Continuous infusion of porcine factor VIII in the management of patients with factor VIII inhibitors

Abstract

The effectiveness of continuous infusion porcine factor VIII (PFVIII) has been evaluated in the treatment of 7 consecutive patients with factor VIII(FVIII) inhibitors. Two patients had hemophilia A and five were nonhemophiliacs with acquired FVIII inhibitors. The median pretreatment anti-porcine FVIII titre was 0.2 (range: 0-15.0) Bethesda units (BU), and the anti-human FVIII titer was 12.0 BU (range: 2.4-50.0). All patients presented with major bleeding. Patients were given a bolus dose of PFVIII followed by continuous infusion. Six patients also received immunosuppressive therapy. Therapeutic FVIII levels (>0.5 U/ml) were achieved in 6 of 7 patients at a median time of 12.5 hr, and then maintained with continuous infusion PFVIII. Six patients were treated for more than 7 days, and in four of these there was a decline in FVIII recovery between days 7 to 11, presumably related to a rising antibody response to PFVIII. These four patients were plasmapheresed and the three patients with autoantibodies recovered therapeutic FVIII levels but this did not occur in the patient with hemophilia. Thrombocytopenia developed in 4 patients at days 18 to 24, with the platelet count falling to 11 to 87 × 10 9 /L, and the PFVIII was discontinued in 3 patients. All patients recovered from the acute bleeding events. With prolonged immunosuppressive therapy, the FVIII inhibitor disappeared in all patients with autoantibodies and there have been no relapses after a median follow-up period of 581 days. This study demonstrates that continuous infusion PFVIII is an effective therapy for patients with FVIII inhibitors, but that prolonged treatment is associated with the development of inhibitors to porcine FVIII and severe thrombocytopenia, which readily corrects with discontinuation of PFVIII. Am.

Porcine factor VIII (Hyate: C®): in vitro stability, microbiological safety and effect of heparin

“…Investigators involved in the use of continuous infusions of F VIII with minipumps have stressed the importance of not extrapolating stability data obtained with a particular factor concentrate or infusion device to others, due to both intrinsic variability in the stability of dierent factor VIII preparations after reconstitution, and the eect of the particular plastic in the infusion device on F VIII stability [4,9,10,12]. Prior reports have documented the in vitro stability of reconstituted PF VIII SW (& 30 U PF VIII mL 71 ) when further diluted with either F VIII-de®cient plasma and stored for 12 h [13], or with NS to a dilution of 1:4 and stored for 24 h [14], but storage of PF VIII SW at room temperature beyond 24 h had not been performed previously. Our studies have demonstrated that PF VIII reconstituted according to the manufacturer's directions with 20 mL sterile water (PF VIII SW ) to a ®nal concentration of & 30 U mL 71 , and stored in plastic syringes at room temperature, consistently retained PF VIII activity ranging from 88 to 98% of baseline for 48 h, and 80±86% of baseline values for 72 h, except in one study when PF VIII stability decreased to 74% at 72 h. Furthermore, PF VIII SW (30 U PF VIII mL 71 ) diluted further with normal saline retained 5 90% baseline activity for 48 h, and 84± 91% for 72 h in concentrations ranging from 10 to 30 U PF VIII mL 71 .…”

“…temperature for 24 h [14]. In the most comprehensive study, the stability of PF VIII reconstituted with normal saline to 30 U mL 71 (standard concentration), 15 U mL 71 and 5 U mL 71 was evaluated at 25 8C and 37 8C [15].…”

Continuous infusion of porcine factor VIII: stability, microbiological safety and clinical experience

“…The delivery of factor VIII (FVIII) by CI may be particularly useful in the treatment of patients with shortened FVIII half‐lives, particularly inhibitor patients, for whom porcine FVIII (pFVIII) is an important treatment option. Its use by continuous infusion has been reported previously by Bona and Rubinger [1,2] who reported on nine FVIII inhibitor patients effectively treated with pFVIII by continuous infusion. Of the nine patients, seven had acquired inhibitors and only two had congenital haemophilia A.…”

Optimization of storage conditions for diluted working solutions of porcine factor VIII and performance of the Bethesda assay for the determination of antiporcine FVIII inhibitor titres

“…These alloantibodies develop in response to the human FVIII, both plasma-derived and recombinant, which is used to treat these patients. The success of this in treating both congenital [10][11][12][13] and acquired haemophilia [14][15][16][17] is related largely to the fact that antibodies directed against human FVIII show lower crossreactivity with porcine FVIII than with human FVIII [18][19][20]. Regardless of their precise aetiology, the neutralizing effect of these antibodies on infused human FVIII renders this treatment approach suboptimal to control bleeding in affected patients [9].…”

“…A widely accepted and effective way to circumvent this problem is to use porcine FVIII. The success of this in treating both congenital [10][11][12][13] and acquired haemophilia [14][15][16][17] is related largely to the fact that antibodies directed against human FVIII show lower crossreactivity with porcine FVIII than with human FVIII [18][19][20]. The administration of porcine FVIII in sufficient doses can overcome the neutralizing effect of the circulating inhibitor and allow for a sufficient level of FVIII to be achieved in the plasma to permit adequate haemostasis [21,22].…”