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Venous thromboembolism (VTE) affects as many as 1 in 1000 individuals in the United States. Although Blacks are disproportionately affected by VTE, few genetic risk factors have been identified in this population. The inducible heme oxygenase-1 (HMOX1) gene encodes a key cytoprotective enzyme with anti-inflammatory, antioxidant and anticoagulant activity acting in the vascular system. A (GT)(n) microsatellite located in the promoter of the HMOX1 gene influences the level of response.Using the Genetic Attributes and Thrombosis Epidemiology (GATE) study, we examined the association between HMOX1 repeat length and VTE events in 883 Black and 927 White patients and matched controls. We found no association between HMOX1 genotypes and VTE in Whites. However, in Black patients, carrying two long (L) alleles (≥ 34 repeats) was significantly associated with provoked (odds ratio (OR) 1.86, 95% confidence interval (CI): 1.19-2.90) or recurrent (OR 3.13, 95% CI: 1.77-5.53) VTE events.We have demonstrated for the first time an association between genetic variation in HMOX1, and VTE in Blacks. Our results support a key role for the heme oxygenase system in protecting patients at increased risk for thrombosis and suggest a potential mechanism for targeted screening and intervention.

We sought to assess the association between air particulate pollutants and feto-infant morbidity outcomes across racial/ethnic subgroups. This is a retrospective cohort study from 2000 through 2007 based on three linked databases: (1) The Florida Hospital Discharge database; (2) The vital statistics records of singleton live births in Florida; (3) Air pollution and meteorological data from the Environmental Protection Agency. Using computerized mathematical modeling, we assigned exposure values of the air pollutants of interest (PM(2.5), PM(10) and the PM coarse fraction [PM(10) - PM(2.5)]) to mothers over the period of pregnancy based on Euclidean minimum distance from the air pollution monitoring sites. The primary outcomes of interest were: low birth weight, very low birth weight, preterm birth, very preterm birth, and small for gestational age (SGA). We used adjusted odds ratios to approximate relative risks. We observed increased risk for overall feto-infant morbidity outcome in women exposed to any of the three particulate pollutants (values above the median). Exposed women had increased odds for low birth weight, very low birth weight and preterm birth with the greatest risk being that for very low birth weight (AOR = 1.27, 95% CI = 1.08-1.49). Black women exposed to any particulate pollutant had the greatest odds for all the morbidity outcomes, most pronounced for very low birth weight (AOR = 3.32, 95% CI = 2.56-4.30). Environmental particulate pollutants are associated with adverse feto-infant outcomes among exposed women, especially blacks. Black-white disparity in adverse fetal outcomes is widened in the presence of these pollutants, which provide a target for intervention.

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 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.

Summary Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the βS-carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with βS-haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0·51, 95% confidence interval 0·29–0·89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined βS-haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.

Introduction Inhibitors are considered to be the most serious complication of clotting factor concentrate (CFC) therapy in hemophilia. The incidence of inhibitors in PTPs with severe hemophilia is very low (∼ 1 per 1,000 patient years). Four cases of PTP inhibitors that developed during hospital admissions were observed at the University of North Carolina over a 14-month period during 2011 – 2012. Due to concern about the possible role of the CFC used during hospitalization, further investigation by the CDC was requested. Methods A review of hemophilia-related hospital practices and procedures, along with a medical record review of admissions from January 2008 – November 2012 was conducted to: 1) compare inhibitor incidence trends in the time periods before and after January 2011; and 2) assess patient risk factors and evaluate hospital practices relative to inhibitor occurrence. A case was a person who developed an inhibitor during a hospital admission and non-cases were inpatients with no history of inhibitor development. The prevalence of inhibitor risk factors were compared between cases and non-cases and across time periods. Unadjusted odds ratios were used to compare the prevalence of exposures between cases and non-cases and comparisons of means of continuous risk factors used parametric and non-parametric tests as appropriate. Results A check of the FDA's Adverse Event Reporting System (FAERS) revealed no identified problems of the CFC in question. The medical record review revealed 134 admissions in 49 patients (59 in period 1 and 75 in period 2) during the 5-year period (see Figure). No other cases were found during the review; however, one of the index cases was found to have developed the inhibitor as an outpatient leaving 3 cases and 45 non-cases for study. The cases ranged in age from 23 – 69 years. One had severe and one had moderate hemophilia A, while the third case had combined factor V-VIII deficiency with FV and FVIII levels of 7% and 10%, respectively. Compared to non-cases, cases had elevated odds of: an infection (OR, 95% CL=4.4, 0.3–53), continuous factor infusion (CI) (4.2, 0.04–6.4), at least one non-surgical procedure (3.9, 0.1–80.5), and used the only hospital-available CFC (2.7, 0.1–73) during the admission and a product switch prior to admission (3.5, 0.1–105) and a family history of hemophilia (2.4, 0.1–51). In addition, cases had more hospital admissions (mean 6.6 vs. 2.4, p = 0.002) and more total hospital days (mean 39.6 days vs. 14.8 days. p = 0.05) than non-cases. Finally, cases received a greater total dose of CFC than non-cases (mean 101 IU/kg vs. 69 IU/kg, p = 0.003) during admission. Two hospital practices changed in period two: 1) the method of preparation and administration of CI involved less diluent and, therefore, a more concentrated infusion solution; and 2) the hospital pharmacy stocked only one brand of CFC in period 2 whereas several brands were available in period 1. The latter change increased the proportion of inpatients using a different product than that used as an outpatient (i.e., product switch) during period 2. Compared to inpatients admitted during period 1, those in period 2 were: more likely to receive the only available CFC and to have a product switch during the admission (p < 0.001). No difference between time periods was seen in the proportion of patients administered CI (58.8% vs. 56.9%) or who were tested for an inhibitor during admission (25% vs. 22%). Conclusions The investigation results support an increase in incidence of inhibitors among inpatients during period 2 compared to period 1, however, the number of cases was small. Nonetheless, because inhibitors are rare in PTPs, the occurrence of 3 cases in a 14-month period after a 3-year time span with no cases is highly suggestive of an actual increase in occurrence. The apparent increase was unlikely due to enhanced surveillance since rates of inhibitor testing during the two time periods were similar. While the odds ratios for some of the risk factors were elevated, the confidence limits were wide indicative of the lack of study power. Although there was no clear indication of a preventable inciting factor and more investigation is needed, the investigation revealed that this inhibitor cluster occurred in patients who had many complications that required lengthy hospitalizations and intense treatment with CFCs, contributing factors that should be considered in future management of hemophilia patients. Disclosures: No relevant conflicts of interest to declare.

Objective The purpose of this study was to evaluate national trends in the rate of pregnancy-related hospitalizations for venous thromboembolism (VTE) from 1994-2009 and to estimate the prevalence of comorbid conditions among these hospitalizations. Study Design An estimated 64,413,973 pregnancy-related hospitalizations among women 15-44 years old were identified in the 1994-2009 Nationwide Inpatient Sample. Trends in VTE-associated pregnancy hospitalizations were evaluated with the use of variance-weighted least squares regression. Chi-square tests were used to assess changes in prevalence of demographics and comorbid conditions, and multivariable logistic regression was used to evaluate the likelihood of VTE during the study period after adjustment for comorbid conditions. Antepartum, delivery, and postpartum hospitalizations were evaluated separately and reported in 4-year increments. Results From 1994-2009, there was a 14% increase in the rate of overall VTE-associated pregnancy hospitalizations; antepartum and postpartum hospitalizations with VTE increased by 17% and 47%, respectively. Between 1994-1997 and 2006-2009, the prevalence of hypertension and obesity doubled among all VTE-associated pregnancy hospitalizations; significant increases in diabetes mellitus and heart disease were also noted. A temporal increase in the likelihood of a VTE diagnosis in pregnancy was observed for antepartum hospitalizations from 2006-2009 when compared with 1994-1997 (adjusted odds ratio, 1.62; 95% confidence interval, 1.48–1.78). Conclusion There has been an upward trend in VTE-associated pregnancy hospitalizations from 1994-2009 with concomitant increases in comorbid conditions. Clinicians should have a heightened awareness of the risk of VTE among pregnant women, particularly among those with comorbid conditions, and should have a low threshold for evaluation in women with symptoms or signs of VTE.