Mortality Trends and Causes of Death in Persons with Hemophilia in the United States, 1999-2014
Authors: Payne Amanda B. , Ghaji Nafisa , Mehal Jason M. , Chapman Christina , Haberling Dana L. , Kempton Christine L , Bean Christopher J. , Soucie John Michael , Hooper William C. 
Published: April 2021

Abstract
Background: Hemophilia, an inherited bleeding disorder, is marked by increased risk of serious bleeding events. Prior to the development of factor concentrates, the most common cause of death among persons with hemophilia (PWH) in the United States (US) was related to bleeding events, and the median age at death was around 25 years (Chorba et al 1994). After the development of factor concentrates, the proportion of deaths caused by bleeding events declined, and the median age at death increased to 57 years (Chorba et al 1994). However, the HIV/AIDS epidemic led to a decrease in the median age at death, and HIV/AIDS became the leading cause of death among PWH (Chorba et al 2001). Development of effective treatment for and prevention of HIV/AIDS has improved outcomes among PWH (Soucie et al 2016); however, national mortality trends among PWH in the US have not been published since 2001.
Methods: Hemophilia-related deaths were examined using the 1999-2014 US multiple cause-of-death mortality data. Hemophilia deaths were identified as deaths for which an International Classification of Disease 10th revision, (ICD-10) code for hemophilia (D66, D67) was listed anywhere on the death record. Age-specific annual and average annual hemophilia-related death rates were calculated as the number of deaths per 100,000 corresponding population, with the bridged-race intercensal estimates of the US resident population as the denominator. Underlying and contributing cause of death codes were categorized according to their ICD-10 codes into 22 groups relevant to hemophilia outcomes, including 'blood/coagulation/immune', 'acute cardiac disease', 'chronic cardiac disease', 'cerebrovascular disease', 'hemorrhage', and 'musculoskeletal disease'. To compare hemophilia-related deaths to non-hemophilia deaths, death records not listing an ICD-10 code for hemophilia were randomly selected in a 1:3 ratio; non-hemophilia deaths were matched to hemophilia deaths by race, age group, and year of death.
Results: From 1999-2014 there were 2,354 hemophilia-related deaths reported in the US. The hemophilia-related death rate decreased from 0.15 hemophilia-related deaths per 100,000 population to 0.08 hemophilia-related deaths per 100,000 population (rate ratio 0.57 [95% confidence interval 0.46-0.71]). The median age at death increased from 49 years in 1999 to 63 years in 2014. The distribution of underlying and contributing cause of death associated with hemophilia-related deaths reflects an aging population. During the first time period (1999-2002) HIV was most commonly listed as an underlying or contributing cause of death , while chronic cardiac complications was most commonly listed as the underlying or contributing cause of death during the last time period (2011-2014) (Figure 1). The underlying and contributing cause of death listed among hemophilia-related deaths also differed by age group (Figure 2). The most common underlying or contributing cause of death among deaths occurring at &lt;20 years of age was intracranial hemorrhage. The most common underlying or contributing causes of death among deaths occurring between 20 and 69 years of age were HIV and/or hepatitis. The most common underlying or contributing cause of death among deaths occurring at 70+ years of age was chronic cardiac complications. Compared to non-hemophilia-related deaths, deaths related to hemophilia were more likely to be related to HIV, hepatitis, hemorrhage, and intracranial hemorrhage. Interestingly, hemophilia-related deaths were less likely to be related to cardiac complications and cancer than non-hemophilia-related deaths (Figure 3).
Conclusions: This report highlights the continued success of interventions to decrease death among PWH. However, this report also highlights possible areas of future research in hemophilia, including monitoring trends in morbidities related to aging, such as cardiac disease and comorbidities due to chronic hepatitis infection.

Disclosures
Kempton: Genentech: Membership on an entity's Board of Directors or advisory committees.