Page 2277 - Hematology_ Basic Principles and Practice ( PDFDrive )

2024 Part XII Hemostasis and Thrombosis

heavy chain mutations). 7,21 All of these mutations either eliminate case-control study suggested that early age of first exposure to FVIII
FVIII protein altogether or alter the molecular conformation of the treatment reflected the severity of the hemophilia conveyed by the
FVIII protein in such a way that innate immune tolerance cannot be particular FVIII gene mutation. Thus more intense FVIII replace-
achieved during fetal development. Consequently, the immune ment and high-risk FVIII gene polymorphisms were more strongly
system recognizes exogenously administered native FVIII protein as associated with inhibitor formation than was age. In fact, there
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“foreign.” The “low-risk” FVIII mutations consist of small gene appeared to be a protective effect against the formation of inhibitors
deletions/insertions, missense mutations, and splice site mutations. It when children were started on primary FVIII prophylaxis regimens
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is postulated that some “nonfunctional” FVIII protein is produced early in life. The United Kingdom Haemophilia Centre Doctors’
with these FVIII gene mutations, which may be sufficient to induce Organisation (UKHCDO) study reported that peak inhibitor forma-
partial central immune tolerance. 21 tion occurs in children younger than 5 years of age. 11
Even with genetic information, it is not possible to predict which The method of FVIII infusion (continuous infusion versus bolus
patients are at highest risk for development of alloantibody inhibitors. administration) and the clinical scenarios for FVIII replacement have
Inhibitors in the high-risk category occur 7- to 10-fold more fre- also been examined for their contribution to inhibitor formation.
quently for large deletions and nonsense mutations (pooled OR, 3.6; Although administration of FVIII by continuous infusion has the
95% confidence interval [CI], 2.3–5.7 and 1.4 CI, 1.1–1.8, respec- advantage of requiring less factor replacement over time and avoids
22
21
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tively) (≈35%) compared with those with intron 22 inversions. the peaks and troughs seen with bolus administration, intense
Furthermore, inhibitors occur less frequency with small FVIII gene replacement of FVIII by continuous infusion was more likely to
22
deletions/insertions (≈7%) or missense mutations (≈4%) (pooled induce inhibitor development than bolus injections (57% versus
OR, 0.5 [95% CI, 0.4–0.6] and 0.3; 95% CI, 0.2–0.4, respec- 14%) in patients who were otherwise considered to be at low risk
tively). 21,22 Intron 22 inversions are associated with a lower inhibitor (i.e., mild hemophiliacs). 32,33 These results were gleaned from the
frequency than would be anticipated for a genotype that produces no retrospective examination of the medical records of 54 mild hemo-
circulating FVIII protein. However, recent data suggest that some of philiacs, of whom only seven had received FVIII by CI; a prospective
these hemophiliacs may possess intrahepatocyte-endogenous FVIII study in a larger population remains to be conducted to confirm this
21
protein fragments, which can induce partial immune tolerance ; finding. On the other hand, intensive FVIII replacement in the
most recently, experimental data confirmed the low-risk categoriza- context of injury, surgery, or inflammation appears conducive to
tion of intron 22 inversion by demonstrating that patients bearing inhibitor formation. In the retrospective CANAL study (concerted
this change produce intracellular peptides that may act as tolera- action on neutralizing antibodies in severe hemophilia A) of previ-
gens. 24,25 There does not appear to be any relationship between the ously untreated patients (PUPs), 65% of those whose first exposure
type of FVIII gene mutation and the relative risks for developing to FVIII therapy was associated with surgery developed an allogeneic
high-titer versus low-titer alloantibody FVIII inhibitors. 21 FVIII antibody inhibitor (relative risk, 3.7), compared with a 23%
inhibitor incidence when first exposure was not related to a “danger
signal” indication. 33
Environmental Factors As concerns surgery, a very common procedure of minor surgery,
circumcision, was analyzed with respect to the occurrence of inhibi-
Despite the strong FVIII-related genetic influences that underlie tors: 3 of 25 patients among those circumcised developed an inhibitor
inhibitor formation, clinical observations indicate that various envi- versus 4 of 36 of age-, therapy- and intron 22 inversion-matched
ronmental or epigenetic pressures contribute to the development of patients not circumcised; all inhibitors were high-titer and median
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alloantibody inhibitors. For example, within the MIBS cohort, there ED was 16 days for both groups. This observational study would
are discordant monozygotic twins (i.e., identical twin brothers with suggest that minor surgery does not increase the risk associated with
the same mutations) in which only one brother developed an inhibi- replacement therapy or intron 22 inversion.
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tor. In addition, among families with high-risk gene mutations, only Perhaps the most controversial “environmental” risk factor for
about 30% of siblings with severe hemophilia A because of the intron alloantibody inhibitor development involves the type of FVIII con-
22 inversion develop inhibitors. Even with multidomain deletions, centrate replacement used by the patient (low- to intermediate-purity
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the highest estimated inhibitor risk only approaches 75%, implying plasma-derived FVIII versus high-purity plasma-derived FVIII versus
that other patients with the same mutation are somehow protected recombinant FVIII concentrates). After more than 20 years the ques-
against inhibitor formation. tion of whether the use of recombinant FVIII concentrates (highest
A concerted effort has been made to explore the importance of purity) leads to a higher inhibitor incidence than the lower purity
other genetic determinants in hemophilia A patients that may con- concentrates remains largely unresolved. 35,36 This debate originated
tribute to alloantibody inhibitor development. Of the immune with the prospective trials of first-generation recombinant FVIII
response genes, the presence of a microsatellite polymorphism in the concentrates in PUPs, which mandated frequent monitoring for
promoter region (134 base pair variant) of the interleukin (IL)-10 inhibitor formation (at least every 3 months). 37,38 In the Kogenate
gene, which may lead to upregulated B-lymphocyte activity, has been trial, the total incidence of any inhibitor formation in patients with
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associated with a 73% incidence of inhibitor formation (OR, 4.4). severe hemophilia A was 29.2% within a median of 9 exposure days.
A G308A polymorphism in the promoter region of the tumor A similar inhibitor incidence rate of 31.5% was found in a prospec-
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necrosis factor α gene (A/A genotype) has been associated with tive trial of Recombinate. Thus when compared with the inhibitor
72.7% inhibitors and an OR of 4.0. On the other hand, there is no incidence rate of approximately 10% reported in older retrospective
robust evidence that polymorphisms of major histocompatibility studies, which used low-purity plasma-derived FVIII concentrates
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complex (MHC) class II alleles or of other inflammatory cytokine and screened less frequently for inhibitors, recombinant FVIII
genes contribute to alloantibody inhibitor development. 22–26 All in seemed to be significantly more immunogenic. Prospective monitor-
all, the associations of distinct human leucocyte antigen haplotypes ing of patients receiving high-purity plasma-derived FVIII concen-
and of polymorphisms of immunoregulatory genes with the risk of trates revealed a similar inhibitor rate as seen in those given
patients developing FVIII inhibitors seems to be modest. recombinant concentrates. 42
Among possible environmental risk factors, age at first treatment A number of variables may have contributed to these observations,
has been implicated as a major independent contributor for inhibitor thus reducing their clinical relevance. The recombinant FVIII trials
development: initial observations suggested that the earlier the first in PUPs were the first large prospective clinical trials of hemophilia
exposure to FVIII-containing products occurred, the greater the risk treatment, so their comparison with results of anecdotal or retrospec-
was for alloantibody inhibitor formation. 26–29 Children treated before tive case reports and case series is inappropriate. 33–39 These trials were
6 months of age have a cumulative inhibitor incidence of 41% also the first to use routine and frequent prospective monitoring for
compared with a 12% incidence if initial exogenous FVIII exposure inhibitor development. In prior studies, testing for inhibitors was
is delayed until after the first year of life. Results of a subsequent done only when deemed clinically important. Continued analysis of