Page 2285 - Hematology_ Basic Principles and Practice ( PDFDrive )

2032 Part XII Hemostasis and Thrombosis

remissions. Recently, Rituximab was used at the time of the first prevent bleeding regardless of whether it is spontaneous in nature or
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anamnesis occurred during ITI but a major response (titer <5 BU) induced by trauma or surgery. However, because APCC contains
was seen in only 3 out of 16 (18%) patients. 157 significant amounts of FIX, which may induce anamnesis, some
Data on the risk of inhibitor recurrence during follow up are experts prefer rFVIIa.
scanty. Essentially, once the inhibitor has been eradicated, the risk of Few treatment options exist for patients with FIX inhibitors who
a recurrence is very low, in the range of 1% to 5%, and may occur have experienced allergic reactions to the FIX antigenic material
many years afterwards, as shown by some studies that tackled the found in plasma, as in PCC, APCC, high-purity plasma-derived FIX
matter. 141,142,144,152,158 concentrate, or even in recombinant FIX concentrates. Anaphylaxis
The new FVIII products (glycol-pegylated, fused to an Fc protein is in fact, a major complication that can occur soon after the infusion
or to albumin) have not yet been used in ITI. The question is whether of FIX-containing replacement therapies, manifesting as either a type
these concentrates display a reduced immunogenicity in vivo, as II (dyspnea and hypoxia, and generalized hypersensitivity) or a type
suggested by preliminary studies in animals or in vitro. 159,160 III (anaphylaxis and hypotension) allergic reaction. The rarity of
anaphylactic complications in patients with hemophilia B with FIX
inhibitors (only an estimated 35 cases have been reported) does not
HEMOPHILIA B negate the seriousness of this complication. 162,166,167 In addition, this
is likely an underreported and perhaps underrecognized event. The
The development of inhibitors to FIX in severe hemophilia B follows major risk factor for developing an anaphylactic reaction is the pres-
the same general principles as in hemophilia A. Inhibitory alloanti- ence of a FIX gene null mutation, leading to an absence of circulating
bodies may arise after administration of FIX-containing replacement FIX antigenic material. 168
products, and this phenomenon was appreciated very soon after Because these severe reactions occur only after initiation of treat-
hemophilia B was documented to be a separate entity from hemo- ment, they have been observed only in children (median age 12
161
philia A. However, several distinct features in the epidemiology and months), occurring early, following a median of 11 exposure days.
treatment of FIX inhibitors in severe hemophilia B deserve a specific The development of anaphylaxis occurs at the same time as the
mention. These include (1) the lower incidence and prevalence of appearance of an inhibitor. A recent survey on the topic has shown
FIX inhibitors; (2) the increased risk for developing anaphylaxis after that allergic reactions can be elicited with either recombinant or
administration of FIX-containing concentrates to FIX inhibitor plasma-derived FIX concentrates at similar rates (3.9%). 169
patients; (3) the risk for developing nephrotic syndrome after expo- Because experience with anaphylaxis is limited by its low inci-
sure to FIX-containing replacement products; and (4) the lower dence, some general practice guidelines have been developed:
success rate of ITI for the eradication of FIX alloantibodies. 162,163
1. For newly diagnosed hemophilia B patients, especially those with
high-risk FIX gene mutations, the initial FIX replacement treat-
Epidemiology ments should be conducted in a medical facility where hemophilia
expertise and resuscitation equipment are available. 162
Patients with severe hemophilia B have a 10-fold lower risk for 2. Once a FIX inhibitor has been documented, FVIIa is the treat-
developing inhibitors compared with those with severe hemophilia A ment of choice for active bleeding and for prophylaxis against
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(3% vs. 30%). FIX gene mutations associated with a very low risk bleeding.
for inhibitor formation are single amino acid substitutions, whereas 3. ITI is generally ineffective in these patients, although tolerance to
the risk for inhibitor development approaches 20% with more sig- FIX has been reported with progressively increasing doses of FIX
nificant mutations, such as frameshift mutations, premature stop (desensitization procedure) administered with hydrocortisone. 162,167
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codons, large deletions, and splice site mutations. Patients with 4. FIX alloantibody formation may be complicated by a nephrotic
hemophilia B who are at highest risk for inhibitor development have syndrome, especially in patients who previously experienced an
a severe phenotype as a result of large gene deletions or other aber- allergic reaction to FIX replacement. The limited data available
rations of the gene product, such as nonsense mutations. Although suggest that this syndrome is not the result of immune complex
the latter mutations are found only in a small fraction of the hemo- deposition, and it does not respond to corticosteroid treat-
philia B population, they account for approximately 50% of the ment. 170,171 If nephrosis occurs, FIX doses should be reduced or
inhibitor population. 164 treatment should be discontinued and rFVIIa therapy should be
used instead. 171
5. In a few refractory cases with or without nephrosis, immune
Diagnosis modulation (anti-CD20, 172,173 cyclosporine A or mycophenolate
174
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mofetil ) resulted in temporary tolerance to FIX.
As in hemophilia A, an inhibitor should be suspected in hemophilia 6. Prophylaxis regimens with FVIIa (or APCC, if anaphylaxis and/
B when a patient ceases to respond to conventional replacement or anamnesis is not an issue) may be useful in the context of
treatment. Given the possibility of anaphylaxis that may occur with high-titer FIX inhibitors; however, controlled trials are necessary
initial treatment of bleeding episodes, patients with high-risk FIX before this approach becomes the standard of care.
gene mutations should be regularly screened for alloantibody inhibi-
tors. The laboratory diagnosis for inhibitors in hemophilia B involves As information available on inhibitors to FIX is scant, the literature
a modification of the BA used for the titration of FVIII inhibitors. on ITI procedures does not support clinically useful decisions.
In this case, FIX-deficient plasma is used instead of FVIII-deficient However, ITI should be used only in those patients who never dis-
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plasma. In contrast to the FVIII inhibitor scenario, FIX inhibitors played allergic symptoms related to FIX concentrates. All in all, ITI
rapidly neutralize FIX in the normal plasma/patient plasma mixing is less effective than in hemophilia A as shown by the North American
studies: there is no time-dependent increase in the inhibitory increase Immune Tolerance Registry (NAITR) where an overall success rate
of FIX alloantibodies over incubation at 37°C with either high- or of 31% was reported. 144,145
low-titer FIX inhibitors.
FACTOR VII DEFICIENCY
Treatment
Congenital Factor VII deficiency is the third most frequent among
Treatment of hemophilia B in patients with FIX inhibitors mirrors the congenital clotting disorders. Recent epidemiologic studies pro-
that of hemophilia A complicated by FVIII inhibitors. Both APCC vided a higher than expected prevalence in the general population,
5
and rFVIIa are the key therapeutic modalities to reverse, control, and of about 1–2 cases/10 , with severe phenotypes accounting for about