Inhibitor Development in Previously Untreated Patients with Hemophilia A: A Prospective Long-Term Follow-Up Comparing Plasma-Derived and Recombinant Products

Wolfhart Kreuz; Carmen Escuriola Ettingshausen; Alex Zyschka; Johannes Oldenburg; Inmaculada Martinez Saguer; Silke Ehrenforth; Thomas Klingebiel

doi:10.1055/s-2002-32664

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2002; 28(3): 285-290
DOI: 10.1055/s-2002-32664

Inhibitor Development in Previously Untreated Patients with Hemophilia A: A Prospective Long-Term Follow-Up Comparing Plasma-Derived and Recombinant Products

Wolfhart Kreuz¹ , Carmen Escuriola Ettingshausen¹ , Alex Zyschka¹ , Johannes Oldenburg² , Inmaculada Martinez Saguer¹ , Silke Ehrenforth¹ , Thomas Klingebiel¹

¹The Centre of Pediatrics III, Department of Hematology and Oncology, Comprehensive Care Centre of Thrombosis and Haemostasis, Johann-Wolfgang-Goethe-University Hospital, Frankfurt am Main and the Institute of Human Genetics (J. Oldenburg) University, Würzburg, Germany
²German Red Cross Blood Bank, Frankfurt Am Main, Germany

Abstract

ABSTRACT

In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter. Of the 72 hemophilia A patients, 22 (32%) developed an inhibitor after 15 ED in median (range 4 to 195); 17 (77%) were high responders (>5 Bethesda Units [BU]), and the remaining 5 patients (23%) were low responders (>0.6 to 5 BU). The severely affected patients (n = 46) showed a significantly higher frequency of inhibitor formation (43%) than did the moderate ones (8%). Comparing the severely affected patients receiving pd products exclusively (n = 35) with those treated with recombinant concentrate (n = 11), 37% of the pd group developed a high-titer inhibitor (>5 BU, median 290 ED in noninhibitor patients) and 36% of the recombinant group (median 49 ED in the noninhibitor patients). However, the exposure status of the recombinant noninhibitor patients is rather low and therefore remains a high risk of developing further inhibitors in the future. The mutation type profile revealed no difference between the pd- and the recombinant-treated patients.

KEYWORDS

hemophilia - inhibitor development - previously untreated patients (PUPs) - FVIII concentrates - mutations

Full Text

References

REFERENCES

1 Kreuz W, Escuriola Ettingshausen C, Martinez Saguer I, Güngör T, Kornhuber B. Epidemiology of inhibitors in haemophilia A. Vox Sang . 1996; 70(Suppl 1) 2-8
2 Brettler D B. Inhibitors in congenital haemophilia. Baillieres Clin Haematol . 1996; 9 319-329
3 Pasi K J. Previously untreated patients and recombinant factor VIII concentrate studies. Blood Coagul Fibrinolysis . 1997; 8(Suppl 1) 29-32
4 Ehrenforth S, Kreuz W, Scharrer I. Incidence of development of factor VIII and IX inhibitors in haemophiliacs. Lancet . 1992; 339 594-98
5 Lusher J, Arkin S, Hurst D. Recombinant F VIII (Kogenate™) treatment in previously untreated patients (PUPs) with haemophilia A: update of safety, efficacy and inhibitor development after seven study years (Abst). Thromb Haemost . 1997; 78 663
6 Gruppo R, Bray G L, Schroth P, Perry M, Gomperts E D. Safety and immunogenicity of recombinant factor VIII (Recombinate) in previously untreated patients (PUPs): a 6.5 year update (Abst). Thromb Haemost . 1997; 78 664
7 Addiego J, Kasper C, Abildgaard C. Frequency of inhibitor development in haemophiliacs treated with low purity factor VIII. Lancet . 1993; 342 462-464
8 DeBiasi R, Rocino A, Papa L. Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. Thromb Haemost . 1994; 71 544-547
9 Muntean W, Male C h, Streif W. Low inhibitor incidence in children treated with pasteurized human factor VIII concentrate (Abst).
10 Yee T T, Williams M D, Hill F GH, Lee C A, Pasi K J. Absence of inhibitors in previously untreated patients with severe haemophilia A after exposure to a single intermediate purity factor VIII product. Thromb Haemost . 1997; 78 1027-1029