Inhibitor development and mortality in non-severe hemophilia A.
BACKGROUND
The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications.


OBJECTIVE
We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA.


METHODS
In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared.


RESULTS
During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6).


CONCLUSIONS
Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients.
Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
C L
CL
Eckhardt
Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
J I
JI
Loomans
Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
A S
AS
van Velzen
Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
M
M
Peters
Department of Hematology, van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands.
E P
EP
Mauser-Bunschoten
Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
R
R
Schwaab
Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy.
M G
MG
Mazzucconi
Regional Reference Centre for Inherited Bleeding Disorders, University Hospital, Parma, Italy.
A
A
Tagliaferri
Institute for Thrombophilia and Haemostaseology, Raphaelsklinik, Munster, Germany.
B
B
Siegmund
Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
S E
SE
Reitter-Pfoertner
Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands.|Jon J. van Rood Center for Clinical Transfusion Research, Leiden University Medical Center, Leiden, the Netherlands.|Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
J G
JG
van der Bom
Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
K
K
Fijnvandraat
D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood*; D001315:Australia; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002423:Cause of Death; D002648:Child; D005060:Europe; D005169:Factor VIII / Q000276:immunology*; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality*; D006470:Hemorrhage / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D055815:Young Adult
D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D015415:Biomarkers; C078147:F8 protein, human; D005169:Factor VIII
cause of death; hemophilia A; hemorrhage; mortality; neutralizing antibodies