44]
[45]
[46]
[48]
[50]
|
|
Conclusion
|
|
Treatment – economic aspects
|
Inform about careful and economical use of factor product[33]
[36]
|
|
Medical, other
|
Explain the sense of having contact details of other (external) physicians involved,
such as general practitioner, paediatrician, dentist, ear, nose and throat specialist,
other[34]
|
|
Social
|
Explain the information need of the kindergarten team, pre-school team, etc.[32]
Emphasize sports recommended for haemophilia patients[32]
|
|
Network
|
Provide the contact details for contact person(s) of patient organization(s)[32]
[36]
Highlight group-fostering activities such as haemophilia camps, meetings of parents
of children with haemophilia and other initiatives
|
Abbreviations: FVIII, factor VIII; ICH, intracranial haemorrhage; ITT, immune tolerance
therapy; MASAC, Medical and Scientific Advisory Council; PUP, previously untreated
patient; SIPPET, Survey of Inhibitors in Plasma-Product Exposed Toddlers; SmPC, summary
of product characteristics; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand
factor.
Haemophilia A – General Aspects
Haemophilia A – General Aspects
HA is a rare, X-chromosomal-recessively inherited bleeding disorder that is caused
by a deficiency of coagulation factor VIII (FVIII).[1] Haemophilia B comprises the lack of coagulation factor IX (FIX).[1] The first name for haemophilia B was ‘Christmas disease’, and there is an interesting
coincidence of the first patient's name and the date the paper was published.[2] The incidence of HA in the general population is approximately 1:10,000, while in
live male births it is 1 in 5,000.[1]
Patients suffering from HA clinically present as ‘bleeders’ (‘for this is the name
given to them’)[3] and if not treated adequately, patients affected (usual boys) experience spontaneous
or excessive bleeding after minor trauma into muscles and joints.[1] Chronic bleeding into joints leads to haemophilic arthropathy,[4] resulting in reduced functionality, reduced range of motion and chronic pain, all
finally causing disability. In a recent study[5] from France and the United Kingdom, the presence of more than two target joints
(target joint: single joint that per definition presents with three- or more spontaneous
bleeds within a consecutive 6-month period),[6] occurrence of joint surgery and increased joint-pain frequency were independent
predictors of lower quality of life.[5] The presence of severe haemophilia has a negative impact on the social status and
quality of life.[7] Results from a study conducted by Pabinger and co-workers showed that, compared
with their healthy controls, a significantly lower portion of haemophilia patients
was in the active work process, and a higher rate was unemployed or already in early
retirement.[7] In addition to that, lower average values in the quality-of-life scores for physical
functioning, role physical, bodily pain, general health and social functioning had
been identified using the short-form 36 (SF-36).[7]
Besides the long-term effects of suboptimally treated haemophilia, intracranial haemorrhage
(ICH) could be the first bleeding manifestation in 1 to 4% of patients.[8] It may happen without having established the diagnosis of haemophilia, especially
in a child without a family history of haemophilia, as ICH in a newborn is often associated
with delivery[9] and other concomitant risk factors such as prematurity or asphyxia. Despite the
use of prophylaxis, the mortality caused by ICH is still around 20%, and it is more
frequent in children equal to or below 2 years of age.[9]
Therefore, the therapeutic objective is to avoid ICH as well as chronic bleeding into
joints, and, most of the times, risk of bleeding correlates with severity of haemophilia.
Haemophilia presents either as severe (plasma activity of coagulation factor of <1
international units per decilitre; IU/dL), moderate (1–5 IU/dL) or mild (>5–40 IU/dL).[10] In general, the lower the plasma FVIII activity, the more severe the disease and
the more frequent bleeding episodes manifest. However, the severity of haemophilia
not always matches the clinical picture, and although patients suffered from severe
haemophilia, in 10 to 15%, their bleeding phenotype was mild.[11]
[12] And, to what extent increased FVIII-trough levels and with that pharmacokinetic
effects are protective again is, as recently published, currently in discussion, as
bleeding did not correlate with more time spent below certain clotting factor levels,[13] although previous models showed a decline in bleeding with an increase of factor
activity,[14] which supports the value of conducting individualised, pharmacokinetic studies prior
to starting prophylaxis.
As it became evident that HA is a potentially debilitating disease, treating physicians
need to know the mode of inheritance. Not all cases arise due to heredity; approximately
30% result from spontaneous mutation.[1] The mother (called ‘carrier’) usually passes the disease to her son, and the chance
that sons from haemophilia carriers have the disease is 50%.[15] Daughters may inherit the disease with a likelihood of 50% and the daughter affected
‘carries’ the altered X-chromosome.[15] The bleeding manifestation of carriers is not uniform, and carriers must not have
subnormal FVIII plasma activity levels <40 IU/dL to experience bleeding symptoms such
as epistaxis, easy bruising, menorrhagia, and post-operative surgical and dental bleeding.[16] However, compared with boys suffering from, e.g., severe haemophilia, female carriers
of haemophilia experience usually a mild bleeding phenotype.[16] Bleeding symptoms similar to boys with severe haemophilia do exist in females who
suffer from severe or moderate haemophilia with FVIII or FIX mutations and extremely
skewed X-chromosome inactivation patterns, but these cases are sporadic.[17]
[18]
The approach towards the diagnosis of HA relies on an accurate patient and family
history, the clinical presentation and subsequent laboratory investigations. As already
mentioned, the clinical presentation not always follows FVIII plasma activity.[11]
[12] And, to make things even more complicated, laboratory results can depend on the
assays and reagents used resulting in varying assay results.[19] Depending on the test used, divergent FVIII activity results in the case of mild
HA can occur, potentially resulting in a misdiagnosis of the HA phenotype.[20] The investigation of the underlying genetic mutation usually completes the laboratory
work-up, asking for a separate informed consent and additionally providing, depending
on the type of mutation, information about the risk for generation of antibodies against
FVIII (e.g. inhibitors) after FVIII substitution.[21]
Like we stated before, most cases are inherited, and as a consequence, the disease
is known (usually to the mother who is the carrier), although circumstances exist
where this is not the case.[22] Parents in this situation typically seek our advice before or shortly after the
birth of the first child or before or shortly after the birth of the second/third
child. The situation is different where HA is not known to the parents, and the patient
presented at the haemophilia centre is usually the consequence of the first bleeding
manifestation, the situation we focus on here.
The most common first bleeding manifestation of haemophilia patients investigated
in a study from the Jodhpur region comprised posttraumatic (N = 20) and gum bleeds (N = 17), followed by skin bleeds, joint bleeds and epistaxis (N = 4 each).[8] These were different from the typical presentations, where skin, joint and muscle
bleeds were most common.[8] Like we said before, severe haemophilia may present with ICH as the only presenting
feature in newborns in 1 to 4%.[8] The prophylactic administration of the coagulation factor significantly reduced
the risk of cerebral bleeding in patients with severe haemophilia without human immunodeficiency
virus (HIV) and inhibitor in a study investigating 10,262 haemophilia patients ≥2
years of age.[23] Around 41% of patients built the paediatric/adolescent age group (2–15 years of
age) in this study.[23]
The mainstay of therapy of patients suffering from haemophilia, especially from severe
haemophilia, is the prophylactic substitution of the missing factor, called ‘prophylaxis’.[6] Two randomized trials have demonstrated its benefit.[24]
[25] However, and depending on several risk factors, during substitution of the missing
clotting factor, patients may develop inhibitors.[26] Inhibitors may interfere with the functional activity of FVIII, thus putting the
patients again at the risk of bleeding despite FVIII substitution, which asks for
immune tolerance therapy (ITT) or, if not successful, for bypassing therapy, which
puts a tremendous burden on the patient and his family.[27] With the global registration of the bispecific monoclonal antibody Emicizumab for
haemophilia patients with inhibitors, a new therapeutic option is now available for
these patients.[28]
The discussion to what extent plasma-derived (pd) FVIII products cause fewer inhibitors
compared with recombinant FVIII (rFVIII) concentrates is ongoing. However, based on
the results of the recently conducted, randomized Survey of Inhibitors in Plasma-Product
Exposed Toddlers (SIPPET) study,[29] post-hoc analyses of surveys of United States Haemophilia and Thrombosis Research
Society members showed that 44/54 US physicians were considering to change their current
practice with 31/44 physicians using pd FVIII for previously untreated patients (PUPs).[30] In their conclusion, Sande et al state that the results of the two consecutive surveys
indicated that the SIPPET study and its post-hoc analyses had influenced clinical
practice in the United States over the survey period of around 20 months, mainly about
considering von Willebrand factor (VWF)-containing pd FVIII for PUPs.[30]
Counselling of Parents of a Newly Diagnosed Boy with Haemophilia A
Counselling of Parents of a Newly Diagnosed Boy with Haemophilia A
Before meeting with the parents of a boy with newly diagnosed HA, one should be aware
that caring for a son/brother suffering from haemophilia can be associated with significant
stress and even traumatic experiences for all family members (especially in the case
of severe haemophilia with inhibitors, need for ITT or a parental history of unfairly
suspected child abuse). In line with this, a dedicated ‘psychosocial care’ approach
has recently been published by Limperg et al.[31] As a consequence, before a counselling procedure takes place at our centre, all
of our team members make sure to adhere to a careful, reflective and diligent counselling.
An essential part of our counselling is the adherence to published standards in the
management of haemophilia, such as the standards published by the World Federation
of Hemophilia (WFH).[32] As a consequence (and having in mind the psychosocial burden), during counselling
of parents of a boy with newly diagnosed HA, we follow our institutional ‘checklist’
([Table 1]). Due to the complexity of all aspects involved, treatment of patients with severe
haemophilia should take place at designated EHTCs or EHCCCs[33]
[34] and compliance with local guidelines and recommendations is a must.[35] Explaining the requirements needed to be present at the centre for receiving the
EHTC or EHCCC status is an excellent opportunity to bring the ‘team’ (family and centre
staff) together (shared decision making).[36]
Challenges Associated with Counselling – Choice of Factor Concentrate
Challenges Associated with Counselling – Choice of Factor Concentrate
In the following, we would like to reflect critically on the medical-scientific information
we take into consideration when it comes to informing parents on product selection
and new treatment options, as these two topics bear the potential for controversial
discussion in the haemophilia medical community (e.g. preference of pd FVIII with
high VWF content in PUPs over rFVIII concentrates, use of Emicizumab in paediatric
patients without inhibitors or use of extended half-life FVIII concentrates for prophylaxis).
Due to the implementation of virus-inactivation and effective surveillance procedures,
pd FVIII clotting factor concentrates no longer carry the risk of transmitting hepatitis
C or HIV, as this happened with non-virus-inactivated clotting factor concentrates
primarily in the 1980s.[37] Today, all clotting factor concentrates are considered to be safe.[38] Regarding pd clotting factor concentrates, the transmission of pathogens cannot
be entirely excluded.[38] This statement includes unknown viruses and other pathogens.[38] Such a statement is not part of the prescribing information of recombinant clotting
factors from the third generation onwards.[38]
Currently, the most severe and relevant adverse reaction is the development of inhibitors.[21]
[26]
[27]
[38] Inhibitor incidences vary from product to product. Regarding recombinant factor
concentrates, they can range from 26% up to nearly 50%.[38] The discussion to what extent pd factor concentrates should be preferred in PUPs
with severe HA (SHA) until the reach of what exposure day (ED) is still open.
Based on this and the results of the SIPPET[29] study, the Medical and Scientific Advisory Council (MASAC) of the United States
National Hemophilia Foundation has issued MASAC Document #243.[39] The MASAC recommends individuals with greater than 50 EDs to any recombinant product
and individuals with more than zero and less than 50 EDs to stay on their current
recombinant product.[39] For individuals with a new diagnosis of haemophilia, a careful risk/benefit evaluation
between the caregiver and patient should take place, considering the options to initiate
therapy with a pd VWF/FVIII product in all PUPs.[39] Alternatively, treatment is started with a recombinant FVIII product as previously
recommended by MASAC or with a ‘newer’ rFVIII product, which may provide an opportunity
for the use of new, extended half-life FVIII products in paediatric patients.[33]
[39] However, currently only two prolonged half-life FVIII products have been registered
in the European Union (EU) for the use in children below the age of 12 years, and
so far, no data on the use of these products in PUPs with SHA are available from peer-reviewed
journals. Additionally, compared with extended half-life FIX concentrates, the prolongation
of half-life of FVIII in extended half-life FVIII products in children is less intense
and whether or not the generally increased clearance of FVIII in this patient group
further reduces this benefit needs discussion.
As we assume here that the respective patient concerned is a PUP, our recommendation
for treatment follows the MASAC recommendation.[39] In cases where we expect an increased risk for the development of inhibitors (e.g.
null mutations,[26] large deletions and nonsense mutations,[21] family history of inhibitors[26]), we start the first 50 EDs of treatment with a virus-inactivated, pd, VWF/FVIII
concentrate, preferentially with a high VWF content.[40]
Challenges Associated with Counselling - New Treatment Options
Challenges Associated with Counselling - New Treatment Options
With the approval of the humanised, bispecific antibody Emicizumab by the European
Medicines Agency (EMA), Emicizumab is now registered and available in Europe for the
routine prophylaxis of bleeding episodes in patients with HA (congenital FVIII deficiency)
with FVIII inhibitors and SHA (congenital FVIII deficiency, FVIII < 1%) without FVIII
inhibitors for patients in all age groups, as documented in the summary of product
characteristics (SmPC).[28]
More new treatment options currently investigated in clinical trials comprise anti-tissue
factor pathway inhibitors (anti-TFPI), an investigational, antithrombin-interfering-ribonucleic
acid (iRNA, Fitusiran) and gene therapy of HA or HB.[41] No paediatric subjects below the age of 12 years so far have been included in the
anti-TFPI trials yet, while recruitment of patients below the age of 12 years has
just started in the phase II/III study of Fitusiran (NCT 03974113). Two gene therapy
studies will enrol patients from 2 to 65 years, who suffer from HA or HB (not yet
recruiting, NCT03217032 and NCT03961243, in both studies a lentiviral gene therapy
approach has been selected). As these therapies will need more years before receiving
registration for paediatric patients, we will not discuss these options here.
The mode of action (moa) of Emicizumab is fundamentally different from the moa of
activated FVIII (FVIIIa).[42] Emicizumab recognizes both enzyme factor IXa (FIXa) and the substrate factor X (FX).[42] By bringing FIXa and FX close, it facilitates FIXa-mediated activation of FX.[42] In preclinical studies investigating non-human primate models of acquired HA, administration
of Emicizumab resulted in haemostatic activities corresponding to a mild HA phenotype.[43]
The use of Emicizumab in paediatric patients can cause neutralizing anti-drug antibodies,
as reported for two patients in the paediatric study for Emicizumab (HAVEN 2).[43] Emicizumab has no on/off mechanism (FVIIIa has), does not bind to phospholipid (FVIIIa
does), there is no differentiation between zymogen (FIX) and enzyme (for FVIIIa there
is, as it is specific for FIXa and FX), it has a low affinity for enzyme and substrate
(FVIIIa's affinity is high), it is in excess over enzyme and substrate (for FVIIIa,
enzyme and substrate are in excess over cofactor) and it has a low level of self-regulation
(FVIIIa has a high level of self-regulation).[42] We feel it is essential to understand that the activation of the FX-activating complex
in the typical setting experiences limitation by the amount of FVIIIa generated during
activation of the coagulation cascade, while in the case of Emicizumab it is the amount
of FIXa made. It may prove challenging if FIXa is administered externally (e.g. by
administration of drugs containing FIXa).[42]
[44] These aspects need attention, especially under the consideration of the long half-life
of Emicizumab.[42]
Emicizumab is effective at prevention of bleeding (prophylaxis).[43] However, some patients treated with Emicizumab will experience a bleeding event
that requires treatment with an additional haemostatic agent.[43] Under these circumstances, the administration of, e.g., FVIII, is considered a safe
option in non-inhibitor patients receiving Emicizumab.[43]
Also, for Emicizumab, there is a MASAC recommendation (#255).[44] Due to a boxed warning regarding the risk of thrombotic microangiopathy and thromboembolism
in the context of concomitant use of activated prothrombin complex concentrates to
treat breakthrough bleeding in patients receiving Emicizumab, Emicizumab is recommended
by the MASAC only to be prescribed by (or in close proximity to) the appropriate staff
of the patient's haemophilia treatment centre, which is also recommended for the following
bleeding events.[44] However, and concerning the use of Emicizumab in infants under 6 months of age,
there are, according to the MASAC, limited data.[44]
The SmPC for Emicizumab[28] confirms the missing of clinical data in patients less than 1 year of age. The number
of infants and toddlers analysed is five (1 month to less than 2 years of age).[28] This fact may prove problematic as the median age of starting home treatment in
PUPs with SHA in a nationwide real-world study with 700 person-years was 1.1 years.[45] The median age at diagnosis was 0.7 months and the median age at first exposure
to FVIII was 9.0 months.[45]
Due to the need for regular prophylaxis, patients with SHA without inhibitors (e.g.
PUPs) belong to the group of patients who would profit most from a potential prophylactic
treatment with Emicizumab.
Additionally it is stated in the updated EMA assessment report of Emicizumab that
due to the missing of pharmacokinetic data for patients below the age of 1 year, pharmacokinetic
simulations had been performed, which indicated for the youngest patients (0–3 months
old) median trough concentrations remaining higher than 30 µg/mL for both once weekly
(QW) and once every 2 weeks (Q2W) dosing regimens (EMA/125963/2019, page 48).[46] Median trough concentrations slightly below 30 µg/mL were predicted with once every
4 weeks (Q4W) dosing regimen in patients below 6 months of age. In summary, meaningful
efficacy with all three dosing regimens is also expected in paediatric patients aged
less than 1 year (EMA/125963/2019, page 49).[46]
FVIII inhibitors do not recognize Emicizumab or interfere with its binding to FIXa
and FX, so that Emicizumab restores haemostasis to a similar degree in patients with
or without FVIII inhibitors, making efficacy, safety and pharmacokinetic results in
paediatric patients with inhibitors generalisable to paediatric patients without inhibitors
(EMA/125963/2019, page 128).[46]
Extrapolation of pharmacokinetic results from an adult to a paediatric patient population
may also be possible due to the similarity of Emicizumab's pharmacokinetics in adult,
adolescent and paediatric patients (EMA/125963/2019, pages 130 and 131).[46]
No safety risks specific for the paediatric patients receiving Emicizumab were identified
(EMA/125963/2019, page 165) and collection of additional safety data for the paediatric
population will take place via the proposed post-approval safety study.[46]
The statements in the SmPC[28] for Emicizumab (paediatric population, 4.4, special warnings and precautions for
use, page 8) reflect the missing data for children below the age of 1 year. Under
consideration of the dynamically and evolving development of the haemostatic system
in this patient population, and the relative concentrations of pro- and anti-coagulant
proteins in these patients,[47] a recommendation exists for a benefit/risk assessment concerning the use of Emicizumab
(e.g. central venous catheter-related thrombosis).[28]
In a recent expert review on Emicizumab for HA without inhibitors, Cafuir et al discuss
the use of Emicizumab in PUPs.[43] Several aspects associated with the potential use of Emicizumab in paediatric patients
raise the concerns of the authors.[43]
First, it is not clear if the early administration of Emicizumab, in fact, would delay
FVIII exposure[43] and what the resulting impact is. Whether or not the delayed exposure to FVIII will
produce less or more inhibitors in young children needs to be monitored over time.[43] Second, in patients below the age of 6 months, predicted Emicizumab concentrations
in plasma are 19 to 33% lower compared with older patients.[43] Third, to what extent simultaneous administration of small FVIII doses and Emicizumab
influence inhibitor development needs investigation in a clinical trial.[43] Also, Cafuir et al refer to the low number of PUPs so far investigated (N = 1), supporting longitudinal studies here.[43] Finally, long-term data regarding a positive effect of Emicizumab on arthropathy
and bone density, known from FVIII, are needed.[43]
Monitoring of Emicizumab and FVIII is a challenge.[43]
[48] The plasma concentration of Emicizumab can now be explicitly measured.[43] To obtain information about the overall coagulation profile, the thrombin generation
assay, non-activated rotational thromboelastometry (NATEM) and a novel point-of-care
whole blood coagulation assay, ClotChip, are evaluated.[43]
Investigation of these options is ongoing due to the interference of Emicizumab with
standard, e.g. one-stage and chromogenic (human reagents), activated partial thromboplastin
time (aPTT)-based clotting assays.[43]
[48] In case of measurement of the pure FVIII-dependent clotting activity, chromogenic
(bovine reagents), aPTT-based clotting assays are the first choice.[43]
[48] Due to this and, even more, complicated in the case of existing inhibitors, the
commonly used laboratory approaches for measuring FVIII activity do not work out as
usual, and again the bovine chromogenic assay is recommended, performed in the case
of inhibitors in specialized laboratories only.[43]
[48]
In summary, due to the limitation of data for paediatric patients with SHA without
inhibitors under 2 years of age and not yet investigated or resolved questions associated
with the use of Emicizumab, we currently advise the parents not to use Emicizumab
if their child is a PUP with SHA without inhibitors. In the case of a child with poor
venous access and ‘dramatic’ family history for inhibitors, we feel that a decision
towards the use of Emicizumab can be justified if the alternative would be no prophylaxis
instead or implementation of a central venous line, e.g. a port device.
Conclusion
As outlined in the Introduction, we explore the familial situation and interactions,
and we try to match the information we provide to the existing knowledge about haemophilia.
In practice, we find that some parents are highly interested and well prepared (which
sometimes is a problem itself!), while others tend to listen and will ask their questions
later. However, a few points mentioned are similar to all. We always inform the parents
about the main character of the disease, namely that HA and, especially SHA, is a
rare and chronic disease. Until no further treatment options are available, in PUPs with SHA, economical[33]
[36] replacement of the missing factor (referring to prophylaxis as standard)[24]
[25] is the state-of-the-art treatment to prevent spontaneous- or trauma-induced bleeding
(e.g. ICH),[8]
[9]
[23] to prevent the development of early haemophilic arthropathy[4] and to reduce inhibitor risk.[49] Depending on the history of the patient and his family, the clinical course, the
severity of the disease and the genetic analysis, we discuss the different factor
concentrates and schedules (pd, recombinant with or without extended half-life, on-demand
and prophylaxis), suitable for the patient.
Besides the medical treatment, other factors such as how to inform other specialities
involved and other institutions (e.g. kindergarten, pre-school), to stress the benefit
of sports recommended and to provide network contact details (e.g. patient organization,
group activities, etc.) are other important, non-purely medical aspects that are often
crucial towards coping with this disease.
As long as no more clinical data are available on the use of Emicizumab in children
below the age of 2 years with SHA without inhibitors, we generally remain reluctant
administering Emicizumab. In line with this, the committee on Coagulation Products
Safety, Supply, Access (CPSSA) of the World Federation of Hemophilia asks for clinical
studies in this age group to support the indication in patients at this very young
age in a recent letter to the editor.[50]
In summary, the counselling of parents of a newly diagnosed boy with HA has become
more challenging as regarding the potential use of Emicizumab in paediatric patients
below the age of 2 years with SHA without inhibitor improved convenience (e.g. subcutaneous
administration) has to be carefully weighed up against safety (e.g. outstanding long-term
efficacy and safety data in a representative cohort of this patient group).
However, optimal diagnostic standards and treatment are only one part of the management
of haemophilia at our centre and management is complex. As an example of complexity,
we referred to the impact haemophilia might have on the other family members.[31] As a consequence, the management of haemophilia should be in the hands of specialized
comprehensive care centres with devoted expert teams and a variety of relevant, specialist
departments in immediate reach.[33]
[34]
Our list may not be complete, or the order of the items prioritised is different at
different centres. However, we hope to have provided a concise review of, in our view,
the most important aspects when it comes to counselling of parents of a boy with newly
diagnosed HA.
