Inhibitors in Hemophilia. Pathophysiology. Characterization and Properties of Inhibitors

Chapter 109

Inhibitors in Hemophilia

Donald I. Feinstein

Inhibitors in Hemophilia A

Factor VIII inhibitors are antibodies that develop in patients with hemophilia A in response to factor VIII contained in various blood products. Most of these antibodies neutralize factor VIII coagulant activity. Although they do not increase the frequency of bleeding episodes, they make treatment of bleeding much more difficult. The incidence of factor VIII inhibitors complicating hemophilia A is approximately 5–10% of all patients with hemophilia A and 10–15% of those with severe hemophilia A. 1,2 However, in more recent studies of inhibitor formation in previously untreated patients receiving highly purified plasma derived factor VIII, the incidence of inhibitors was 18–35%, MLID91246858 MLID92031936 MLID92311847  3–5 and with intermediate purity factor VIII concentrates the incidence was 25–52%. MLID92167720 MLID93133254  6–8 In prospective studies using recombinant factor VIII, the incidence was approximately 20%. MLID93133254  7,8 In most of these prospective studies, the inhibitors were detected early, with a median number of exposure days before inhibitor formation of 9–11, MLID93133254  7,8 and about 50% were low titer and transient. Thus, most patients with severe hemophilia who are destined to develop an inhibitor do so early after exposure to factor VIII. MLID93133254 MLID88108142  7–9 The reason for the variable incidence with newer and more purified concentrates is not explained.

Although the great majority of inhibitors develop in severe or moderate forms of hemophilia A, well-documented cases include patients with mild hemophilia A. MLID69278299 MLID71136796 MLID91082821  2,10–14 In general, these patients develop only low-titer inhibitors following exposure to factor VIII. After abstinence from products containing factor VIII, the inhibitors disappear after 4–12 weeks, and the inhibitors do not necessarily reappear on re-exposure.

Patients with low-titer inhibitors (3–5 Bethesda units) that do not rise after further exposure to factor VIII are known as low responders (approximately 25% of hemophiliacs with inhibitors), whereas those that rise markedly with further exposure to factor VIII (anamnestic response) are known as high responders (approximately 75% of hemophiliacs with inhibitors). MLID76206851  15 Inhibitor titers usually begin to rise 2–3 days after exposure to factor VIII, reach a maximum within 7–21 days, and then decrease very slowly (Fig. 109-1). Once formed, high-titer inhibitors tend to persist for long, although variable periods, and detectable levels of inhibitor may be present 1–2 years later without re-exposure to factor VIII. By contrast, low-titer inhibitors in low responders occasionally disappear and may not reappear with exposure to factor VIII.

Pathophysiology

The reasons for the development of inhibitors in a minority of patients with hemophilia A remain unknown. Brother pairs have a higher-than-expected incidence or absence of inhibitors. MLID88108142 MLID77224277  9,16 Another factor suggesting genetic susceptibility is the finding of a lesser incidence of HLA-A1 and a higher incidence of certain complement components located close to HLA-DR in hemophiliacs with inhibitors. 17 By contrast, no correlation exists between factor VIII gene deletions and the development of factor VIII inhibitors. MLID85296150 MLID85213871  18,19 Shapiro and Hultin 10 suggested that immune tolerance might be involved to explain the development of inhibitors in patients with hemophilia A. Since factor VIII does not cross the placenta, tolerant hemophiliacs could be exposed to factor VIII in utero only as a result of maternal-fetal hemorrhage. Thus, according to this hypothesis, only nontolerant hemophiliacs would develop inhibitors following exposure to factor VIII. Induction of tolerance in hemophiliacs with inhibitors results in the disappearance of the inhibitor in a significant number of patients, which supports this theory. MLID84272861 MLID86286530  20–22

Characterization and Properties of Inhibitors

Factor VIII inhibitors in hemophilia A are IgG. Although light chain and heavy chain subtyping has demonstrated restricted heterogeneity, MLID73127873 MLID68199215 MLID69211684 MLID75206132 MLID77158812 MLID81226753 MLID81193362  23–30 heavy chain subtyping of these antibodies has shown a significant predominance of the IgG4 subtype. MLID77158812 MLID77066042  25,28,31 IgG4 does not fix complement, which might explain why hemophiliacs do not develop immune complex disease. Factor VIII inhibitors show species specificity, both in vitro and in vivo, in that human factor VIII is usually neutralized to a greater extent than is bovine or porcine factor VIII, and infusion of porcine factor VIII into a patient with an inhibitor often raises the factor VIII level.

The reaction between factor VIII and inhibitors is time and temperature dependent. Two different patterns of antigen/antibody reaction have been described. In the type I pattern, characteristic of most alloantibodies, as seen in hemophiliacs, factor VIII is completely inactivated in the presence of excess inhibitor, MLID67093871 MLID73003152  32–34 whereas in the type II pattern characteristic of many autoantibodies, the inhibitor frequently does not completely inactivate factor VIII in vitro in the presence of excess inhibitor. MLID73127873 MLID73003152  23,35–37 In the latter cases, despite the demonstration of a significant amount of residual factor VIII activity in vitro, the patient bleeds as if there were no coagulant function in vivo. MLID83023663 MLID82044272  38,39