Inhibitors in Hemophilia. Pathophysiology. Characterization and Properties of Inhibitors, страница 5

In addition to their unpredictable efficacy, these concentrates have other limitations. Dosage is relatively arbitrary, and no reliable in vitro method is available that reflects in vivo efficacy. These concentrates also induce a hypercoagulable state and may be associated with thromboembolic complications. These concentrates contain a small amount of factor VIII antigen and can induce an anamnestic response after their use. If selected for use in critical situations, these concentrates should be used early in the course of the bleeding episode. MLID80066000  55

Human Factor VIIa Concentrate

Purified components of the prothrombin complex have recently been used to treat hemorrhages in patients with inhibitors. A highly purified concentrate containing factor VIIa achieved good hemostasis MLID83239008  75 and more recently, a recombinant preparation of human factor VIIa has shown significant efficacy in patients with inhibitors. MLID89272459  63,76 Recombinant factor VIIa is currently an experimental drug.

Suppression of Inhibitors

Long-term goals in the management of these patients should be aimed at the prevention of anamnesis and suppression of further antibody production. Immunosuppressive therapy has been attempted in many patients, with variable and unpredictable results. MLID69211684 MLID74047581 MLID73226034 MLID75089231 MLID76232703  10,26,77–82 In general, with few exceptions, corticosteroid therapy alone is not efficacious in patients with hemophilia A and inhibitors. MLID76232703  82 By contrast, Dormandy and Sultan MLID76175273  83 collected the experience of many investigators using cyclophosphamide and factor VIII. Some degree of success was achieved on 40 occasions in 18 of 45 patients. The data reported by Hultin et al. MLID76232703  82 are in agreement with these observations. Although total elimination of antibody occurs very rarely, immunosuppressive therapy may be helpful in patients requiring factor VIII infusion, particularly low responders with low inhibitor titers. MLID76232703  82 Rarely, treatment of inhibitors soon after their appearance and before re-exposure to factor VIII may be an important determinant of successful outcome. MLID76232703  82 Despite these encouraging reports, the use of immunosuppressive drugs has not gained wide acceptance.

The induction of immune tolerance by the frequent regular infusions of factor VIII has become increasingly accepted, but the financial implications of this therapy are great. MLID84272861  20,61 A patient who is a high responder with a high-titer inhibitor is given daily or alternate-day infusions of various amounts of human factor VIII. MLID84272861  20,61 Following chronic administration of factor VIII, the inhibitor titer first increases and then progressively decreases, with most patients achieving either a very low titer (<2.5 U), or the inhibitor is undetectable. Moreover, the patient no longer has anamnesis with continued exposure to factor VIII. Similar results have been achieved at some centers, either with less amounts of factor VIII MLID83276392 MLID87049531  21,61,84–86 or by giving factor VIII repeatedly but at irregular intervals. MLID83000167  87 Immune tolerance usually must be maintained by giving low doses of factor VIII every few days.

Successful outcomes of the induction of tolerance occur in about 75% of patients and appear to be more common in patients <20 years of age, in patients who are low responders, and in those receiving higher doses of factor VIII (E50 U/kg/day). Human immunodeficiency virus status does not appear to affect outcome (Kasper CK, personal communication, 1993).