Korean J Hematol.  2009 Dec;44(4):205-211. 10.5045/kjh.2009.44.4.205.

Maintenance Therapy with Activated Prothrombin Complex Concentrate (aPCC) for Hemophilia Patients with High Levels of Responding Inhibitors

• Yoo KY
• Choi YM
• Park YS

• KMID: 2252098
• DOI: http://doi.org/10.5045/kjh.2009.44.4.205

Abstract

BACKGROUND
Eleven percent of severe hemophilia A patients and 5% of severe hemophilia B patients may develop inhibitors. We have conducted aPCC-based maintenance therapy for hemophilia patients with high levels of responding inhibitors and we analyzed the efficacy, safety, the factor consumption and the expense of this treatment, as compared to on-demand therapy. METHODS: Eleven hemophilia patients with high levels of responding inhibitors were eligible for the study. We tried to evaluate the longitudinal bleeding episodes, the inhibitor titers, the X-ray findings, the adverse events and the factor consumption between on-demand therapy and maintenance therapy. The bypassing agent in this study was aPCC having a longer half-life. The dosage was 30~50 U/kg, 3 times a week. RESULTS: The mean follow-up period was 6.8 months for on-demand therapy and 10.6 months for maintenance therapy. The mean dosage of aPCC was 45.2 U/kg. The episodes of hemarthrosis decreased by 61.4% (P=0.003) and other significant bleedings decreased by 45.2% (P=0.109). The inhibitor titers decreased in 7 patients and these increased in 4 patients, but anamnesis took place in only 1 patient. Radiologically, 2 patients improved, 1 patient got worse and 7 patients were stable. Neither adverse signs nor symptoms were noticed. The mean factor consumption changed from 55.8x10(3) U for aPCC and 48.6 mg for rFVIIa on-demand therapy to 216x10(3) U for aPCC and 4.8 mg rFVIIa for maintenance therapy. Maintenance therapy cost 67% more than on-demand therapy monthly (P=0.041). CONCLUSION: aPCC-based maintenance therapy for hemophilia patients with high responding inhibitors cost 67% more than on-demand therapy, but it reduced by 61.4% the episodes of hemarthrosis and 45.2% of the other significant bleedings. aPCC-based maintenance therapy can very effectively reduce the bleeding episodes of hemophilia patients with high levels of responding inhibitors.

Keyword

Hemophilia; Inhibitor; aPCC; Maintenance therapy

MeSH Terms

Factor VIIa
Follow-Up Studies
Half-Life
Hemarthrosis
Hemophilia A
Hemophilia B
Hemorrhage
Humans
Hypogonadism
Mitochondrial Diseases
Ophthalmoplegia
Prothrombin
Recombinant Proteins
Factor VIIa
Hypogonadism
Mitochondrial Diseases
Ophthalmoplegia
Prothrombin
Recombinant Proteins

Reference

References

1. Leissinger CA. Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors. Haemphilia. 1999; 5(Suppl 3):25–32.

2. Váradi K, Negrier C, Berntorp E, et al. Monitoring the bioavailability of FEIBA with a thrombin generation assay. J Thromb Haemost. 2003; 1:2374–80.

3. Negrier C, Goudemand J, Sultan Y, Bertrand M, Rothschild C, Lauroua P. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost. 1997; 77:1113–9.

4. Arnold WD, Hilgartner MW. Hemophilic arthroa-pthy. Current concepts of pathogenesis and management. J Bone Joint Surg Am. 1977; 59:287–305.

5. Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX scientific and standardization committee of the international society for thrombosis and haemostasis. Thromb Haemost. 1991; 66:384–6.

6. Kim DH, Ko SH, Kim DC, Lee SK, Song HS. The effects of measurement time and blood temperature on thromboelastographic parameters. Korean J Anesthesiol. 2002; 42:306–11.

7. Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia. 2004; 10(Suppl 2):10–6.

8. Barrowcliffe TW, Kemball-Cook G, Gray E. Factor VIII inhibitor bypassing activity: a suggested mechanism of action. Thromb Res. 1981; 21:181–6.

9. Yoshioka A, Kamisue S, Tanaka I, et al. Anamnestic response following infusion of prothrombin complex concentrates (PCC) and activated prothrombin complex concentrates (aPCC) in haemophilia A patients with inhibitors. Blood Coagul Fibrinolysis. 1991; 2(Suppl 1):51–8.

10. Ewing NP, Pullens L, De Guzman C. Anamnesis inpatients with hemophilia and inhibitors who receive activated prothrombin complex concentrates for prophylaxis. J Thromb Haemost. 2007; 5(Suppl 1):P–T. -158.

11. Villar A, Arnonis S, Morfini M, et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A. Haemophilia. 2004; 10:352–9.

12. Siegmund B, Richter H, Pollmann H. Prophylactic treatment with FEIBA of a haemophilia A patient with inhibitor: what are the costs, what are the benefits? Haemophilia. 2005; 11:638–41.

13. Morfini M, Auerswald G, Kobelt RA, et al. Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Hemophilia Centres. Haemophilia. 2007; 13:502–7.

14. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis on hemophilia patients with inhibitors. J Thromb Haemost. 2007; 5:1904–13.

15. Jimenez-Yuste V, Rodriguez-Merchan EC, Alvarez MT, Quintana M, Martin-Salces M, Hernandez-Navarro F. Experiences in the prevention of arthropathy in haemophilia patients with inhibitors. Haemophilia. 2008; 14(Suppl 6):28–65.

16. Hilgartner MW, Makipernaa A, Dimichele DM. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia. 2003; 9:261–8.

17. Ewenstein B, Giangrade P, Morfini M, et al. Evaluation of FEIBA for prophylaxis in patients with inhibitors. Haemophilia. 2004; 10(Suppl 3):): abstract 22 PO 10.

18. Valentino LA. The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series. Haemophilia. 2009; 15:733–42.

19. Lambert T, Fressinaud E, Goudemand J, Rafowicz A. Can longterm prophylaxis with APCC improve the bleeding rate and quality of life of frequently bleeding haemophiliacs with inhibitors? Haemophilia. 2006; 12(Suppl 2):): abstract 14 PO 399.

20. Cheng S, Chen Y, Chiang J. FEIBA prophylaxis in hemophila A patients with inhibitors decreases bleeding episodes, improves joint function and enhance quality of life. Haemophilia. 2006; 12(Suppl 2):): abstract 14 PO 371.

21. Dimichele D, Négrier C. A retrospective postlicensure survey of FEIBA efficacy and safety. Haemophilia. 2006; 12:352–62.

22. Leissinger CA, Becton DL, Ewing NP, Valentino LA. Prophylactic treatment with activated prothrombin complex concentrate (FEIBA) reduces the frequency of bleeding episodes in paediatric patients with haemophilia A and inhibitors. Haemophilia. 2007; 13:249–55.