Use of Porcine Factor VIII in the Management of Seventeen Patients with Factor VIII Antibodies

Gatti, Loredana; Mannucci, Pier Mannuccio

doi:10.1055/s-0038-1661106

Cited by 76 publications

(81 citation statements)

References 4 publications

(4 reference statements)

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“…Approximately 25% of all hemophilia A patients treated with fVIII products develop antibodies that inhibit fVIII activity and limit treatment efficacy (1). Patients with fVIII-inhibitory antibodies can be treated using porcine plasma-derived fVIII products, which generally display low cross-reactivity with the human fVIII antibodies (2,3). Currently there is not a recombinant porcine fVIII product available for clinical use.…”

Section: Cellsmentioning

confidence: 99%

High Level Expression of Recombinant Porcine Coagulation Factor VIII

Doering

Healey

Parker

et al. 2002

Journal of Biological Chemistry

154

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Recombinant human factor VIII expression levels, in vitro and in vivo, are significantly lower than levels obtained for other recombinant coagulation proteins. Here we describe the generation, high level expression and characterization of a recombinant B-domain-deleted porcine factor VIII molecule. Recombinant B-domaindeleted porcine factor VIII expression levels are 10-to 14-fold greater than recombinant B-domain-deleted human factor VIII levels by transient and stable expression in multiple cell lines. Peak expression of 140 units⅐10 6 cells ؊1 ⅐24 h ؊1 was observed from a baby hamster kidneyderived cell line stably expressing recombinant porcine factor VIII. Factor VIII expression was performed in serum-free culture medium and in the absence of exogenous von Willebrand factor, thus greatly simplifying protein purification. Real time reverse transcription-PCR analysis demonstrated that the differences in protein production were not caused by differences in steady-state factor VIII mRNA levels. The identification of sequence(s) in porcine factor VIII responsible for high level expression may lead to a better understanding of the mechanisms that limit factor VIII expression.Factor VIII (fVIII) 1 is a large (ϳ 300 kDa) glycoprotein that functions as an integral component of the intrinsic pathway of blood coagulation. Mutations in the fVIII gene that result in decreased or defective fVIII protein give rise to the genetic disease, hemophilia A, which is phenotypically characterized by recurrent bleeding episodes. Treatment of hemophilia A entails intravenous infusion of either human plasma-derived or recombinant fVIII material. Approximately 25% of all hemophilia A patients treated with fVIII products develop antibodies that inhibit fVIII activity and limit treatment efficacy (1). Patients with fVIII-inhibitory antibodies can be treated using porcine plasma-derived fVIII products, which generally display low cross-reactivity with the human fVIII antibodies (2, 3). Currently there is not a recombinant porcine fVIII product available for clinical use.Since the introduction of recombinant fVIII for the treatment of hemophilia A, commercial suppliers have struggled to keep up with high patient demand (4). The shortage of recombinant fVIII material has precluded prophylactic treatment of severely affected patients, limited the implementation of immune-tolerance regimens, and kept treatment costs high. Unfortunately, fVIII is expressed and recovered at low levels in the heterologous mammalian cell culture systems used for commercial manufacture. The importance of this problem has fueled significant research efforts to overcome the low fVIII expression barrier, and several basic mechanisms have been identified that limit fVIII expression (for review, see Kaufman et al. (5)) Despite these findings, fVIII expression levels remain low, and a product shortage persists.The porcine fVIII cDNA sequence has been reported and shown to encode the homology-defined internal protein domain structure, A1-A2-B-ap-A3-C1-C2 (6, 7). Porcin...

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Section: Cellsmentioning

confidence: 99%

High Level Expression of Recombinant Porcine Coagulation Factor VIII

Doering

Healey

Parker

et al. 2002

Journal of Biological Chemistry

154

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“…Porcine factor VIII in some patients seems less immunogenic compared to human factor VIII, but immediate-type allergic reactions due to non-factor VIII por cine protein constituents and thrombocytope nia can occur. A retrospect analysis of surgery in haemophilic inhibitor patients using por cine factor VIII has been reported on more occasions [2][3][4][5][6]. In high-titred patients, a co agulation-active principle called the factor VIII by-passing activity (Feiba, Autoplex) can be utilised to assist haemostasis.…”

Section: Introductionmentioning

confidence: 99%

Major Surgery in Haemophilic Patients with Inhibitors Using Recombinant Factor VIla

Ingerslev

Freidman

Gastineau³

et al. 1996

Pathophysiol Haemos Thromb

101

118

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In the haemophilic patient, development of antibodies that inhibit the function of the missing coagulation factor causes several delicate problems. Most importantly, antibodies will block the function of the specific coagulation factor, and often the antibody activity is so fierce that effective substitution therapy is outruled. In consequence, alternative measures must be adopted to control bleeding. Amongst those most commonly employed, like factor IX concentrates, activated prothrombin complex concentrates, and factor VIII of porcine origin, a new recombinant activated factor VII molecule has been evaluated clinically for some years with promising results. The aim of the present paper was to present a series of patients suffering from haemophilia A or B in whom inhibitors have complicated the clinical picture, and in whom a surgical procedure was indicated. As part of a compassionate use program devised by the producer of this genetically engineered factor VIla, 12 patients underwent life-saving or essential surgery where the recombinant factor VIla product was used to promote haemostasis in 13 surgical procedures. Due to a short in vivo half-life of activated factor VIla, frequent administration was scheduled, injecting factor VIla every 2-3 h for up to 2 days after which dosage intervals were prolonged. In one case, a global evaluation of the end treatment result was not reported, but in all of the other 12 cases the end result were considered excellent (n = 11) or efficient (n = 1). In none of the cases was other types of coagulation factor treatment modalities necessary. In conclusion, recombinant factor VIla seems a tempting alternative to traditional treatment of the haemophilic patient with inhibitors, in whom surgery is called for. With other types of haemostatic agents, surgery in haemophilic inhibitor patients has only been studied rarely, and operations have generally been restricted to life-threatening situations.

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“…This is one of the largest studies of factor VIII inhib itors carried out to date [7][8][9]. All 4 studies have similar ranges.…”

Section: Resultsmentioning

confidence: 95%

“…The purifica tion procedure of porcine factor VIII has been improved since 1980 by using ion exchange chromatography with polyelectrolytes [6] (Hyate:C®, Porton Products, UK). This new concentrate has been extensively used in the UK [7], Italy [8,9], the USA [10] and elsewhere [11,12], It has even been used for home therapy and the induction of immune tolerance in a small number of patients [13].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Anti-Human and Anti-Porcine Factor VIII Inhibitor Levels in 63 Patients with Severe Haemophilia A

Fiks-Sigaud¹,

Bendelac²,

Parquet³

et al. 1993

Vox Sanguinis

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The levels of anti-human and anti-porcine factor VIII inhibitors, measured in 63 severe haemophilia A patients, lay in the ranges of <0.2-2,600 and <0.2-1,300 Bethesda units per ml (BU/ml), respectively, with a median cross-reactivity of 33%. In 4 patients, human and porcine inhibitor levels were determined using both plasma, either human or porcine, and factor VIII concentrate, either very high purity human or porcine (Hyate:C®). A good correlation between titres was found, whatever the source of factor VIII (plasma or concentrate). The cross-reactivity varies from 0 to over 100%, indicating that the evaluation of both human and porcine inhibitors should be mandatory before any treatment with Hyate:C. Results show that of the 46 patients with human inhibitor of more than 5 BU/ml, 21 (46%) with a low porcine inhibitor (<5 BU/ml) could benefit from Hyate:C.

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Use of Porcine Factor VIII in the Management of Seventeen Patients with Factor VIII Antibodies

Cited by 76 publications

References 4 publications

High Level Expression of Recombinant Porcine Coagulation Factor VIII

High Level Expression of Recombinant Porcine Coagulation Factor VIII

Major Surgery in Haemophilic Patients with Inhibitors Using Recombinant Factor VIla

Comparison of Anti-Human and Anti-Porcine Factor VIII Inhibitor Levels in 63 Patients with Severe Haemophilia A

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