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2128 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2129

followed by half this amount every 12 to 18 hours. Dosing should be with inhibitors. Of the reported cases, many patients were younger
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monitored by assays of factor IX before and after bolus administration. than 12 years of age, and suffered from severe hemophilia B as a result
Factor IX also can be administered as a constant infusion in hospital- of large deletions of the factor IX gene. The nephrotic syndrome may
ized patients after the bolus administration. The dose of factor IX to be be transient and remit upon cessation of factor IX replacement. The
infused per hour can be estimated based on a factor IX half-life of 18 to pathogenesis of the nephrotic syndrome is not known. Patients with
24 hours. Thus, in a 60-kg adult who receives highly purified factor IX, hemophilia B and factor IX antibodies who experience anaphylaxis with
6000 U of the factor should raise the factor IX level to approximately factor IX infusions and have hemorrhage should be treated with factor
100 percent of normal. Over the next 12 to 18 hours, the level decreases VIIa concentrates because both unactivated prothrombin complex con-
by approximately 50 percent. Thus, the patient needs approximately centrates and FEIBA contain factor IX. 112
3000 U of factor IX during that period or 250 U of factor IX per hour
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as an infusion. These calculations are only estimates of aver- Curative Approaches for Hemophilia: Liver Transplantation
age responses, so factor IX dosing should be monitored by factor and Gene Therapy
IX assays and the dose adjusted appropriately. Prophylactic therapy Normal livers have been transplanted successfully into patients with
for hemophilia B also can be attempted in individuals selected in the same hemophilia A or B, with resulting cure of the hemophilic condition. 113,114
manner as that described for hemophilia A patients. The prophylactic The procedure is most often performed for end-stage chronic viral hep-
dose of factor IX is 25 to 40 U/kg of body weight two times per week or atitis that afflicts many older hemophilic patients. However, given the
50 to 100 U/kg every 7 to 10 days if using extended half-life products. obvious limitations of this approach, it cannot be considered a viable
Although currently available factor IX concentrates are safe in treatment option to treat hemophilia per se.
terms of transmission of HIV and hepatitides B and C viruses, patients On the other hand, gene replacement therapy for hemophilia
treated prior to 1985 may have been infected with these agents. offers an ideal theoretical approach for prophylactic therapy or even for
a definitive cure. Proof of concept of gene therapy as a viable long-term
COURSE AND PROGNOSIS option for the treatment of hemophilia B has been established, as dis-
Unless treated properly, severe hemophilia B is fraught with the same cussed below. Currently, however, the challenges associated with gene
transfer of the much larger FVIII gene have slowed down progress in
complications of recurrent hemorrhages as hemophilia A. Thus, hemar- the development of gene therapy for hemophilia A, although these lim-
throses and chronic hemophilic arthropathy are common in inade- itations are being addressed.
quately treated patients. In addition to joint deformities, chronic active There are several approaches by which the defective gene encoding
hepatitis is common in patients treated before 1985. Approximately factor VIII or factor IX can be introduced into a congenitally deficient
50 percent of older and severely affected patients now are HIV-positive. host (Chap. 29). Viruses have evolved to introduce genetic material into
Patients treated after 1985, when HIV testing became available, are not target cells, and are usually employed as the vector, or “Trojan Horse”
likely to have contracted HIV. to allow transfection or transduction of the genetic information. 115,116
Patients with severe hemophilia B may develop inhibitory antibod- Several potential vectors have been used in clinical gene therapy studies
ies against factor IX, making treatment very difficult. 110,111 Approximately for hemophilia and other single gene disorders over the past 2 decades,
3 percent of patients with severe hemophilia B develop specific inhibitor including adenoviruses, recombinant adeno-associated viral vectors
antibodies, frequently restricted in immunoglobulin composition to the (rAAVs), and retroviral vectors, which include the lentiviral vectors
IgG subclass and κ light chains. Most inhibitors can be detected when based on HIV-1. At present, rAAVs are favored by the majority of
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the aPTT of a mixture of normal plasma and the patient’s plasma is pro- ongoing trials in hemophilia, although preexisting immunity to some
longed. In contrast to the inhibitors in hemophilia A patients, inhibitor of these naturally occurring serotypes, which limits their use, is quite
antibodies against factor IX are not time and temperature dependent; prevalent (up to 40 percent) in human populations. Although concerns
thus, incubating the mixtures for 2 hours at 37°C usually is unnecessary. exist about oncogenic genotoxicity (also known as insertional mutagen-
Inhibitors to factor IX can be quantitated by modifying the Bethesda esis) associated with the earlier generation lentiviral vectors, they also
method for detecting factor VIII inhibitors. Many patients with inhib- have theoretical benefits; specifically, they are capable of infecting both
itors have mutations that result in the absence of circulating factor IX dividing and nondividing cells with resultant persistent expression after
antigen, most commonly because of deletions and nonsense mutations. integration into the host cell genome. In addition, they avoid the vector-
mediated cytotoxicity (such as hepatic transaminitis) and immunologic
TREATMENT OF PATIENTS WITH FACTOR IX reactions associated with rAAV. 117
Certain vectors (such as rAAV) can be injected intravenously—
INHIBITOR ANTIBODIES usually on a single occasion—with resultant tropism of the vector and its
When the inhibitor titer is less than 5 BU/mL, the factor IX inhibitor payload to the liver. Previously, gene transfer via multiple intramuscular
possibly can be neutralized using large doses of highly purified factor IX injections was also evaluated, and while not unduly toxic, sustained lev-
concentrates. However, when the inhibitor titer is greater than 5 BU/mL, els of factor IX greater than 1 percent were not maintained long-term.
acute bleeding in patients should be treated with the same agents These “in vivo” gene transfer protocols vary from “ex vivo” gene therapy,
used to bypass factor VIII inhibitors (see Table 123–5). Recombinant in which a specific type of cell is targeted before being reintroduced into
factor VIIa in doses of 90 to 120 mcg per kilogram body weight admin- the host. Target cells used for gene transfer in hemophilia have included
istered intravenously every 2 to 3 hours can be used. Alternatively, human fibroblasts, hematopoietic stem cells, and platelets.
FEIBA at a dose of 50 to 100 U per kilogram body weight every 8 to Despite a number of early phase clinical trials over 20+ years, it was
12 hours (not to exceed 200 U/kg per day) or nonactivated prothrombin not until 2011 that the first report of predictable and consistent mainte-
complex concentrates can be used. nance of factor IX levels (in the range of 1 to 6 percent of normal) was
Induction of immune tolerance can be attempted in hemophilia achieved in six subjects with hemophilia B. The bleeding frequency and
B patients using daily infusions of purified factor IX preparations. clotting factor usage was reduced by 90 percent in these patients. This
However, significant adverse reactions, including anaphylaxis and experience, from the groups at University College London and St. Jude’s
nephrotic syndrome, have been reported in severely affected patients Research Hospital in Memphis, Tennessee, was updated with a followup

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