Bleeding phenotype according to factor level in 825 children with nonsevere hemophilia: data from the PedNet cohort
Marloes S. de Kovel 1), Carmen Escuriola-Ettingshausen 2), Christoph Königs 3), Susanna Ranta 4), Kathelijn Fischer 5)
PedNet Study Group
M.T. Alvarèz Román 6), O. Benitez Hidalgo 7), J. Blatny 8), M. Bührlen 9), M. Carvalho 10), H. Chambost 11), A. Rosa Cid 12), C. Oudot 13), C. Escuriola-Ettingshausen 14), K. Fischer 15), C. Van Geet 16), H. Glosli 17), N. Gretenkort Andersson 18), R. Ljung 19), C. Königs 20, M. Koskenvuo 21), C. Male 22), T. Stamm Mikkelsen 23), A. Molinari 24), J. Motwani 25), B. Nolan 26), R. d’Oiron 27), J. Oldenburg 28), M. Olivieri 29), H. Pergantou 30), F. Pinto 31), S. Ranta 32), M. Kartal-Kaess 33), E. Zápotocká 34), G. Kenet 35), M. Carcao 36), G. Rivard 37)
1-PedNet Haemophilia Research Foundation, Baarn, The Netherlands
2-Hämophilie-Zentrum Rhein Main GmbH, Frankfurt, Germany
3-Goethe University Frankfurt, University Hospital, Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Hemostasis, Frankfurt, Germany
4-Pediatric Coagulation Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
5-Center for Benign Haematology, Thrombosis and Haemostasis Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
6-Unidad de Coagulopatías, Hopital Universitario La Paz, Madrid, Spain
7-Unitat Hemofilia, Hospital Vall d’Hebron, Barcelona, Spain
8-Department of Paediatric Haematology, Children’s University Hospital, Brno, Czech Republic
9-Gesundheit Nord, Klinikum Bremen Mitte, Prof.-Hess-Kinderklinik, Bremen, Germany
10-Immunohemotherapy Department, Congenital Coagulopathies Reference, Centro Hospitalar e Universitário São João, E.P.E., Porto, Portugal
11-APHM, La Timone Children’s Hospital, Center for Bleeding Disorders & Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France
12-Unidad de Hemostasia y Trombosis, Hospital Universitario y Politécnico La Fe, Valencia, Spain
13-Centre Regional d’Hemophilie, Centre Hospitalo Universitaire, Toulouse, France
14-HZRM Hämophilie Zentrum Rhein Main GmbH, Mörfelden-Walldorf, Germany
15-Van Creveld Kliniek, University Medical Center Utrecht, Utrecht, The Netherlands
16-Catholic University of Leuven, Campus Gasthuisberg, Service of Pediatric Haematology, Leuven, Belgium
17-Oslo University Hospital HF, Oslo, Norway
18-Department of Clinical Sciences-Paediatrics, Lund University, Lund Department of Pediatrics and Malmö Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden
19-Department of Clinical Sciences-Paediatrics, Lund University, Lund, Sweden
20-University Hospital Frankfurt, Department of Paediatrics and Adolescent Medicine, Frankfurt, Germany
21-New Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
22-Department of Paediatrics, Medical University Hospital of Vienna, Vienna, Austria
23-Department of Pediatrics, University Hospital of Aarhus at Skejby, Aarhus, Denmark
24-Dipartimento di Ematologia ed Oncologia, Unità Trombosi ed Emostasi, Ospedale Pediatrico Giannina Gaslini, Genova, Italy
25-Department of Haematology, The Children’s Hospital, Birmingham, United Kingdom
26-Department of Paediatric Haematology, Our Lady’s Children’s Hospital for Sick Children, Crumlin, Dublin, Ireland
27-Centre de Référence de l’Hémophilie et des Maladies Hémorragiques Constitutionnelles, et HITh UMR_S1176 INSERM, Hopital Bicêtre, APHP Université Paris Saclay, Le Kremlin Bicêtre, France
28-Institut für Experimentelle Hämatologie und Transfusionsmedizin, Universitätsklinikum Bonn, Germany
29-Dr. V. Hauner Children’s Hospital, University of Munich, Munich, Germany
30-Haemophilia Centre/Haemostasis and Thrombosis Unit, Aghia Sophia Children’s Hospital, Athens, Greece
31-Department of Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom
32-Pediatric Coagulation Unit, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
33-Division of Pediatric Hematology & Oncology, Department of Pediatrics, Inselspital, University Hospital, University of Bern, Bern, Switzerland
34-Department of Pediatric Hematology and Oncology, Prague, Czech Republic
35-National Hemophilia Center Sheba Medical Center, Tel Hashomer & Amalia Biron Research Institute of Thrombosis & Hemostasis, Tel Aviv University, Tel Aviv, Israel
36-Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
37-Division of Hematology/Oncology, Hôpital St Justine, Montréal, Québec, Canada
Abstract
Introduction
Information on bleeding phenotype in nonsevere hemophilia may be used to determine target factor levels for prophylaxis or gene therapy in severe hemophilia.
Objectives
To assess the association between endogenous factor level and bleeding phenotype in children with nonsevere (factor [F]VIII/FIX activity 1%-25%) hemophilia A (HA) and B without prophylaxis.
Methods
Data on annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR), and onset of bleeding were extracted from the international PedNet cohort including children born since 2000. Mean ABR and AJBR were modeled and compared according to FVIII/FIX endogenous activity (1%-2%, 3%-5%, 6%-10%, 11%-15%, 16%-20%, and 21%-25%) using negative binomial regression. Onset of bleeding was analyzed using Kaplan–Meier survival curves.
Results
Eight hundred twenty-five children (40% with moderate hemophilia; 87% with HA) with median follow-up of 7.4 years/child were included. The median age at onset of bleeding and median bleeding rates changed with increasing endogenous activity. From endogenous FVIII 1% to 2% to 21% to 25%, the age at onset of bleeding changed from a median of 1.4 to 14.2 years, ABR from 1.6 to 0.1/y, and AJBR from 0.5 to 0.0/y. From endogenous FIX 1% to 2% to 16% to 25%, the onset of bleeding changed from a median of 1.7 to 6.1 years, ABR from 0.5 to 0.1/y, and AJBR from 0.1 to 0.0/y. The negative correlation between AJBR and factor level was most strongly pronounced up to a factor level of 6% in HA and hemophilia B.
Conclusion
Endogenous factor activity of >5% was identified as a threshold to significantly lower joint bleeding rate, while FVIII levels >15% and FIX levels >10% were sufficient to achieve the goal of 0 bleeds in this pediatric cohort.