Inhibitors in Hemophilia. Pathophysiology. Characterization and Properties of Inhibitors, страница 6

Successful regimens using factor VIII infusions combined with immunosuppressive drugs appear to shorten the induction of immune tolerance significantly, attaining remission at a much lower cost. MLID86123621  88

In recent studies, MLID88174925 MLID90175503  89,90 high-dose intravenous immunoglobulin given together with high-dose factor VIII and cyclophosphamide appeared to have a synergistic effect in achieving a state of immune tolerance. Intravenous IgG may have both a short- and long-term immunosuppressive effect. MLID85110011 MLID89114721  91–93 Anti-idiotypic antibodies are present in the IgG preparations MLID85011599 MLID90053531  94–96; the emergence of anti-idiotypic antibodies may be the explanation for the occasional occurrence of spontaneous remission and some instances of remission induced by immunosuppressive agents. MLID90053531 MLID85059880 MLID89134724  95,97,98

Inhibitors in Hemophilia B

Inhibitors to factor IX occur in hemophilia B secondary to alloimmunization following transfusion similar to hemophilia A. Although the overall incidence of inhibitors complicating hemophilia B is only 2.4–2.8%, MLID74303213  10,99 the incidence in patients with severe hemophilia B is approximately 12%. 10 Patients with major gene deletions who do not have demonstrable factor IX protein in their plasma may be especially susceptible to the development of factor IX antibodies, MLID83192505  100 but more recent observations have not supported this conclusion.

Like factor VIII inhibitors, factor IX inhibitors are IgG. MLID77202199  10,101–103 Some have restricted light chain and heavy chain heterogeneity, MLID83286434  102,104 whereas others are polyclonal. MLID77202199 MLID81232699  103,105 The kinetic behavior of factor IX inhibitors differs from that of factor VIII inhibitors in that factor IX inhibitors produce an immediate loss of factor IX activity, with no progressive loss on further incubation. 10,101

Laboratory Evaluation and Quantification

Factor IX inhibitors should be suspected in a hemophiliac if transfused factor IX either appears to have a short half-life or is not efficacious in achieving hemostasis, or both. This can be suspected in the laboratory whenever a partial thromboplastin time of a mixture of the patient's plasma and normal plasma is longer than that of a mixture of patient plasma and factor IX-deficient plasma known not to contain an inhibitor. Specificity can be determined by doing factor IX assays of an incubation mixture of patient plasma and normal plasma over time. A modification of the Bethesda assay is used to quantitate the inhibitor level. 53

Therapy

In patients with hemophilia B who have inhibitors, the clinical course is not different from that seen in those with hemophilia A with inhibitors. Most of these cases can be managed with factor IX complex concentrates or the anti-inhibitor/coagulant complex. Whether the efficacy of these concentrates is due to neutralization of the inhibitor or to bypassing activity similar to that observed in hemophilia A, or both, is unknown. In addition, the induction of immunotolerance has been achieved in hemophilia B patients with the infusion of high doses of intravenous IgG in combination with cyclophosphamide and factor IX concentrates. MLID87067471  106