The hemophilia community is living in exciting times, thanks to recent and relevant
developments in this field and great expectations for new treatment approaches that
are able to significantly and positively affect patients' outcomes and quality of
life.[1]
[2]
[3]
[4]
[5] Interestingly, one most important innovation, a hemostatic agent enabling a very
effective prophylaxis of bleeding given subcutaneously (the bispecific antibody against
factor [F] X and activated FIX emicizumab),[2]
[3] is being introduced for patients who developed alloantibodies against FVIII, the
so-called inhibitors. The management of these patients has always been considered
challenging because inhibitors make the standard effective and safe replacement with
FVIII concentrates unfeasible and, therefore, make difficult the treatment of bleeding,
leaving patients at a high risk of complications, both in the acute phase and in regard
to long-term morbidity.[6] Due to the epidemiological impact of inhibitors (present in ∼30% of previously FVIII-unexposed
patients and persistent/high titer in two-thirds of cases),[6]
[7] searching for pathophysiological mechanisms and strategies for management is particularly
important in hemophilia A (HA). Indeed, a relevant body of literature addressing such
issues has been generated over the last decades. However, significant challenges are
also raised by the inhibitors encountered, albeit less frequently, in clinical practice
in other congenital bleeding disorders (CBDs): (1) in hemophilia B (HB) and von Willebrand's
disease (VWD), additional morbidity due to allergic reactions can occur;[6]
[8] (2) in rare CBDs, little information concerning management is available;[9] and (3) in deficiencies of platelet membrane glycoproteins, the clinical impact
of alloantibodies and alternative treatment approaches are poorly understood.[10] With this background, the 11 chapters presented in this latest issue of Seminars in Thrombosis and Hemostasis deal with the current state of the art of pathophysiology and management of alloantibodies
in CBDs. It is easy to understand why seven of them focus on hemophilia, particularly
on HA, discussing, at this current time of possible evolving scenarios, the most recent
literature data. Alloantibodies in HB, VWD, rare CBDs, and congenital deficiencies
of platelet surface glycoproteins are reviewed in the remaining four chapters.
Three chapters focus on novel approaches to gain insight into molecular mechanisms
of inhibitor development in hemophilia. In this respect, the role of genetic factors,
particularly of the causative mutation type, and their complex interaction with nongenetic
risk factors are well established, with extensive studies in HA.[11]
[12] Margaglione and Intrieri therefore briefly review available evidence concerning
both genetic, nonmodifiable and potentially modifiable risk factors, highlighting
the so far unanswered need for clinical scoring systems to predict and quantify the
inhibitor risk in each patient.[13] These authors also report how complex and multifactorial phenomena, such as inhibitor
development, are currently being addressed by the “omics” technologies, that is, the
holistic approaches developed for studying biomolecules such as DNA, RNA, and proteins
when, in the lack of a definite or proposed hypothesis, all data are acquired and
analyzed to generate hypotheses. Thus, genome-wide expression studies investigate
the activity of the genome rather than inherent genome variations and may identify
which genes (and to what extent) are “switched on” in any given situation, such as
when inhibitors develop. These studies may enable a more accurate estimation of the
personal risk profile, even at periodic assessment, to draw information to predict
and, perhaps, prevent inhibitor formation.[13]
The increasingly acknowledged pivotal role of the modulation of immune response in
inhibitor generation is addressed in the next article by Delignat et al.[14] These authors summarize the latest findings regarding the molecular interactions
leading to the recognition of FVIII by the immune cells and to the possible outcomes
of such interactions, that is, T-cell activation or tolerance induction, the validity
of the proposed risk factors for FVIII alloimmunization in the light of the danger
signal theory, and the possible therapeutic approaches to prevent or control the anti-FVIII
immune response. These strategies, evaluated in preclinical models of HA, are aimed
to prevent HLA-DR (human leukocyte antigen - antigen D related) mediated interactions
between antigen-presenting cells and T cells, or to inhibit B cells, or to induce
T-cell specific tolerance.[14]
Searching for therapeutic approaches able to prevent or eradicate inhibitors is not
exclusive of hemophilia. Hassan et al report an interesting overview of alloantibody
prevention or eradication strategies used in other diseases in the attempt of drawing
lessons for HA.[15] In patients with Pompe's disease, the possibility of effectively preventing inhibitors
with rituximab, methotrexate, and intravenous immunoglobulins is, however, associated
with a high risk of adverse events. In patients with rheumatoid arthritis and inflammatory
bowel disease, treatment with methotrexate alone is likely to be able to prevent inhibitors.
However, besides side effects, it is unclear whether such prevention persists after
cessation of immunomodulatory therapy with methotrexate. A combination of cyclophosphamide
and corticosteroids, used to treat antibody-mediated pure red cell aplasia, could
be taken into consideration to eradicate inhibitors in HA patients who are refractory
to immune tolerance induction (ITI).[15] Overall, the transferability of these concepts to HA should be carefully investigated.
Two further chapters deal with the management of bleeding in hemophilic patients with
inhibitors, currently based on bypassing agents (activated prothrombin complex concentrate
and recombinant activated FVII).[16] As reported by Barg et al,[17] treatment of bleeding should be tailored according to the characteristics and response
of each patient, taking into account that no validated assay is currently available
to predict the risk of bleeding or the response to treatment, monitoring its efficacy
and safety. These authors report their institutional approach for individual therapy
tailoring, including the use of global hemostatic assays, increasingly used to assess
coagulation status in this setting and potentially useful even for the emerging nonreplacement
therapies.[17] Consistent with the search for individualized treatment, the survey performed by
the Italian Association of Hemophilia Centers, reported by Coppola et al,[18] describes the treatment regimens with bypassing agents adopted in inhibitor patients
and criteria for clinical choices.[18] Interestingly, to avoid severe, recurrent, and/or difficult-to-treat bleeding, prophylactic
regimens with both bypassing agents are used in almost 40% of patients. These regimens
are quite heterogeneous, with adjustment of doses and frequency of administration
to optimize clinical outcomes, mainly in younger patients.[18] Due to the huge impact of inhibitor development on costs of treatment, pharmacoeconomic
analyses are crucial in this setting but remain controversial. As reviewed in the
article by Messori,[19] relevant issues include treatment in high-titer versus low-titer inhibitors, influence
of FVIII products on inhibitor risk, effectiveness of different ITI regimens, different
types and regimens of bypassing agents, and, presently, the development of new nonreplacement
approaches. In particular, data on cost-effectiveness of ITI are not conclusive; however,
the high investment of inhibitor eradication seems to be offset in the long term by
the subsequent savings in the cost per patient. Interestingly, even from the pharmacoeconomic
perspective, novel treatments (i.e., emicizumab) are likely to deserve substantial
advantages in patients with inhibitors.[19]
The last chapter concerning alloantibodies in HA deals with those arising in patients
with nonsevere HA. Recent data indicate that at variance with severe HA, inhibitor
development in this setting shows a lifelong risk but is similarly associated with
a deterioration of clinical outcomes, with increased bleeding and mortality rates.[20]
[21] Abdi et al review available data on risk factors for inhibitors in nonsevere HA,
including specific F8 missense mutations as well intensive treatment, for example, on the occasion of surgical
interventions or severe bleeding treated with high doses of FVIII concentrate. Even
in this setting, adequate prevention and treatment of inhibitors is limited by the
poor knowledge of the underlying immunological mechanisms required to identify high-risk
patients, to understand the association between clinical risk factors and inhibitor
occurrence, and to provide the opportunity to develop new preventive and therapeutic
strategies.[22]
The development of inhibitors against FIX is less frequent in HB (1.5–3% of all patients)
than in HA and occur almost exclusively in severe patients and in tight association
with specific F9 genotypes.[23] However, rigorous epidemiological studies of incidence are lacking, and recent analyses
in the highest-risk population of previously unexposed patients with severe disease
suggest that inhibitor rates are higher than previously reported.[24] In spite of comparative rarity, inhibitor development in HB is associated with a
relevant morbidity not only due to the bleeding risk but particularly due to the occurrence
of allergic/anaphylactic reactions after FIX concentrate exposure. These issues are
comprehensively reviewed by Santoro et al,[25] who report the data available on risk factors, pathophysiology, and clinical aspects
of inhibitors in HB, focusing on the challenging management in patients with a history
of allergy or anaphylaxis. Indeed, ITI is often unsuccessful and can be affected by
complications such as nephrotic syndrome. For these reasons, alternative therapeutic
strategies, now in development, are highly needed.[25]
Similar low frequency and possible serious complications are reported for alloantibody
development in VWD. Franchini and Mannucci review the few available data on such complications,[26] described almost exclusively in type 3 VWD, again with higher risk in patients carrying
severe gene abnormalities (complete or partial deletions). Beyond difficult-to-treat
bleeding, the management in some cases is even more challenging because anti-von Willebrand
factor (VWF) alloantibodies, particularly when in high titer, may precipitate VWF
with immune complex-mediated activation of the complement system and be responsible
for life-threatening anaphylactic reactions following reexposure to VWF.[26] Overall, the rarity of alloantibody development in CBDs other than HA hampers collection
of adequate information about risk factors, clinical aspects, and management. This
limitation particularly applies to inhibitors anecdotally reported in rarer CBDs,
that is, FV, FVII, FXI, and FXIII deficiencies. The available data for these are described
by Franchini et al,[27] who highlight that incidence of inhibitors is unknown or underestimated, risk factors
are not elucidated (an association with specific gene mutations has been shown only
in FXI deficiency), and management is typically driven by clinical experience, often
extrapolated from patients with hemophilia and inhibitors. These authors, therefore,
welcome the implementation of collaborative international collection of data in this
setting to improve knowledge and management of these cases.
The last chapter of this issue by Poon and d'Oiron[28] deals with alloantibodies arising in patients with deficiencies of platelet membrane
glycoproteins following platelet transfusions. These antibodies are directed against
HLA antigens and/or the missing glycoprotein(s) (GPs), with anti-αIIbβ3 and anti-GPIb-IX
in Glanzmann thrombasthenia and Bernard–Soulier's syndrome, respectively, being the
most studied clinical settings. Circulating alloantibodies may render future platelet
transfusion ineffective, causing platelet refractoriness. Moreover, anti-αIIbβ3 and
anti-GPIb-IX may cross the placenta during pregnancy and cause thrombocytopenia and
bleeding in the fetus/neonate. The authors review a series of unresolved issues of
platelet antibodies, i.e., poor knowledge of risk factors for their development, inadequate
standardization of diagnostic assays that are not widely available, and lack of clear
relationship between platelet antibodies and platelet refractoriness in clinical practice.
However, an alternative therapeutic agent to platelet transfusion, recombinant FVIIa,
has been shown to be helpful in the management of patients with platelet disorders,
particularly those with platelet antibodies and/or platelet refractoriness.
In conclusion, the excellent contributions published in this issue clearly depict
the current scenario of alloantibodies in CBDs, with many pathophysiological, clinical,
and therapeutical shadows faced by clinicians and researchers. Despite these uncertainties,
newer, relevant lights are now expected to cast the shadows aside, for the first time
in the history, earlier in inhibitor than in noninhibitor patients.
