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2126 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2127

TABLE 123–6. Examples of Tolerance Protocols for for preparing factor VIII concentrates since 1985 have eliminated the
risk of HIV transmission.
Hemophilia A Inhibitor Patients with Good-Risk Factors
Risk of Viral Disease Transmission By New Factor VIII Products
Immune Tolerance Time to Negative All available factor VIII concentrates, both plasma-derived and recom-
Protocols Dose Inhibitor binant products, are considered safe and effective with almost no risk
High-dose regimen 200 U/kg factor VIII 4.6 months of transmitting currently known viral diseases. However, occasional
per day exceptions have been observed. For example, solvent-detergent treat-
Low-dose regimen 50 U/kg factor VIII 9.2 months ment does not inactivate viruses without lipid envelopes, including the
three times per hepatitis A virus and parvovirus. As a result, outbreaks of hepatitis A
week have been reported in patients receiving some solvent detergent–treated
products. These outbreaks of viral diseases usually have been related to
Data from DiMichele DM: Immune tolerance in haemophilia: The long breakdowns in the manufacturing process.
journey to the fork in the road. Heamophilia 159(2):123–134, 2012. Prions Prions are infectious particles consisting of proteinaceous
material devoid of a nucleic acid genome. They are thought to be vari-
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intravenous γ-globulin have been used in patients with an inhibitor. ant forms of a normal protein with an altered conformation. The “infec-
The Malmö protocol uses nearly all of these approaches in combina- tious” nature of prions may result from their ability to bind to other
tion, including extracorporeal adsorption of antibody to a Sepharose A proteins and induce similar conformational changes in them such that
column, administration of cyclophosphamide, daily administration of new “infectious” particles can be generated. Prions are responsible for
factor VIII, and intravenous γ-globulin. 84 several neurodegenerative disorders, including Creutzfeldt-Jakob dis-
The most promising approach to eradication of an inhibitor is use ease (CJD) in humans, scrapie in sheep, and spongiform encephalopathy
of immune tolerance regimens. The basis of this approach is adminis- in cows. Prions are resistant to most currently available viral inactiva-
tration of frequent (daily or thrice weekly) doses of factor VIII until the tion techniques. Removal of prion particles using iodine column chro-
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inhibitor titer is undetectable. Low- and high-dose regimens have been matography has been claimed. Although prion diseases generally are
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described (Table 123–6). Predictors of success have been described in transmitted by ingestion of infected neural tissues, a new variant of CJD
clinical studies in patients with high titer inhibitors and include young appears to occur in people who have eaten beef from cows infected with
age at detection of inhibitor; inhibitor titer less than 10 BU before start- a form of prion causing bovine spongiform encephalopathy. This form
ing immune tolerance induction (ITI); peak titer less than 100 BU after of CJD has been reported mainly in the United Kingdom and in certain
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starting ITI; historical peak titer less than 200 BU; age less than 5 years other European countries and has been related to the bovine disease.
old between diagnosis and start of ITI; and genotype (small deletions For example, prions have been found in tonsillar tissue of patients with
and insertions, and missense mutations). Factor VIII inhibitor bypass- new-variant CJD, heightening concern about whether prions of this
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ing agents are used for prevention and treatment of acute bleeds that type might be transmitted by blood products. Conclusive data about
occur during immune tolerance induction. possible prion infection of hemophilic patients are lacking, so contin-
Other approaches to treatment of factor VIII inhibitors include ued vigilance is necessary.
immunosuppressive drugs, like cyclosporine and rituximab. 85–87 How-
ever, these drugs, although occasionally successful, seem to be more HEMOPHILIA B (FACTOR IX DEFICIENCY,
effective in patients with acquired hemophilia resulting from autoanti-
bodies against factor VIII. CHRISTMAS FACTOR DEFICIENCY)

Infectious Complications ETIOLOGY AND PATHOGENESIS
Hepatitis Almost all multitransfused patients with hemophilia treated Hemophilia B occurs in one of every 25,000 to 30,000 live male births.
before 1985 were infected with one or more viruses that caused hepati- As with hemophilia A, hemophilia B is found in all ethnic groups and
tis. Although many infected patients did not suffer acute symptoms, at has no geographic predilection.
least 50 percent developed chronic persistent or chronic active hepatitis Factor IX is a vitamin K-dependent, single-chain glycoprotein con-
that in many cases, resulted in cirrhosis. Hepatitis C and B viruses are sisting of 415 amino acids. It is activated by the factor VIIa–tissue factor
commonly associated with chronic liver disease. Many adult hemophilia complex, or factor XIa, forming the active enzyme factor IXa (Chap. 113).
patients treated with concentrates before 1985 have circulating antibod- Once activated, factor IXa activates factor X in the presence of factor
ies to hepatitis B surface antigen, and hepatitis C. Hepatitis C infection VIIIa, phospholipid (activated platelets), and calcium. Factor VIIIa is
progresses more rapidly in the presence of HIV infection. Until recently, a necessary cofactor for activity of factor IXa. Therefore, deficiency
therapy with pegylated interferon, and ribavirin reduced viral load and of either factor IX or VIII leads to a similar lack of factor X-activating
improve survival of many affected patients; however, newer approaches activity on the platelet surface. Factor Xa converts prothrombin to
using serine protease inhibitors and nucleotide polymerase inhibitors thrombin in the presence of factor Va, activated platelets, and calcium.
has led to a high rate of sustained virologic responses. All patients with Hemophilia B can result from either the absence or the dysfunction
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hemophilia should be vaccinated against hepatitis A and hepatitis B. of factor IX molecules. Clinical severity of hemophilia B is roughly
Human Immunodeficiency Virus Many of the older, severely correlated with factor IX functional activity.
affected hemophilia A patients who were treated before 1985 have
antibodies to HIV, indicating infection with the virus. The incidence
of HIV antibodies in mildly affected patients is much lower and cor- GENETICS AND MOLECULAR BIOLOGY
relates with treatment with factor VIII concentrates before viral inacti- The factor IX gene is located on the long arm of the X chromosome. It is
vation procedures were used. In one study, 14 percent of patients treated approximately 33 kb long, which is much smaller than the gene for fac-
only with cryoprecipitate from 1979 to 1985 were infected with HIV, tor VIII. Because it is less complex, the factor IX gene has been studied
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whereas 88 percent of patients treated with factor VIII concentrates in greater detail than the factor VIII gene. Figure 123–11 is a schematic
became infected. Screening of donor populations and new techniques of the gene and the protein product. The protein consists of a signal
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