Page 2271 - Hematology_ Basic Principles and Practice ( PDFDrive )

2018 Part XII Hemostasis and Thrombosis

IgG1 antibodies can bind complement, this may point to an alternative Regulatory T cells (Tregs), which can suppress the activity of
mechanism for anaphylactic-type reactions without evidence of IgE helper T cells, may have a role in determining whether an individual
mediation. Factors that may confer an increased risk for anaphylactic patient will be immunologically reactive or tolerant to FVIII. T-cell
reactions to FIX include Hispanic race, personal or family history of proliferation in response to FVIII stimulation has been observed in
other allergies, and severe hemophilia B (FIX: C <1%) caused by large Treg-depleted peripheral blood from normal (nonhemophilic) human
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deletions and nonsense mutations of the F9 gene. It is unclear why subjects. In contrast, high levels of Tregs have been shown to suppress
anaphylactic reactions are more common with FIX deficiency than in inhibitor development in mice models; hemophilia A mice treated
FVIII deficiency. It is possible that the extravascular distribution of FIX with rapamycin (a small molecule inhibitor of the serine kinase
is more likely to provoke such a reaction. In addition, therapeutic doses mammalian target of rapamycin [mTOR]) failed to develop inhibi-
of FIX contain much more protein than therapeutic doses of FVIII, tors on exposure to FVIII and had increased number of Tregs com-
which may trigger anaphylaxis. Total deletions of the F9 gene may also pared with control mice. Hemophilia A mice had lower inhibitor
include deletions of adjacent genes whose absence may predispose titers in response to FVIII with infusion of Tregs taken from wild-type
patients to anaphylaxis. mice than without, and Tregs created with chimeric antigen receptor
The acute management of anaphylaxis involves supportive care technology have been shown to suppress anti-FVIII immune responses
and the use of non–FVIII or non–FIX-containing bypassing agents in vitro.
to treat bleeding. Desensitization by repeated administration of Immunologic tolerance to FVIII in people without hemophilia A
concentrate may be successful, particularly in patients with hemo- is not complete. Rarely, usually as a result of autoimmune disease,
philia B. Because of the timing of anaphylactic reactions in hemophilia immunologic tolerance to FVIII fails and autoantibodies to FVIII
B, it is recommended that the first 10 (in those with missense muta- develop; this is known as acquired hemophilia A. Furthermore, anti-
tions) to 20 (in those with deletion and nonsense mutations) FIX bodies to FVIII, detectable by enzyme-linked immunosorbent assay
treatments be given in a controlled setting. (ELISA) and Bethesda assay as well as other methods, can be found
in the plasma of some individuals who do not have hemophilia A. T
cells that are reactive to FVIII can also be found in normal individu-
Inhibitory Antibody Development als, although this reactivity is transient and less intense than in
hemophilia A patients. The relevance of these observations for
This important treatment-related complication is dealt with in hemophilia A patients who have inhibitors is not known. Further
detail in Chapter 136. The current chapter deals with selected understanding of the mechanisms that might prevent normal indi-
issues concerning pathophysiologic mechanisms and inhibitor viduals from developing clinically important autoantibodies to FVIII,
detection only. such as T-cell suppression by Tregs or neutralization of inhibitory
antibodies by antiidiotypic antibodies (antibodies to the antigen-
binding region of the inhibitory antibody), might provide insight
Factor VIII Inhibitors: Pathophysiology into inhibitor suppression in hemophilia A patients.
Fortunately, the majority of patients with hemophilia A who are
FVIII inhibitors in patients with hemophilia A are antibodies of the exposed to replacement FVIII products do not develop inhibitors.
IgG isotype and are typically of the IgG1 and IgG4 subclasses, The reasons for tolerance to FVIII in some patients are not clear.
although inhibitory antibodies of other subclasses are observed as Genetic factors play a role in inhibitor risk (see Chapter 136). It has
well. Some evidence indicates that IgG4 antibodies are predominant been hypothesized that some patients are exposed in utero, via
in patients with high-titer inhibitors, while IgG1 antibodies are more maternal–fetal hemorrhage, to small quantities of maternal FVIII
abundant in patients with low-titer inhibitors. The predominance of that induce immunologic tolerance in the fetus. However, there has
IgG4 antibodies may be a consequence of prolonged exposure to been no observed association between inhibitor risk and intrauterine
exogenous FVIII because this phenomenon has been observed with procedures such as amniocentesis, or with breastfeeding.
repeated administration of other antigens. Inhibitory antibodies may Another theory to explain the development of FVIII inhibitors in
have higher binding affinity than noninhibitory antibodies. some patients is that of immunologic “danger signals”: if a patient
Inhibitors may be classified by the kinetics of their binding to has exposure to FVIII at the same time as exposure to pathogen-
FVIII. Type I inhibitory kinetics is characterized by a linear relation- associated molecular patterns, such as infectious agents or vaccines,
ship between the antibody concentration and the logarithm of the or to damage-associated molecular patterns, such as might occur in
residual FVIII activity; at high antibody concentrations, the inhibi- the setting of surgery or in the setting of a major bleed, this may
tion of FVIII is near total. FVIII inhibitors in patients with congenital induce an immunogenic, rather than a tolerogenic, immune response
hemophilia A usually have type I kinetics. Inhibitors with type II to FVIII. Although specific danger signals, for example molecular
kinetics do not display a linear relationship, and even high antibody patterns that are agonists for toll-like receptors or other receptors in
concentrations do not result in complete inhibition of FVIII activity. the innate immune system have not yet been definitively identified
Type II kinetics are commonly seen in acquired hemophilia A. in association with FVIII inhibitor development; some clinical data
Inhibitors are produced when a FVIII-specific memory B cell is are consistent with the danger signal hypothesis.
stimulated to differentiate into an anti-FVIII antibody–secreting cell
(plasma cell). This differentiation is dependent on binding of FVIII
to the B-cell receptor, and subsequent interaction with a CD4 posi- Transient Inhibitors
tive helper T cell. The important role of helper T cells in the genesis
of inhibitors is supported by diverse data: T-cell proliferation in Some FVIII inhibitors may disappear spontaneously without specific
response to FVIII is increased in hemophilia A patients who have management. Inhibitors may ultimately prove to be transient despite
inhibitors compared with those without. Blockade of CD3, a com- continued on-demand FVIII exposure. This typically occurs with low
ponent of the T-cell receptor complex, has been shown to decrease titer inhibitors (<5 Bethesda units [BU]) but can occur with some
inhibitor formation in vitro, as has stimulation of cytotoxic higher titer inhibitors as well (≤10 BU). Transient inhibitors are also
T-lymphocyte antigen 4 (CTLA-4), an inhibitory receptor involved possible in patients with hemophilia B, but this phenomenon is not
in the downregulation of T-cell stimulation. Decrease of inhibitor well characterized.
titers, and even loss of inhibitors altogether, has been observed in
hemophilia A patients with inhibitors who have HIV infection,
particularly those with very low numbers of CD4-positive T cells. Factor IX Inhibitors: Pathophysiology
T-cell activation that effectively produces inhibitors requires
co-stimulation from antigen-presenting cells (e.g., via the CD40/ As severe hemophilia B is much less common than severe hemophilia
CD40 ligand pathway or the CD28/B7 pathway). A and as a much lower percentage of hemophilia B patients develop