Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

被引：278

作者：

Gouw, Samantha C. ^{[1
]}

van den Berg, H. Marijke ^{[2
]}

Fischer, Kathelijn ^{[2
,3
]}

Auerswald, Guenter ^{[4
]}

Carcao, Manuel ^{[5
]}

Chalmers, Elizabeth ^{[6
]}

Chambost, Herve ^{[7
,8
]}

Kurnik, Karin ^{[9
]}

Liesner, Ri ^{[10
]}

Petrini, Pia ^{[11
]}

Platokouki, Helen ^{[12
]}

Altisent, Carmen ^{[13
]}

Oldenburg, Johannes ^{[14
]}

Nolan, Beatrice ^{[15
]}

Perez Garrido, Rosario ^{[16
]}

Mancuso, M. Elisa ^{[17
]}

Rafowicz, Anne ^{[18
]}

Williams, Mike ^{[19
]}

Clausen, Niels ^{[20
]}

Middelburg, Rutger A. ^{[21
]}

Ljung, Rolf ^{[22
,23
]}

van der Bom, Johanna G. ^{[21
,24
]}

机构：

[1] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Paediat, Utrecht, Netherlands

[2] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands

[3] Univ Med Ctr Utrecht, Van Creveldklin, Utrecht, Netherlands

[4] Klinikum Bremen Mitte, Gesundheit Nord, Prof Hess Kinderklin, Bremen, Germany

[5] Hosp Sick Children, Div Haematol Oncol, Toronto, ON M5G 1X8, Canada

[6] Royal Hosp Sick Children, Dept Haematol, Glasgow G3 8SJ, Lanark, Scotland

[7] Hop Enfants La Timone, Serv Hematol Pediat, Marseille, France

[8] Aix Marseille Univ, Marseille, France

[9] Univ Munich, Dr v Haunersches Kinderspital, Munich, Germany

[10] Great Ormond St Hosp Sick Children, Hemophilia Ctr, Dept Haematol, London WC1N 3JH, England

[11] Karolinska Hosp, Dept Pediat, Clin Coagulat Disorders, S-10401 Stockholm, Sweden

[12] St Sophia Childrens Hosp, Haemophilia Haemostasis Unit, Athens, Greece

[13] Hosp Valle De Hebron, Hosp Traumatol, Unitat Hemofilia, Barcelona, Spain

[14] Univ Klinikum Bonn, Inst Expt Hamatol & Transfus Med, Bonn, Germany

[15] St James Hosp, Dept Paediat Haematol, Dublin, Ireland

[16] Hospit Univ Virgen del Rocio, Hosp Gen Unidad Hemofilia, Seville, Spain

[17] Osped Maggiore Policlin, Fdn Ist Ricovero & Cura Carattere Sci Ca Granda, Angelo Bianchi Bonomi Hemophilia & Thrombosis Ctr, Milan, Italy

[18] Ctr Reg Traitement Hemophilie & Autres Malad Bice, Serv Hematol, Paris, France

[19] Childrens Hosp, Dept Haematol, Birmingham B16 8ET, W Midlands, England

[20] Univ Hosp Aarhus Skejby, Dept Pediat, Aarhus, Denmark

[21] Sanquin Fdn, Ctr Clin Transfus Res, Leiden, Netherlands

[22] Skoanes Univ Sjukhus, Dept Pediat, Malmo, Sweden

[23] Skoanes Univ Sjukhus, Malmo Ctr Thrombosis & Haemostasis, Malmo, Sweden

[24] Leiden Univ, Med Ctr, Dept Clin Epidemiol, NL-2300 RC Leiden, Netherlands

来源：

BLOOD | 2013年 / 121卷 / 20期

关键词：

PREVIOUSLY UNTREATED PATIENTS; IMMUNOLOGICAL DANGER SIGNALS; MUTATION TYPE; RISK-FACTORS; CLASS-II; POLYMORPHISMS; PROPHYLAXIS; IMPACT; GENE; TOLERANCE;

D O I：

10.1182/blood-2012-09-457036

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity <0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

引用

页码：4046 / 4055

页数：10

共 32 条

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