Treatment related factors and inhibitor development in children with severe haemophilia A

Abstract

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A

“…This was true after treatment for life-threatening conditions but not for surgeries such as Port-A-Cath insertion. 3 …”

“…2,3 Inhibitors tend to develop within the first 10 exposure days (defined as a 24-hour period during POSSIBLE GAME-CHANGERS IN HEMOPHILIA which one or more exposures to FVIII therapy was recorded) and rarely develop after 50 exposure days. Beyond that, there are several controversial points that are thought to favor antibody production, as discussed below.…”

“…3 In a prospective study of hemophilia A (FVIII Յ 2%), boys Ͻ 30 months of age were randomized to receive 25 IU/kg of FVIII every other day versus on-demand treatment. In the prophylaxis arm, 2 of 32 developed an inhibitor, whereas none (0 of 33) did in the on-demand arm.…”

Faktor Risiko Timbulnya Inhibitor Faktor VIII pada Anak dengan Hemofilia A

“…[4][5][6][7][8]17 Beberapa penelitian yang mengelompokkan usia mendapat terapi pengganti pertama kali pada usia 0-6, 6-12 bulan, dan di atas 1 tahun, menemukan hubungan antara usia mendapat terapi dengan timbulnya inhibitor. 4,5 Pengelompokkan usia yang sama dengan penelitian kami terdapat pada penelitian Santagostino dkk 17 dan Maclean dkk 18 . Studi kasus kontrol oleh Maclean dkk, 18 dalam kurun waktu 25 tahun (1982-2007) tidak mendapatkan hubungan antara usia saat mendapat terapi dengan timbulnya inhibitor.…”

“…4,5 Pengelompokkan usia yang sama dengan penelitian kami terdapat pada penelitian Santagostino dkk 17 dan Maclean dkk 18 . Studi kasus kontrol oleh Maclean dkk, 18 dalam kurun waktu 25 tahun (1982-2007) tidak mendapatkan hubungan antara usia saat mendapat terapi dengan timbulnya inhibitor. Hasil yang sama didapatkan pada studi kasus kontrol yang dilakukan Santogostino dkk 33 pada 183 anak.…”