ALBERT

Description: Introduction: The majority of published studies evaluating inhibitors have focused mainly on patients with severe hemophilia A. In non-severe hemophilia A (NSHA) patients, the development of inhibitors can have a profound clinical impact, with major bleeding complications similar to that of patients with severe or acquired hemophilia. Yet, epidemiological data on inhibitors in NSHA patients, specifically mortality, is scarce and currently limited to the European and Australian cohort [Eckhardt CL, et al. J Thromb Haemost. 2015 Jul;13(7):1217-251]. Objectives: To determine the all-cause and inhibitor-related mortality in NSHA patients in the United States using the ATHNdataset Methods: Subjects and study design The ATHNdataset is a 'limited dataset' as defined under the United States Health Insurance Portability and Accountability Act (HIPAA) to be free of protected health information, with data collection by more than 130 hemophilia treatment centers (HTC) across the United States. It includes patients with congenital bleeding disorders in the United States who have authorized the sharing of their demographic and clinical information for research. Data collection and definitions The ATHNdataset was queried on December 31, 2018 to extract the following information on NSHA patients: Patient demographics, inhibitor status, date of death, and primary cause of death. The presence of inhibitors was defined as: (i) ≥ 2 positive Bethesda inhibitor assay titers of ≥ 1.0 BU/mL; or (ii) a decrease in plasma FVIII coagulant activity (FVIII:C) to at least 50% of baseline activity and/or spontaneous bleeding symptoms in patients with inhibitor titers between 0.6 and 1.0 BU/mL. Patients who had a negative inhibitor history or have never been tested for FVIII inhibitors were classified as negative for inhibitors. Statistical analyses The person-year mortality rate was calculated as the ratio of the number of deaths to the number of person-years at risk, presented as rates per 1000 person-years. Person-years at risk was calculated for each patient as the time between the start of the observation period (January 1, 2010 or date of birth for patients who are born later) and the end of the observation period (date of death, loss-to follow-up or December 31, 2018). Patients who were deceased or lost to follow-up before January 1, 2010 were not included in the analysis. Inhibitor person-years at risk for inhibitor patients was calculated from January 1, 2010 if the first positive inhibitor test occurred prior to January 1, 2010 or from the date of the first positive inhibitor test that occurred during the observation period until the end of the observation period. Inhibitor-related death was attributed to all patients who had a positive inhibitor history. Mortality rates were compared between inhibitor and non-inhibitor patients using z- test. Results: Between 1/1/2010 and 12/31/2018, the ATHNdataset included 6,606 NSHA patients who were born between 1920 and 2018. Patients were observed for a total of 56,064 person-years. 85.57% (n = 5,653) of these patients were observed for the full nine years. The average follow-up time per patient was almost 8.5 years. Inhibitors developed in 171 (2.59%) NSHA patients. The median age for inhibitor development was 13 years (IQR, 6 - 37 years) and the mean age was 22 years. Demographics characteristics of the patients are listed in Table 1. All-cause mortality At the end of follow-up, there was a total of 136 deaths in the NSHA population, occurring at a median age of 63 years (IQR, 51 - 75 years). The overall all-cause mortality rate was 2.43 per 1,000 person-years (95% CI: 2.02 - 2.83). The most common primary cause of death was cancer (n=27, 19.9%) (Table 2). Inhibitor-related mortality Three deaths were associated with inhibitors. Inhibitor-related mortality rate was 2.40 per 1,000 person-years, whereas among the never inhibitor group, the mortality rate was 2.44 per 1,000 person-years (p = 0.790). Mortality risk ratio between inhibitor and never inhibitor was 0.98 (95% CI: 0.31 - 3.08). Conclusion: In NSHA patients, the development of inhibitors occurred at a relatively early age and was not associated with increased mortality. Disclosures Kempton: Novo Nordisk: Research Funding; Octapharma: Honoraria; Genentech: Honoraria; Spark Therapeutics: Honoraria. Key:Uniqure BV: Research Funding.

Description: Copper deficiency has long been recognized as cause of hematopoietic dysfunction, and diagnosis is straightforward if it is pursued. Over a three year period, we diagnosed copper deficiency in seven pts referred to our university-based hematology and BMT outpatient clinics for evaluation and treatment of myelodysplastic syndrome (MDS) or neutropenia/anemia. This represents approximately 3% of new outpatient referrals carrying an ICD-9 code corresponding to MDS or neutropenia. Patient characteristics are shown in Table 1. Three of the seven pts carried a presumptive diagnosis of MDS, and one had received several months of decitabine therapy. Two patients were actually referred for consideration of stem cell transplantation; the others were referred for evaluation of cytopenias. Six of the seven patients had been evaluated by a hematologist prior to referral. Only 3 of 7 pts in our series had recognized risk factors for copper deficiency such as prior gastric bypass or other GI dysfunction; postulated risk factors in the other pts are included in Table1. All pts in our series were anemic and leukopenic, with absolute neutropenia at presentation. In contrast, platelet counts were normal or elevated in all pts, consistent with most previous reports. Five of the seven pts in our series had neuropathy or myelopathy of variable severity. The hematologic abnormalities responded rapidly and completely to oral and/or IV copper replacement in all pts, although neurologic recovery was slow and incomplete. Conclusions: Our experience indicates that copper deficiency is a relatively common cause of neutropenia and anemia, and the consequences of missing the diagnosis may be substantial, including performance of unnecessary transfusion, chemotherapy, and even stem cell transplantation. Normal or elevated platelet counts and concomitant neuropathy or myelopathy are important clues to the diagnosis. Furthermore, copper deficiency must be considered even in pts without obvious GI absorption abnormalities. Serum copper and ceruloplasmin assays should be incorporated into the routine evaluation of most pts with cytopenias and suspected MDS. Age/gender Ref. diagnosis Risk factor Associated symptoms Serum copper (80–155 mcg/dl) Ceruloplasmin (21–53 mg/dl 53F MDS–RAEB unknown Severe sensory-motor neuropathy 29 7 43F MDS–RA Excess carbonated soda intake? Severe sensory-motor neuropathy 2

Description: Introduction Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that restores the function of missing activated factor VIII (FVIII) by bridging activated FIX and FX in persons with hemophilia A (PwHA). Prophylaxis with emicizumab once weekly or every two weeks resulted in significant reductions in bleeds, including joint bleeds, and a favorable safety profile in PwHA without FVIII inhibitors in the HAVEN 3 study (NCT02847637; Mahlangu et al. 2018). Recurrent joint bleeds in PwHA can lead to hemophilic arthropathy, and hemophilia A has been associated with decreased bone mineral density (Kempton et al. 2014). To explore the potential effect of emicizumab prophylaxis on bone and joint health beyond bleed prevention, we measured joint health scores and bone and joint biomarkers in HAVEN 3. Methods Hemophilia joint health scores (HJHS; v2.1) were evaluated at baseline and Week 49 of emicizumab prophylaxis in 107 PwHA in HAVEN 3. Biomarkers of bone formation (osteocalcin [OC], N-terminal propeptide of type I procollagen [P1NP]), bone resorption (C-terminal telopeptide of type I collagen [CTX-I]), osteoblasts (osteoprotegerin), osteoclastogenesis (soluble receptor activator of nuclear factor- kappaB Ligand [sRANKL]), cartilage turnover (cartilage oligomeric matrix protein [COMP]), and inflammation (interleukin 1 beta, interleukin 6, and tumor necrosis factor) were measured in 117 PwHA (Table 1) receiving emicizumab at baseline and after 3, 6, 12, and 18 months of treatment. In all, 94 of 117 PwHA with samples for biomarker analysis were part of the HJHS evaluation. Results PwHA previously on FVIII prophylaxis and those with no target joints at study entry had lower (indicating healthier) HJHS scores at baseline. Mean improvements from baseline of −2.25 (95% confidence interval [CI]: −4.12, −0.39) in total HJHS and −2.23 (95% CI: −4.07, −0.38) in HJHS joint-specific domain (excluding gait) were observed after 49 weeks of emicizumab prophylaxis in PwHA with one or more target joints at study entry (n=71). Improvement was consistent across HJHS for different locations (knee, ankle, elbow). No significant differences in the measured biomarkers between PwHA previously on FVIII prophylaxis or on on-demand treatment, or in those with or without target joints, were seen at baseline. Mean baseline values of most bone and joint biomarkers were within normal ranges, or similar to published levels in healthy individuals, although large variability was observed between individuals. None of the measured biomarkers changed significantly during emicizumab prophylaxis. Higher OC, P1NP, and CTX-I levels were observed in adolescent vs adult PwHA at all time points, which is consistent with reported increases of these biomarkers during skeletal growth. Data suggest a potential association of COMP levels with HJHS scores at baseline (Pearson correlation coefficient 0.46, p=0.0001). Data on two additional cartilage biomarkers, CTX-II (C-terminal telopeptide of type II collagen) and CS-846 (a chondroitin sulfate epitope) are being generated. Conclusions Reduction in joint bleeds was previously reported in HAVEN 3, including over 99% target joint resolution with long-term follow up (Callaghan et al. 2019). This analysis provides further evidence of the positive effect of emicizumab on joint health, showing significant and clinically relevant improvements in HJHS (defined as a ≥2-point reduction in HJHS joints domain [Kuijlaars et al. 2017]) after as few as 49 weeks of emicizumab prophylaxis. The biomarkers measured in blood as surrogates of bone and joint health did not show significant changes over the first 18 months of emicizumab prophylaxis. This may reflect heterogeneity between individuals, and effects on the measured biomarkers by factors other than joint health. However, improvement in bone and joint biomarkers would have been unexpected as the observed means at baseline were already similar to levels reported in healthy individuals. Although data from animal models have suggested that FVIII may play a role in bone health beyond protection against bleeds, in this study we observed no indication of worsening in any of the measured bone and joint health markers that might have resulted from reduced exposure to FVIII in PwHA who switched to emicizumab prophylaxis. Additional data are needed to better understand the long-term effect of emicizumab prophylaxis on bone and joint health. Disclosures Kiialainen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Kempton:Novo Nordisk: Research Funding; Octapharma: Honoraria; Pfizer: Honoraria; Genentech, Inc.: Honoraria. Castaman:Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chang:Genentech/Roche: Equity Ownership; Genentech, Inc.: Employment. Paz-Priel:Genentech, Inc.: Employment. Adamkewicz:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Levy:F. Hoffman La Roche: Equity Ownership; Genentech, Inc: Employment.

Description: Abstract 3184 Poster Board III-121 INTRODUCTION Inhibitor formation is a major complication of hemophilia A (HA). Although only 25% of new inhibitors occur in those with mild or moderate HA, they often lead to an increased frequency of bleeding with potentially devastating consequences. In contrast to severe HA, knowledge of risk factors for the development of inhibitors in those with mild and moderate hemophilia A is limited. This study was carried out to assess the role of intensive exposure to factor VIII (fVIII), in inhibitor formation in those with mild or moderate HA. METHODS A retrospective case-control design was utilized. Cases were initially identified among participants of the Universal Data Collection (UDC) surveillance system as those with mild or moderate HA (fVIII 1-40%) having a current or past inhibitor titer of 〉 1 BU/ml. Hemophilia severity and inhibitor titer were verified by the Hemophilia Treatment Center (HTC) and patients were eligible for enrollment if they had an inhibitor titer 〉 1 BU/ml on two consecutive occasions or had one inhibitor titer 〉 1 BU/ml followed by initiation of immune tolerance therapy. Additional cases were identified by the HTC. Control subjects had no history of inhibitor titer 〉 0.6 BU/ml and had previously received fVIII. Negative inhibitor status was confirmed by Nijmegen assay performed in a central laboratory. After informed consent was obtained, exposure information during the year prior to inhibitor development (cases) or the year prior to enrollment (controls) was gathered from clinical records and subject interview. The primary risk factor of interest was intensive treatment with fVIII defined as having received 6 or more consecutive days. Other risk factors investigated include: age, baseline fVIII activity, race, prior number of fVIII exposure days, vaccination within the prior year, product type and fVIII genotype. RESULTS Forty-three cases and 65 controls met eligibility criteria and were enrolled at 16 HTCs. Seven cases and three controls were not included in the analysis after genotyping demonstrated mutations typically associated with severe disease, such as intron-22 inversion. The final analysis included 36 cases and 62 controls. Ten of these cases were originally identified in the UDC system. The mean baseline fVIII activity was similar between groups (p=0.73). The median age was 31 years (Inter-quartile range (IQR), 10-51 years) in cases and 27.5 years (IQR, 18-46 years) in controls (p=0.80). The distribution of subjects having 〈 50, 50-100 or 〉 100 prior fVIII exposure days was similar between groups (p=0.40). Fifty percent of cases had received intensive treatment with fVIII compared with 17.7% of controls (p 30 years (1.55 vs. 13.54, heterogeneity p=0.02). After multivariate adjustment, intensive treatment with fVIII remained strongly associated with inhibitor formation (OR 7.65; 95% CI, 1.69-34.44). In the multivariate model, the OR for intensive treatment in those 〈 30 years of age was 3.36 (95% CI, 0.6-16.8) compared with 15.24 (95% CI, 2.38-97.2) in those 30 years of age or older. However, this interaction between age and intensive treatment did not reach statistical significance (Wald test p=0.23). CONCLUSION Intensive treatment with fVIII is a strong independent risk factor for inhibitor development in those with mild or moderate hemophilia A and the risk appears to be greater in adults 30 years of age or older. Disclosures Kempton: Biomeasure Inc: Consultancy; CSL Behring Foundation: Research Funding. Manco-Johnson:Baxter BioScience: Honoraria; Bayer HealthCare: Honoraria; CSL Behring: Honoraria; NovoNordisk: Honoraria; Octapharma: Honoraria. Abshire:CSL Behring, Novo Nordisk, Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background: Numeracy, defined as the ability to handle basic probability and numerical concepts including computation, estimation, logic, and problem solving, is an under-recognized component of health literacy. Numeracy has been shown to influence performance of health tasks in non-hemophilia populations. Little is known about numeracy in the hemophilia population. Since hemophilia treatment requires understanding of numerical concepts to manage factor replacement, it is likely that numeracy also influences performance of health tasks by patients with hemophilia. A greater understanding of numeracy status and the characteristics influencing numeracy in the hemophilia population may allow healthcare providers to better influence health task performance. The objective of this study is to explore numeracy in the hemophilia population using two different tests of numeracy and to evaluate characteristics that are associated with low numeracy. Methods: Using a cross-sectional design, adults with moderate or severe hemophilia A or B who spoke and read English were enrolled at their annual visit at the Emory/Children's Health Care of Atlanta Hemophilia Treatment Center (HTC). Numeracy was measured using the validated Schwartz Woloshin (SW) test requiring answers in words and the unvalidated stick figure test requiring answers using images. Subjects were considered numerate with the SW numeracy test if all three questions were answered correctly or with the stick figure numeracy test if all four questions were answered correctly. Demographic and socioeconomic characteristics collected included age, race, ethnicity, household income (more or less than $50,000), level of education completed (more or less than completion of college), and duration of time followed at this HTC. Clinical information including type and severity of hemophilia, history of viral infections, history of depression, and use of chronic medication were abstracted from the medical records. Descriptive statistics of each variable and bivariate associations between numerate status and each dependent variable were calculated. Multivariable modeling using logistic regression was performed using the validated SW numeracy test as the dependent variable. Results: Of 91 enrolled participants with complete data, all were men. Most had hemophilia A [n=82 (90%)] and severe disease [69 (76%)]. Median age was 34 years [interquartile range (IQR) 18]. Sixty-three (69%) were Caucasian; 5 (6%) were Hispanic; 55 (61%) reported income of

Description: Abstract 1301 Poster Board I-323 Background Neutralizing factor VIII (FVIII) alloantibodies (“inhibitors”) develop in about 15% of all patients with hemophilia A following replacement therapy. The pathogenesis of this important treatment-related alloimmune complication is complex and involves both genetic and environmental factors, and likely their interactions. The type of hemophilia-causing FVIII gene (F8) mutation influences the risk of developing inhibitors with large deletions conferring the greatest risk and subtypes of single-base substitution mutations the lowest. Additional genetic factors that include possible transcription-modulating polymorphisms in the promoter regions of the structural loci encoding tumor necrosis factor a (TNFA), interleukin 10 (IL10), and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) were recently found to be associated with alloimmunization risk in the Malmo International Brother Study (MIBS). We recently demonstrated that mismatched FVIII replacement therapy due to the presence of common F8 nonsynonymous-single-nucleotide polymorphisms (ns-SNPs), which result in single amino acid changes in FVIII but do not cause hemophilia, may represent a novel genetic determinant of risk and contribute to the greater frequency of inhibitor development in black compared to white patients with hemophilia A (Viel et al. N Engl J Med. 360:1618-27, 2009). Because the implicated immune response gene variants described above were not controlled for in our initial study, however, we are now evaluating their influence on inhibitor development in this sample of black Americans with hemophilia A. Methods We used PCR and genomic DNA from 78 black hemophilia A patients to genotype a SNP in the TNFA promoter (-308 G〉A) and a CA-dinucleotide repeat polymorphism in the IL10 promoter (IL10G) by direct sequencing and fragment-length analysis, respectively. The inhibitor status, baseline severity, age at enrollment, and biologic relationships of these study subjects were already known as was their hemophilic F8 mutations and the background haplotypes on which they reside. Analyses for genotype-specific associations with inhibitor status were performed with and without controlling for background F8 haplotype. Results Although we found the frequency of the 134bp IL10 risk allele (102bp in our modified assay) to be 20.3%, which is similar to that observed previously in the largely Euro-Caucasian MIBS cohort (26.8%), no obvious association between inhibitor risk and genotypes containing this allele was identified in the black hemophilia A patients studied, even after controlling for the background F8 ns-SNP haplotype. The frequency we identified for the -308A TNFA risk allele (8.8%) was similar to that observed previously in non-hemophilic African Americans (12%), but was far less frequent than observed in the MIBS (32.9%). Analogous to the IL10 results, we identified no association between inhibitor development and TNFA genotypes containing the risk allele (which was only G/A heterozygotes since no homozygous A/A individuals were identified) in this black patient cohort, even after controlling for their ns-SNP haplotypes. Conclusions We found no association between inhibitor development in black Americans with hemohilia A and promoter variants in two immune response genes recently implicated as risk genotypes in the MIBS. While we did not replicate the prior findings, the small sample size of our present study could explain these results if a true functional variant in one of these genes either has a small effect or is in poor linkage disequilibrium with the typed variant in this black patient population. Our findings therefore require confirmation in a larger study, which is currently under way. Disclosures Howard: Haplomics, Inc.: Equity Ownership, Patents & Royalties. Kempton:Biomeasure Inc: Consultancy; CSL Behring Foundation: Research Funding.

Description: Inhibition of the platelet ADP receptor, P2Y12, has been shown to reduce thrombin-stimulated exposure of platelet phosphatidylserine and tissue factor (TF)-dependent thrombin generation in human platelet rich plasma (ATVB2003;23(10):1941–1947). Platelets stimulated by the combination of convulxin (Cvx) and thrombin develop two populations of platelets, one with low coagulation factor binding and a second with high levels of coagulation factor binding (Blood2000;95(5):1694–1702). Platelets in the population with increased coagulation factor binding have been termed COAT platelets. Previously we have demonstrated that the percentage of COAT platelets correlates with increased thrombin generation on Cvx plus thrombin-stimulated platelets compared to platelets stimulated with thrombin alone (Blood2003; 102(11): 293a). In this study we investigated whether inhibition of the platelet P2Y12 receptor reduced the development of the COAT platelets in addition to reducing thrombin generation. METHOD: A well established cell-based model of hemostasis was used. Components included: LPS-stimulated monocytes expressing TF, coagulation factors (II, V, VII, VIII, IX, X, XI) at plasma concentrations, coagulation inhibitors (AT, TFPI) at plasma concentrations, platelets from normal donors, and calcium chloride. Thrombin generation in the system was measured by cleavage of a chromogenic substrate and compared to a standard curve. Model systems without the addition of Cvx (20 ng/ml) were compared to model system with the addition of Cvx with and without a 2-methylthiol AMP (2MeSAMP, an inhibitor of the P2Y12 receptor). To determine the percentage of COAT platelets formed, samples were removed at 9.5 minutes after the model system was initiated, fixed in 1% paraformaldehyde, and analyzed on FACScan flow cytometer for binding of factor V using a polyclonal primary and secondary. RESULTS: In the absence of 2MeSAMP approximately 30% of Cvx plus thrombin-stimulated platelets were COAT platelets. In the presence of 2MeSAMP, none of the platelets were COAT platelets. 2MeSAMP led to a significant reduction in the peak and rate of thrombin generation in the presence of Cvx but no change in the total amount of thrombin generated as measure by the area under the curve. CONCLUSIONS: Inhibition of the platelet P2Y12 receptor prevents COAT platelet formation. The absence of COAT platelet formation correlates with a reduction in both the rate of thrombin generation and the peak of thrombin generated. COAT platelet formation and up-regulated thrombin generation induced by the combination thrombin plus moderate concentrations of Cvx are P2Y12-dependent.

Description: Background: Distress can affect a patient's ability to cope with and manage disease. Patients may feel uncomfortable initiating conversations about distress with their provider. Systematic screening for distress in patients with bleeding disorders may help identify distressed patients and guide treatment services planning. Objectives: Describe prevalence of distress in adult patients with bleeding disorders and the specific problems, health characteristics, and behaviors most associated with distress in this population. Methods: Patients who attended the Emory Comprehensive Bleeding Disorder Clinic for a regularly scheduled visit between January 1st, 2012 through February 28th, 2014 and who completed a distress screen, pain screen, and clinic questionnaire during the visit were evaluated cross-sectionally. Distress was measured by the National Comprehensive Cancer Network Distress Management Tool which allowed patients to rate recent distress on a 0-10 point scale and also asked patients to identify from a checklist whether any of 38 specific issues among 5 different categories were recently problematic. A distress rating of 5 or more was categorized as high distress, 1-4 as mild/moderate distress, and 0 as no distress. Pain was measured by the Brief Pain Inventory Short Form which asked patients to rate their various pain types on 0-10 point scales. Patients reported current behavioral and demographic information including employment status, alcohol, and tobacco use on the clinic questionnaire. Depressive symptoms were measured on a 0-6 point scale using the Patient Health Questionnaire-2 screening tool. Primary diagnosis, age, prophylaxis use, and HIV and HCV status were taken from medical records. Unadjusted logistic regression models to identify predictors of high distress were used. Adjusted logistic regression models that controlled for possible confounders were used to examine whether diagnosis and employment were associated with high distress. In the adjusted model examining employment, because depression and pain were collinear, we ran two models; one including depression and one including pain. Results: Of the 168 patients who formed the cohort, most were male (69%) and most had hemophilia as the primary diagnosis (67%). Nearly three-quarters identified as White race with one-quarter Black or African-American. Average patient age was 36 years and ranged from 18 to 83 years. HCV and HIV prevalence in the cohort were 35% and 13%, respectively. High distress prevalence (distress rating ≥ 5) was 31.6% (Figure 1). Patients who reported at least one emotional concern from the problem checklist were more likely to report high distress (Figure 2). In unadjusted analyses, patients who were older, unemployed or disabled, required assistance in daily life activities, reported opioid use, used crutches, had higher depressive symptoms, exercised less, and who reported high pain levels were more likely to report high distress. Diagnosis, gender, race, alcohol consumption, tobacco use, prophylaxis use, and HIV and HCV status were not associated with high distress. Unemployment, disability, higher depression symptoms, and high pain were associated with high distress in multivariate models (Table 1). Conclusions: Nearly one-third of patients with bleeding disorders reported high distress while an additional 40% reported mild/moderate distress. Further study is needed to determine if high distress impacts clinical outcomes of patients with bleeding disorders as has been demonstrated in other chronic disorders. Table 1 Multivariate analysis results Adjusted Odds Ratios for High Distress (95% CI) Predictor Model 1 (n=148) Model 2 (n=126) Model 3 (n=137) Diagnosis Severe/moderate hemophilia 1.0 Mild hemophilia 1.91 (0.53 6.85) Other bleeding disorders 1.02 (0.28 3.74) Employment Work full-time 1.0 1.0 Student, part-time, retired, homemaker, other 0.51 (0.14 1.86) 0.29 (0.07 1.18) Unemployed 6.15 (1.33 28.44) 5.49 (1.09 27.82) Disabled 3.41 (1.08 10.78) 2.37 (0.64 8.87) Age 1.02 (0.99 1.05) 1.02 (0.99 1.05) 1.02 (0.99 1.06) Pain Score 0 (no pain) 1.0 1-4 (low pain) 1.12 (0.34 3.73) 5-10 (high pain) 4.85 (1.29 18.33) Depression score 2.61 (1.78 3.83) 2.29 (1.52 3.45) All models also adjusted for race and HIV/HCV positivity Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Description: Background: Health literacy (HL) is the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Numeracy, a component of HL, is defined as the ability to handle numerical concepts. Both low HL and low numeracy have been associated with poor adherence to treatment regimens in a variety of chronic diseases. For the management of hemophilia, a chronic bleeding disorder, adherence to treatment regimens can be difficult and requires completion of multiple complex tasks. We hypothesized that lower HL and lower numeracy are associated with decreased adherence to treatment in persons with hemophilia (PWH). A secondary aim of this study was to evaluate other demographic and clinical characteristics that may be associated with adherence. Methods: In a cross-sectional study, adult PWH completed questionnaires to assess the main outcome variable, adherence measured by the validated hemophilia regimen treatment adherence scale (VERITAS) and the primary independent variables, HL as measured by the shortened Test of Functional Health Literacy in Adults (sTOFHLA) and numeracy as measured by the Schwartz-Woloshin questions. Other potential independent or confounding variables including general demographic and clinical information, the General Self-Efficacy (GSE) Scale, the Wake Forest Physician Trust Scale (WFPTS), and the Haem-A-QoL were also collected. Analysis proceeded from descriptive statistics to bivariable associations using simple linear regression and multivariable analysis using multiple linear regression. Results: All were men (n=99); 91% had hemophilia A and 78% had severe disease. Mean age was 34 years (standard deviation (SD) 11.5). White race was reported by 69% and 6% were Hispanic. Income was reported to be ≥$50,000 in 39%; and 37% had received an undergraduate degree or higher. Mean length of time seen at the Hemophilia Treatment Center (HTC) was 16.0 years (SD 11). HIV infection was noted in 26%, and 59% were HCV positive; depression history was reported in 21%; 49% infused replacement factor prophylactically. Most of the study population (95%) had high HL; but only 23% were numerate. The mean VERITAS-Pro was 45.6 (SD 12.7) and mean VERITAS-PRN was 51.0 (SD 11.2) with a lower score indicating greater adherence. On bivariable analysis, adherence was significantly associated with depression history, GSE score, WFPTS score, and Haem-A-QoL score (p 〈 0.05). On multivariable analysis, HL score and numerate status were not significantly associated with adherence (see Table). Being on any chronic medication, longer time seen at HTC, higher physician trust, and better quality of life were significantly associated with higher adherence. Depression history was significantly associated with lower adherence. This model overall accounted for a moderate proportion of the variability of adherence between subjects (adjusted R2 = 0.296). Conclusion: In this study population, HL and numeracy were not associated with adherence. A large majority of the PWH in our study were health literate; however, the study population was limited to those who made it to their scheduled HTC appointments and were sufficiently on time to allow completion of study questionnaires which may have biased this study toward a more literate population. This study population did show that being on any chronic medication, longer time seen at the HTC, higher physician trust, and better quality of life were significantly associated with better adherence. Depression history was significantly associated with lower adherence. These factors provide a better understanding of characteristics that influence adherence and may prove important for optimizing the care of PWH. Table: Multivariable Linear Regression of the Association of Adherence with Predictors (n=91) Predictor Beta Coefficient Standard Error p-value* sTOFHLA score -0.09 0.22 0.67 Numerate 1.04 3.01 0.73 On chronic medication(s) -5.13 2.47 0.041 Depression history 6.89 3.02 0.025 Time seen at HTC -0.27 0.11 0.022 WFPTS score -0.51 0.18 0.006 Haem-A-QoL score 0.12 0.038 0.0024 *Significant if 〈 0.05 sTOFHLA: The higher the score, the better the HL; WFPTS: The higher the score, the higher the physician trust Haem-A-QoL: The lower the score, the better the quality of life Disclosures No relevant conflicts of interest to declare.

Description: Background: The Patient Reported Outcomes Measurement Information System (PROMIS) provides measures of health status that assess physical, mental, and social well-being from the patient perspective. As a complement to disease-specific measures, standardized PROMIS measures allow for comparisons across health attributes, health conditions, and with general populations. The validity and utility of PROMIS measures have been established in numerous adult and pediatric patient populations encompassing a broad range of diseases and chronic conditions but has not yet been evaluated in hemophilia. The aims of this study are to: 1) describe PROMIS measures reported by adults with hemophilia during routine non-acute care encounters, 2) assess how measures compare to those reported by the PROMIS reference sample, and 3) evaluate the sensitivity of PROMIS to indicators of hemophilia clinical severity. Methods: Adult hemophilia patients were recruited to participate in this cross-sectional study during routine clinic visits that occurred at either of two U.S. Hemophilia Treatment Centers during October 2017 through June 2018. After consent was obtained, participants completed the PROMIS-29 on a tablet. The PROMIS-29 short form includes 4 questions for each of 7 domains: depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities. Questions were based on the previous 7 days and used a 5-point response option. Responses were then scored on a T-score metric with a mean of 50 and a standard deviation (SD) of 10 based on the original PROMIS reference sample of US adults. Higher scores indicate worse severity for depression, anxiety, pain interference, fatigue, and sleep and better functioning for physical and social roles. Scores 5 or more away from 50 indicate at least mild impairment. Demographic characteristics were self-reported. Clinical characteristics including hemophilia severity (defined by factor levels) were obtained from medical records. Patients also completed the Brief Pain Inventory where they rated their average pain from 0-10. Responses were categorized as no (0), low (1-4), and high pain (5-10). Mean PROMIS measures were compared using T-tests or unadjusted linear regression. Results: Of 112 participants, 103 were males who completed the PROMIS questionnaire. Median age was 33 years and ranged from 18-75 years. Half had severe hemophilia and 60% reported using routine continuous factor prophylaxis. Two-thirds of patients reported no pain on average while another 14% reported high pain. Overall PROMIS scores for each domain among the hemophilia cohort were similar to scores reported in the PROMIS normative sample with mean T-scores near 50 (domain means ranged from 45.7-52.9). However, PROMIS domain scores differed significantly by certain characteristics revealing sub-groups of patients who experienced significantly worse health compared to the normative reference sample. Patients reporting higher average pain reported worse health across all 7 domains compared to those with less pain. Physical function was most impacted by pain: those reporting the highest pain reported worse physical function (mean=36.8, SD=7.9) compared to those with low (mean=41.6, SD=8.3) and no pain (mean=50.7, SE=7.7). Patients with HIV reported higher depression, anxiety, pain, and fatigue, and worse physical function compared to patients without HIV. An emergency department visit in the past 6 months was also related to worse depression, anxiety, fatigue, sleep, and social functioning. Scores did not vary by hemophilia severity, prophylaxis use, or current inhibitor status and were similar to those reported by the referent population. Conclusion: The 7 PROMIS domains were sensitive to several adult hemophilia disease severity indicators in a non-acute care setting. Overall scores reported by patients with hemophilia generally mirrored the normative PROMIS sample scores. However, patients with hemophilia who experienced pain reported scores significantly worse than the normative sample. PROMIS instruments provide a potentially valuable tool to study the impact of hemophilia and suggest usefulness in research and clinical practice. Additional studies are needed to assess responsiveness in PROMIS score with changes in disease status over time and in women with hemophilia. Disclosures No relevant conflicts of interest to declare.