The treatment of thrombocytopenic purpura (ITP) by high-dose IgG or much lower doses of anti-D have become mainstays of therapy. Yet the use of these 2 effective interventions followed empiric clinical observations that were serendipidous rather than scientifically based. For example, in their landmark study, Imbach and coworkers demonstrated the effectiveness of high doses of IgG in ITP (Imbach et al, The Lancet. 1981;1:1228-1230). One hypothesized mechanism was that the administered IgG could remove thrombocytopenia-causing immune complexes composed of viral particles (Imbach et al, Blut. 1983;46:117-124). The dose dependent effect of IgG on the platelet count was dramatic and initially reinforced this postulated mechanism of action. The observations by Fehr and associates clarified what has become the accepted mechanism of action of IgG in ITP (Fehr et al, N Engl J Med. 1982;306:1254-1258). These investigators found that the rise in the platelet count paralleled the inhibition of Fc-dependent RE function.
Today, 20 years later, it is not too late to try to better understand a successful treatment. At best, progressively strategic modifications of an effective therapy could result. At worst, enhanced clinician comfort could be gained by knowing what was done and why it worked.
In this issue, Hansen and Balthasar (page 2087) use a rat model of immune thrombocytopenia to study the mechanism of action of high-dose IgG. A few initial caveats: any in vivo experiment crossing 3 species has profound complexities. More importantly, the pathogenic, platelet-clearing antibody was not at steady state (more about that later). The results are compelling. Like the human situation, the high-dose IgG raised the platelet count in a dose-dependent fashion. But unlike the human situation, the investigators were able to measure the pathologic antibody and found its clearance was increased by the administered IgG.
These observations extend our understanding of the efficacy of high-dose IgG. But questions remain: Would the same effect occur if the pathologic antibody was produced at steady state (human disease) rather than a single injection? If altered pathogenic antibody clearance helps explain the effectiveness of high-dose IgG in ITP, does this mechanism have relevance to anti-D in ITP? Questions are answered. More questions remain.
