Page 2276 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 136

INHIBITORS IN HEMOPHILIAS

Guglielmo Mariani, Barbara A. Konkle, and Craig M. Kessler

With the availability of plasma-derived and recombinant replacement increasing number of exposure days and is uncommon (≈2/1000
products safe from transmission of known infectious agents, the patient-years) after 150 exposure-days.
development of antibodies neutralizing factor VIII (FVIII) or factor There appears to be a bimodal distribution of inhibitor occurrence
IX (FIX) has become the major complication of hemophilia in severe hemophilia. The incidence peaks in early childhood in those
treatment. younger than 5 years of age (64.3/1000 treatment-years), falls sub-
Antibodies to FVIII can be detected (1) in healthy individuals, stantially between the ages of 10 and 49 years of age (5.3/1000
(2) as expression of an autoimmune disorder, and (3) in patients with treatment-years), and rises again in older age (10.5/1000 treatment-
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FVIII or FIX deficiency (hemophilia A and B). Clinically speaking, years). The latter finding raises the possibility that there is a
11
only those antibodies that affect the clotting activity, which are breakdown of tolerance with aging. Another epidemiologic study
therefore termed inhibitors, are considered relevant because they conducted by the same organization and covering a period of 22
render patients refractory to treatment. In hemophilias, inhibitors years, showed that the rate of inhibitor development may vary over
12
occur after factor replacement therapy with FVIII or FIX concen- time, although the reasons appear unclear. At any rate, there is no
trates. Patients with a severe deficiency (FVIII or FIX less than 1% doubt that inhibitor formation has a negative impact on overall
of normal) are particularly at risk. mortality in severe hemophilia A patients, essentially cancelling out
1
Inhibitor formation in hemophilia was first reported in 1941. A the improved life expectancy realized in patients with severe hemo-
44-year-old man with classic hemophilia had been treated numerous philia A population over the last 30 years. 13
times with blood products, and his hemostasis subsequently became
refractory to transfusions. The authors realized that transfusion may
have caused this heretofore-unknown complication and suggested Genetic Factors
that coagulation times should be checked after administration of
blood products to monitor for the phenomenon. This report was One of the most significant risk factors associated with the develop-
2–5
soon followed by numerous cases reporting the development of a ment of inhibitory alloantibodies in hemophilia A is the presence of
substance that counteracted infused blood product components. The a positive family history. The increased concordance rate of inhibitor
nature of the inhibitor was shown to be an immunoglobulin (Ig) G occurrence in brother and twin pairs 14,15 provided the initial indica-
antibody mainly of the IgG4 subclass. 6 tion that genetic factors play a role in inhibitor development. Having
Alloantibody inhibitors arise much more frequently in patients a first-degree relative with an inhibitor raises the risk for inhibitor
7
with severe hemophilia A (15%–20% with a range of 8%–52%) development threefold, resulting in an approximately 50% chance of
than in those with severe hemophilia B (≈3%–7%). Their occurrence inhibitor development compared with a control cohort in which
is associated with higher morbidity and mortality if modern therapies there is a 15% risk. 14,15
are not available, increased cost of care, and more complicated treat- Patient ethnicity first emerged as a possible risk factor for inhibitor
ment regimens. development in retrospective analyses of the prevalence of inhibitors
in various racial cohorts included within large pooled populations of
hemophiliacs. 15–18 African Americans (AA) and Latinos were observed
HEMOPHILIA A to have a twofold higher rate of inhibitor formation compared with
whites. For instance, in the Malmö International Brother Study
Epidemiology (MIBS), inhibitors were noted in 27.4% of whites and in 55.6% of
15
AA. This same trend was subsequently appreciated in prospective
It is curious that hemophilia A and B, which share an almost identical analyses of inhibitor development in the initial recombinant FVIII
clinical phenotype, would have such a disparate incidence of alloan- concentrate safety and efficacy trials. 19
tibody inhibitor development. The explanation may reside in the type One potential and provocative explanation for the increased
of genetic mutation responsible for each disease. In hemophilia A, propensity of AA with hemophilia to produce FVIII relative to
the severe phenotype is most often caused by a null mutation, which immunoreactivity is a mismatch between the host endogenous wild-
is less common in hemophilia B. Null mutations result in complete type FVIII haplotype polymorphisms found only in AA (H3, H4,
absence of a translated protein product and are more likely to pre- and H5) and their exposure to the exogenous FVIII polymorphisms
dispose to inhibitor formation. Also, FIX shares significant homology found in the commercially available brands of recombinant FVIII
with the other vitamin K–dependent clotting factors, possibly pro- concentrates (either H1 or H2) used for replacement therapy. The
8
tecting against inhibitor development. Finally, it is hypothesized that risk for alloantibody inhibitor development is significantly higher
because FIX is smaller and more abundant than FVIII, some FIX among AA with haplotypes H3 or H4 than it is in those with the
may cross the placenta, thereby inducing tolerance in the developing H1 or H2 haplotype (odds ratio [OR] of 3.4). These observations
fetus. 8 await confirmation in larger studies. 20
Among patients with severe hemophilia A, approximately 30% Emerging data consistently indicate that certain FVIII mutations
7,8
will develop an alloantibody inhibitor (compared with 3% of those producing phenotypically severe hemophilia A are strong predictors
9
with moderate hemophilia and 0.3% with mild hemophilia). Inhibi- of inhibitor development. 21–23 Three general categories of mutations
tor formation occurs early after initiation of replacement therapy. in FVIII have been considered for patients at “high risk” for inhibitor
Data from prospective clinical trials of recombinant FVIII reveal that formation: (a) inversions of intron 22 (intrachromosomal recombina-
inhibitor development typically arises within a median of 8 to 10 tions), (b) large deletions affecting more than one domain, and (c)
“exposure-days” (treatment-days), but a wide range is not uncom- nonsense mutations involving the light chain (the risk for inhibitor
10
mon. The risk for inhibitor development decreases inversely with formation is twofold higher with light chain mutations than with
2023