ALBERT

Description: Sickle cell disease is a common hemolytic disorder with a broad range of complications, including vaso-occlusive episodes, acute chest syndrome (ACS), pain, and stroke. Heme oxygenase-1 (gene HMOX1; protein HO-1) is the inducible, rate-limiting enzyme in the catabolism of heme and might attenuate the severity of outcomes from vaso-occlusive and hemolytic crises. A (GT)n dinucleotide repeat located in the promoter region of the HMOX1 gene is highly polymorphic, with long repeat lengths linked to decreased activity and inducibility. We examined this polymorphism to test the hypothesis that short alleles are associated with a decreased risk of adverse outcomes (hospitalization for pain or ACS) among a cohort of 942 children with sickle cell disease. Allele lengths varied from 13 to 45 repeats and showed a trimodal distribution. Compared with children with longer allele lengths, children with 2 shorter alleles (4%; ≤ 25 repeats) had lower rates of hospitalization for ACS (incidence rate ratio 0.28, 95% confidence interval, 0.10-0.81), after adjusting for sex, age, asthma, percentage of fetal hemoglobin, and α-globin gene deletion. No relationship was identified between allele lengths and pain rate. We provide evidence that genetic variation in HMOX1 is associated with decreased rates of hospitalization for ACS, but not pain. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Description: Introduction: The final events of the activated clotting cascade include the conversion of fibrinogen to fibrin and stabilization of the growing fibrin clot by factor XIII (FXIII). A missense variant in the alpha chain of fibrinogen, α-fibrinogen (FGA) Thr312Ala (rs6050, NM_000508.3:c.991A〉G, NP_000499.1:p.[Thr331Ala]), has been previously shown to interfere with FXIII-dependent cross-linking, leading to stiffer blood clots. It is believed this pathophysiology underlies the increased risk of venous thromboembolism (VTE) associated with the variant. The Thr312Ala variant has been shown to be significantly associated with VTE among White, Non-Hispanic populations. The only investigation of the variant in a Black population (Rasmussen-Torvik et al 2007) found no significant relationship between Thr312Ala and VTE, but the authors cite the relatively small number of participants included in the analysis as a possible reason for a null finding. We investigated the association between FGA Thr312Ala and VTE in a case-control study enrolling a relatively large racially diverse study population. Methods: Conditional logistic regression was used to assess the association between FGA Thr312Ala and VTE among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, a case-control study enrolling 1,042 VTE cases and 1,213 controls with no history of VTE, frequency-matched on age, sex, and race. Crude models conditioned on the matching factors, and adjusted models conditioned on the matching factors and controlled for patient characteristics found to be associated with both case/control status and FGA Thr312Ala genotype. Among all patient characteristics evaluated, the β-fibrinogen (FGB) promoter region variant -455 G〉A (rs1800790, NM_001184741.1:c.-463G〉A) was the only patient characteristic associated with both case/control status and FGA Thr312Ala genotype. Potential effect modification was assessed using likelihood ratio tests. Results: Among 660 White controls and 528 White cases in the GATE study, carrying at least one FGA rs6050 G (Ala) allele was associated with increased odds of VTE compared to not carrying a G allele (odds ratio (OR) and 95% confidence interval (CI) 1.2 [1.0-1.5]) in a crude model. This association was strongest when restricting to n=205 idiopathic (unprovoked) cases, n=125 recurrent cases, or n=112 cases exhibiting both deep vein thrombosis (DVT) and pulmonary embolism (PE) (Table 1). This association was modified by obesity status, with the effect among obese enrollees being multiplicative (Table 2). In contrast, there was no association between carrying at least one FGA rs6050 G (Ala) allele and VTE among 553 Black controls and 514 Black cases in the GATE study (OR and 95% CI 1.0 [0.8-1.2]) when assessing the association among all cases (Table 1). However, the odds of VTE was higher among Black participants carrying the G allele compared to those not carrying the allele when restricting to n=103 PE only cases (OR and 95% CI 1.5 [1.0-2.4]). The association between FGA Thr312Ala and VTE did not appear to be modified by obesity status among Black participants (Table 2). Conclusions: These results indicate that the FGA Thr312Ala (rs6050, NM_000508.3:c.991A〉G, NP_000499.1:p.[Thr331Ala]) polymorphism is associated with VTE among White participants in the GATE study, with the strongest effect seen in participants exhibiting both DVT and PE. However, the association among Black participants appears limited to PE, indicating further exploration of genetic risk factors for VTE in Black populations is warranted in order to better understand genetic risk factors for all types of VTE in this population. Disclosures Payne: Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees. Patel:Daiichi Sankyo: Other: DSMB member.

Description: Introduction: Black Americans have been reported to have a higher incidence of venous thromboembolism (VTE) compared to white Americans. The underlying cause of this disparity is not well characterized. Protein S, protein C, and antithrombin deficiency are known risk factors for VTE. There is inconsistent data regarding racial variation on the effect of protein S, protein C, and antithrombin levels and/or deficiency and risk of VTE. Most prior studies have not included a large black study population. The aim of this investigation is to compare levels of protein C, protein S, and antithrombin between VTE cases and controls by race among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, accounting for genetic differences such as hemoglobin genotype that may contribute to differences in protein levels by race. Methods: Testing for protein S, protein C, and antithrombin deficiency was performed on a subset of participants enrolled in the GATE study, a case-control study comprised of VTE cases and controls frequency-matched on age, sex, and race (self-identified). Controls had no history of VTE and did not receive anticoagulant therapy. Antigen and activity levels in cases were measured at least one month after completion of anticoagulation therapy. A priori cutoff levels for determining deficiency status were standardized per Centers for Disease Control Hemostasis Laboratory reference ranges. Beta hemoglobin genotype was determined by either a multiplex genotyping assay or sequencing of the beta hemoglobin gene. Differences in protein levels between cases and controls were compared using the Wilcoxon rank sum test. Conditional logistic regression analysis was performed to evaluate the association between protein S, protein C, or antithrombin deficiency and VTE. Crude models were conditioned on the matching factors, and adjusted models were conditioned on the matching factors and controlled for patient characteristics found to be associated with VTE and protein S, protein C, or antithrombin deficiency. Potential effect modification was assessed using likelihood ratio tests. Results: Among 2,454 subjects enrolled in the GATE study, 1,436 subjects (63.6%) had samples available for analysis. Protein S activity and total protein S antigen levels were significantly lower among VTE cases compared to controls in both white and black participants; however, antithrombin levels were higher among VTE cases compared to controls in white participants only. (Table 1) The prevalence of protein S and protein C deficiency was higher among VTE cases compared to controls in both white and black participants in the GATE study (Table 2). The prevalence of antithrombin deficiency was similar between VTE cases compared to controls. Adjusting for the effect of family history of VTE, history of cancer, and hemoglobin genotype, the effect of protein S and protein C deficiency on odds of VTE was stronger among black participants compared to white participants (Table 2). Conclusions: The effects of protein S and protein C deficiency on the odds of being a VTE case were higher among black participants in the GATE study, controlling for confounding variables including hemoglobin genotype. While these results indicate protein S and protein C deficiency may be important contributors to disparities in VTE occurrence, additional investigations using a larger study populations and different study designs are warranted. Disclosures Patel: Daiichi Sankyo: Other: DSMB member. Payne:Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: treatment product donation.

Description: Introduction: Cardiopulmonary fitness is significantly reduced among individuals with sickle cell disease (SCD). Cardiopulmonary fitness is also an important predictor of morbidity and all-cause mortality in the general population. However, the relationship between fitness and clinical outcomes in SCD has not been well studied. The objectives of this analysis were to: 1) determine the factors associated with fitness in a cohort of adults with SCD, and 2) evaluate the relationship of fitness to hospitalization for pain and acute chest syndrome (ACS) and overall mortality. We hypothesized that clinical factors such as age, sex, hemoglobin, SCD genotype and cardiopulmonary disease significantly affect fitness, and that poor fitness is a predictor of more frequent hospitalizations for pain and ACS and higher mortality in adults with SCD. Methods: A cohort of adults with SCD was constructed from participants enrolled in phase 2 of the Cooperative Study of Sickle Cell Disease (CSSCD) who underwent exercise testing (modified Balke treadmill protocol). Primary measure for fitness was total treadmill duration. Retrospective pain or ACS hospitalization rates were calculated using events in the 3 years prior to exercise testing. Mortality and prospective hospitalization rates for pain and ACS were calculated using events after exercise testing with a minimum 6 month follow-up. Results of pulmonary function testing (PFT), echocardiography, and laboratory testing within 3 years of exercise testing were included in our analysis. Standard descriptive analyses were performed (SPSS V24). Multivariable negative binomial and Cox proportional hazards models were constructed to evaluate the relationship of fitness to ACS and pain hospitalization rates and mortality, respectively. Multivariable linear models were constructed to determine factors associated with fitness. Results: A total of 223 participants had valid exercise testing data (64% female, 70% hemoglobin SS or S/b0 thalassemia, mean age 43.3 ± 7.5 years, mean hemoglobin 9.1 ± 2.2 g/dl, mean follow-up 2.7 ± 0.7 years after exercise testing). Participants completed a mean of 11.6 ± 5.2 min on the treadmill, with 87% completing ≥ 3 stages but only 17% completing all 10 stages. We categorized fitness into tertiles of treadmill duration (5.7 vs. 11.8 vs. 18.1 min, p 〈 0.001). Age (45.2 vs. 43.1 vs. 41.3 years, p = 0.007), baseline hemoglobin (8.5 vs. 9 vs. 9.8 g/dl, p = 0.003), as well as the proportion of females (77 vs. 71 vs. 40%, p 〈 0.001) and participants with abnormal PFT (58 vs. 35 vs. 39%, p = 0.008), differed significantly across fitness tertiles. Pain or ACS hospitalization rates during the 3 years prior to exercise testing were not significantly different across fitness tertiles. Using multivariable linear regression, male sex (β = 3.1, p 〈 0.001), lower age at exercise testing (β = -0.14, p = 0.003), and higher hemoglobin (β = 0.44, p = 0.049) were independently associated with higher fitness, with abnormal PFT trending toward significance (β = -1.28, p = 0.07). In this model, genotype, tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s, and pain and ACS hospitalization rates prior to exercise testing were not significantly associated with fitness. Using a negative binomial regression model, we found that fitness did not predict future pain or ACS episodes after adjustment for age, sex, genotype, hemoglobin and TRJV. Fitness also did not predict survival in our cohort (hazard ratio, 0.97; 95% CI [0.84, 1.13], p = 0.71), in which death was reported in only 9 participants. In our Cox regression model, male sex (HR 7.1; 95% CI [1.3, 38.9]; p = 0.02) and lower hemoglobin (HR 0.56; 95% CI [0.36, 0.88]; p = 0.01) were independent predictors of death, but age at exercise testing, abnormal PFT and TRJV ≥ 2.5 m/s were not. Conclusions: In adults with SCD, lower fitness is significantly associated with female sex, older age, lower hemoglobin and abnormal PFT. Fitness did not predict survival or future pain or ACS events in the CSSCD. Given that cardiopulmonary fitness remains an important predictor of all-cause mortality in the general population, larger scale prospective studies in SCD are needed to evaluate the impact of regular exercise on improving fitness, quality of life, clinical outcomes and mortality in this population. Disclosures Badawy: Ann & Robert H. Lurie Children's Hospital of Chicago: Employment; Ann & Robert H. Lurie Children's Hospital of Chicago: Research Funding; Salveo Health Communications LLC: Consultancy. Payne:National Center on Birth Defects and Developmental Disabilities: Employment. Liem:Ann & Robert H. Lurie Children's Hospital of Chicago: Employment; Ann & Robert H. Lurie Children's Hospital of Chicago: Research Funding; National Institute of Health: Research Funding.

Description: Background: Sickle cell anemia (SCA) is a life threatening monogenic disorder associated with early death. Platt et al. reported median ages of death (42 years males; 48 years females) from the Cooperative Study of Sickle Cell Disease (CSSCD). Forced expiratory volume in one second (FEV1) on pulmonary function testing (PFT), is commonly used to monitor disease severity in individuals with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease. FEV1 (% predicted) has been shown to predict mortality in the general population, but no PFT result has predicted earlier death in SCA. We tested the hypothesis that abnormal pulmonary function was associated with earlier death. Methods: A prospective cohort study using the CSSCD data was constructed. We evaluated a total of 430 participants from the CSSCD study who had evaluable PFT, using data from the first PFT at age 21 years and older, and reviewed centrally for quality. Predicted values were determined for each subject based on age, gender, height, and race for FEV1, forced vital capacity (FVC), and the FEV1/FVC ratio using the Global Lung Function 2012 equations. Abnormal results for FEV1, FEV1/FVC, and FVC were determined by comparison to their lower limits of normal. Predicted values for total lung capacity (TLC) were obtained utilizing the prediction equations published, and adjusted by 12% to account for the effect of race on these values; a value

Description: Background: Vaso-occlusive pain episodes (VOE) are the most common complication and reason for hospital admission in individuals with Sickle Cell Anemia (SCA). Recently our team demonstrated that in adults with SCA followed prospectively for approximately 5 years, a lower baseline Forced Expiratory Volume in 1 second percent predicted (FEV1%), which is associated with earlier mortality, but evidence of obstructive or restrictive lung function patterns is not (Blood 2015, in press). Based on the evidence that abnormal pulmonary function is associated with earlier mortality, we tested the hypothesis that baseline pulmonary function patterns were associated with SCA-related morbidity, including VOE and acute chest syndrome (ACS) events. Procedure: A prospective cohort of adults with SCA followed in the Cooperative Study for Sickle Cell Disease (CSSCD) was constructed based on a planned secondary analysis. Data from the first PFT record at age 21 and older were used for this study. Percent predicted values were determined for each participant based on their age, gender, height, and race for FEV1 and the ratio of FEV1 to forced vital capacity (FEV1/FVC) using the Global Lung Function 2012 equations (Eur Respir J, 2012; 40(6): 1324-1343). Assessment of lower airway obstruction was based on % predicted FEV1/FVC. Percent predicted total lung capacity (TLC), a measure of restrictive lung disease, was determined using published equations and corrected based on race. All PFT evaluations were checked for quality. Negative binomial regression models were used to determine the association between future VOE, ACS events, and spirometry measurements after adjusting for age, sex, hemoglobin, and fetal hemoglobin levels. Results : A total of 430 adults with SCA were evaluated. Ages of the study participants ranged from 21.7-66.4 years with a median age of 32.6 years at the time of first PFT and median follow-up was 5.5 years. Only FEV1/FVC% predicted as a continuous covariate was a significant predictor of future VOE. Lower FEV1/FVC% predicted was associated with higher future pain event rates with a rate ratio of 1.022 (95% CI 1.002 - 1.042; p=0.028). For every 10% decrease in FEV1/FVC% predicted there is a 23% increase in the rate ratio. TLC% predicted did not predict future VOE (p=0.762). FEV1/FVC% predicted or TLC% predicted did not predict future ACS events (p=0.618 and p=0.430 respectively). When FEV1/FVC% predicted and TLC% predicted 〈 5th percentile were used in the regression equation instead of continuous values, neither abnormal lung function parameter was associated with an increased incidence of VOE or ACS events. Conclusions: For the first time, we have demonstrated that spirometry evaluation with FEV1/FVC% predicted, as a measure of lower airway obstruction, identifies a group of adults with SCA at increased risk for future vaso-occlusive pain episode. Table 1. Covariate Rate Ratio (95% CI) P Age at PFT* -.112 (.850, .941) .000 Male 1.032 (.581, 1.836) .914 Average Fetal Hemoglobin .985 (.894, 1.085) .754 Average Hemoglobin .954 (.763, 1.193) .682 Negative FEV1/FVC percent predicted** .022 (1.002, 1.042) .028 Final Negative Binomial Regression model for vaso-occlusive pain episodes after lung function testing (N= 430) *PFT is Pulmonary Function Test ** Negative FEV1/FVC percent is reverse-coded so that lower values are associated with rate ratios above 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: Development of inhibitory alloantibodies, commonly known as "inhibitors," against exogenously infused factor VIII (FVIII) is the most significant complication of hemophilia therapy. The aim of this study was to understand the epidemiology of inhibitors in persons with severe hemophilia A (PWHA) in the United States using a national database, the Community Counts Registry for Bleeding Disorders Surveillance. Methods: The Community Counts Registry collects detailed medical information on patients with bleeding disorders who receive treatment within the US Hemophilia Treatment Center Network (USHTCN). Patients with severe hemophilia A with (PWHA-I) and without an inhibitor (PWHA-NI) enrolled in the registry between 12/1/2013 and 7/9/2018 were included in this cross-sectional exploratory analysis. PWHA designated as having an unknown history of inhibitor were excluded. Data elements included basic demographics (age, sex/gender, race, ethnicity, employment, insurance status), clinical characteristics (age of diagnosis, treatment characteristics), inhibitor characteristics (age at detection, inhibitor-specific treatments, titers, status), and outcome data (bleeding events, joint disease and procedures, intracranial hemorrhage, ED visits, hospitalizations, chronic pain, opioid use, and days missed from school/work). Data were categorized with reported frequencies, and comparisons between PWHA-I and PWHA-NI were made using Chi-square tests. Results: Of 4375 patients with severe hemophilia A, 1142 (26.1%) had a reported history of inhibitor. Among the cohort were 13 (0.30%) female and 7 (0.16%) transgender patients. PWHA-I and PWHA-NI were similarly distributed among sex/gender categories. PWHA-I were more frequently Hispanic, Latino/a, or Spanish origin or black or African American and less frequently white. Nearly all patients were insured, although PWHA-I more frequently utilized public insurance as opposed to commercial insurance as primary insurance, which may align with the lower rate of employment among PWHA-I (Table 1). PWHA-I more frequently reported a history of intracranial hemorrhage. Notably, no association was identified between inhibitor history and history of joint bleed, history of invasive joint procedure, or limitations of activity level at the time of assessment. During the 12 months prior to assessment, a lower percentage of PWHA-I reported hemophilia-related chronic pain, but those PWHA-I with chronic pain reported opioid use at a modestly increased rate. PWHA-I were more frequently seen in the emergency department and hospitalized than PWHA-NI during the 12 months prior to reporting, and PWHA-I reported more days missed from work or school (Table 1). Within the PWHA-I cohort, 45.7% of patients had inhibitors detected prior to age 2 years. The majority (64.8%) of PWHA-I had a history of immune tolerance induction and 56.3% reported using routine doses of FVIII concentrates to treat bleeding events. Bypassing agents and increased FVIII concentrates were each used for ~20% of PWHA-I (Table 2). Conclusions: This study provides an estimate of the burden of inhibitors in persons with severe hemophilia A in the US, representing approximately 52.9% of all severe hemophilia A patients treated in the USHTCN (CDC, unpublished data). History of an inhibitor reduced patient productivity and increased ED and hospital utilization. Future efforts will focus on a longitudinal analysis of this cohort to better understand the natural history and outcome of inhibitors and their impact on patient quality of life and health care utilization. Acknowledgments: This study was performed with the advice of the Community Counts Inhibitor Interest Group and was supported by funds from an ASH HONORS Award for Mr. Sande. Disclosures Payne: Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation. Kempton:Novo Nordisk: Research Funding; Genetech, Inc: Honoraria, Research Funding; Shire: Honoraria; Bayer AG: Honoraria; Spark Therapeutics: Honoraria; Grifols: Honoraria; Catalyst Biosciences: Honoraria. Manco-Johnson:CSL Behring: Honoraria; Novo Nordisk: Honoraria; Biogentek: Honoraria; Bayer AG: Honoraria, Research Funding; Baxalta, now part of Shire: Honoraria. Sharathkumar:CSL Behring: Honoraria; Shire: Honoraria; Bayer: Honoraria.

Description: The genetics of blood coagulation has been an ongoing area of research; and with the advent of next generation sequencing panels, there is a significant increase in the number of variants identified in coagulation factor genes. Several published reports and online databases document the variants observed in patients with bleeding disorders; however, the clinical interpretation of these variants is not always straight-forward. To enable gene-specific variant interpretation in coagulation factor deficiency disorders, the National Institutes of Health (NIH)-funded effort, Clinical Genome Resource (ClinGen), has developed the Coagulation Factor Deficiency Variant Curation Expert Panel (CFD-VCEP). The CFD-VCEP is comprised of expert clinicians, genetic counselors, clinical laboratory diagnosticians and researchers working toward the goal of developing and implementing standardized protocols for sequence variant interpretation for coagulation factor genes. The CFD-VCEP adapts the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for precise and consistent variant classification to genes involved in blood coagulation deficiencies. These guidelines recommend the use of 28 criteria codes based on the evidence category and the strength of the evidence (see Figure below). The first two genes under the purview of CFD-VCEP are F8 (OMIM: 300841) and F9 (OMIM: 300746). Pathogenic variants in the F8 and F9 genes resulting in the loss of protein function cause Hemophilia A and B, respectively. Owing to the similarity between these two genes with respect to their role in the coagulation cascade as well as the resulting phenotype, specification of variant curation guidelines for both genes has been undertaken simultaneously. With the completion of guideline specification for F8 and F9, the CFD-VCEP will subsequently continue this effort for other coagulation factor genes, while also curating F8 and F9 variants reported in ClinVar and other variant databases. Modifying the ACMG/AMP guidelines involves gene- and disease-informed specifications of the recommended criteria codes. This includes identifying which codes are applicable and which are not, defining gene- and disease-specific cut-offs such as for population frequency, and making code strength adjustments when appropriate. The specified guidelines are further refined based on their performance on a set of pilot variants (n = 30) for each gene compared to existing assertions of variant classification in ClinVar and by diagnostic laboratories represented in the CFD-VCEP. F8 and F9 variants classified by the CFD-VCEP will be submitted to ClinVar at the 3-star review status, with the tag of "FDA-recognized database", and the CFD-VCEP plans to begin this process by the second quarter of 2020. The considerations by the CFD-VCEP in the guideline-specification process and results from the pilot analysis will be discussed. This effort will lead to the standardized use of evidence criteria for the evaluation of variants in F8 and F9, which will reduce the number of variants of uncertain significance and those of conflicting interpretations, making genetic testing results more informative for providers and patients. The CFD-VCEP also encourages sharing de-identified data on variants among laboratories, which enables accurate and consistent curations. Figure Disclosures Lee: UNC Hemophilia Treatment Center: Employment. Carcao:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kemball-Cook:European Association for Haemophilia and Allied Disorders: Other: Freelance . Leebeek:CSL Behring: Research Funding; uniQure BV: Consultancy, Research Funding; Baxalta/Shire: Research Funding. Miller:Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention: Consultancy.

Description: Key Points Among adults with SCA, decreased FEV1 percent predicted was associated with earlier death. Obstructive and restrictive pulmonary function patterns do not predict earlier death in adults with SCA.

Description: 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