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2124 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2125

pain associated with loss of function, and several weeks of replacement antibodies against factor VIII has been, and continues to be, one of the
therapy may be needed postoperatively. 57 more serious complications of replacement therapy.

Home Therapy Factor VIII Inhibitors
Home therapy using available factor VIII concentrates was introduced Other than the transmission of viral diseases by factor VIII infu-
in the United States in 1977 and was a major advance in the treatment sions, the main complication of hemophilia A replacement therapy is
of all forms of hemophilia. 58,59 Current practice for home therapy is to the development of specific inhibitor antibodies that neutralize factor
treat patients at home using a regular prophylactic regimen. Patients, VIII. The reported prevalence of anti–factor VIII inhibitors in severe
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age 6 years and older, can be taught to treat themselves with factor VIII. hemophilia A patients is variable, ranging from 3.6 percent to 27 per-
The training of patients and their families for home therapy is best cent. In the white population the estimated prevalence is approximately
accomplished in a regional comprehensive hemophilia diagnostic and 13 percent, compared to 27 percent and 25 percent in the black and
treatment center or an affiliate of one of these centers. Patients are given Hispanic population, respectively. The risk of inhibitor development
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an adequate quantity of factor concentrates and the supplies required is higher in patients with large deletions and nonsense mutations when
for intravenous administration. Prompt treatment of hemarthroses and compared to small deletions/insertions and missense mutations. Fre-
hematomas made possible by home therapy has markedly improved the quent testing for inhibitors in previously untreated patients receiving
morbidity and mortality associated with hemophilia. In addition, the newer highly purified factor VIII products from plasma or by recombi-
quality of life of hemophilia A patients has improved dramatically. 59,60 nant technology revealed the frequent occurrence of transient inhibitors
to factor VIII, many of which were of low titer and did not necessitate
Prophylactic Therapy cessation of treatment with the same product. Although still controver-
The advent of stable and safe factor VIII concentrates has made pro- sial, some believe that the risk of inhibitors does not appear to be higher
phylactic therapy for hemophilia A in severely affected patients feasi- with the use of highly purified products than the risk reported in ear-
ble. Such therapy is now the treatment of choice for all severely affected lier studies using products of intermediate purity that contain VWF. 69–74
hemophilia patients (unfortunately, such treatment is not available or Some studies have reported that VWF is immunomodulatory, so that
affordable for all patients). Administration of 25 to 40 U of factor VIII products containing VWF may be less likely to induce inhibitors com-
per kilogram of body weight three times per week or every other day pared to highly purified products. One outbreak of inhibitors in Europe
markedly decreases the frequency of hemophilic arthropathy and other appeared to be related to the neoantigenicity of an intermediate-purity
long-term effects of hemorrhagic episodes. 60–62 Primary prophylaxis is plasma-derived factor VIII concentrate. Fortunately, inhibitors disap-
usually initiated before the age of 2 years or after the first joint bleed, peared from affected patients when use of the product was stopped. 75
which is usually when the child begins to walk. Central venous cathe- Table 123–4 lists the risk factors that have been associated with
ters may be required sometimes for very young children; however, they the development of inhibitors. They arise most frequently in severely
are associated with a risk of infections and thrombosis. Secondary affected patients, following treatment at an early age. Many have gross
63
prophylaxis is started after the onset of hemarthrosis and can be used gene rearrangements or the intron 22 inversion abnormality of the fac-
for short periods of time or to manage target joints. The consumption tor VIII gene.
of factor concentrate is higher when patients are on prophylaxis when Factor VIII inhibitors are antibodies, most often of the immuno-
compared to on-demand but analysis of the economic impact of pro- globulin (Ig) G class and frequently restricted to the IgG subclass.
67
4
phylactic therapy, weighing the benefits against the high costs of factor VIII Antibodies against the A and C domains of factor VIII are most com-
2
concentrates, suggests the clinical benefit of prophylaxis is warranted, mon. These antibodies interfere with the interactions of factor VIII with
as evidenced by significant improvement in the clinical condition of other hemostatic components. 67,76
patients and improvement in the quality of life. 62,64 Early diagnosis of factor VIII inhibitors is essential. Although
the presence of an inhibitor can be suspected on clinical grounds, as
COURSE AND PROGNOSIS when a patient does not respond to conventional doses of factor VIII,
After the advent of factor VIII concentrates in the 1960s, the morbidity
and mortality from bleeding in hemophilia were significantly reduced,
and by the late 1970s the life expectancy of hemophilia A patients began TABLE 123–4. Risk Factors for Development of
to approach that of normal individuals in those populations. However, Anti–Factor VIII Antibodies in Hemophilia A Patients
use of replacement therapy has not been without significant complica- Disease severity: 80% of hemophilia A patients with inhibitors
tions. Prior to 1985, common and serious adverse side effects of treat- have <1% factor VIII activity
ment included chronic liver disease resulting from hepatitides B and C Early exposure to factor VIII concentrates: majority of high-titer
and, from about 1978, infection with HIV. Factor VIII concentrates inhibitors develop after <90 days of exposure to factor VIII
65
were prepared from many thousands of donors, making contamination
of factor VIII concentrates by bloodborne viruses highly likely. With Genetic factors
the introduction of heat- or solvent-detergent–treated concentrates in 1. Family history of inhibitor development
1985, contamination of blood products with these viruses has been 2. Ethnic background: Blacks > Hispanics > whites
eliminated for all practical purposes. However, AIDS became a leading 3. Molecular defects: inversion and crossing over defect in intron
65
cause of death in older patients with hemophilia. Chronic liver disease 22, gene deletions, and nonsense point mutations resulting in
in hemophilia A patients resulting from transfusion-related hepatiti- patients without factor VIII antigen
des B and C may be accelerated by HIV infection and by the associated Method of purification of factor VIII concentrate
hepatotoxicity of antiviral drug therapy. Fortunately, patients treated
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prophylactically after 1985 can expect almost normal life spans free of Adapted and modified from Roberts HR: Inhibitors and their man-
the complications of hepatitis, AIDS, and other currently recognized agement, in Hemophilia & Other Bleeding Disorders, edited by Rizza,
bloodborne viral diseases. However, the development of inhibitor G Lowe, p 371. WB Saunders, New York, 1997.

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