Summary Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion‐dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion‐dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old ( n = 75) and younger adults ages 18–39 ( n = 201). The older adult cohort was characterized by higher numbers of iron‐related comorbidities and transfusion‐related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

Thalassemia is an inherited genetic disorder requiring multiple transfusions to treat anemia caused by low hemoglobin levels. Thus, thalassemia patients are at risk for infection with blood-borne pathogens, including human T cell lymphotropic viruses (HTLV) that are transmitted by transfusion of cellular blood products. Here, we examined the prevalence of HTLV among 234 U.S. thalassemia patients using sera collected in 2008. Sera were tested for antibodies to HTLV-1/2 using enzyme immunoassay (EIA) and a confirmatory western blot (WB) that differentiates between HTLV-1 and HTLV-2. Demographic information and clinical information were collected at study enrollment, including HIV and hepatitis C virus (HCV) status. Three patients (1.3%) were WB positive; two were HTLV-1 and one could not be serotyped as HTLV-1/2. All three HTLV-positive persons were HIV-1 negative and one was HCV seropositive. The HTLV seroprevalence was higher than that of HIV-1 (0.85%) and lower than HCV (18.8%) in this population. All three patients (ages 26-46 years) were diagnosed with β-thalassemia shortly after birth and have since been receiving multiple transfusions annually. Two of the HTLV-positive patients confirmed receiving transfusions before HTLV blood screening was implemented in 1988. We identified a substantial HTLV-1 seroprevalence in U.S. thalassemia patients that is much greater than that seen in blood donors. Our findings highlight the importance of HTLV testing of patients with thalassemia and other diseases requiring multiple transfusions, especially in recipients of unscreened transfusions. In addition, appropriate counseling and follow-up of HTLV-infected patients are warranted.

Background Transfusions are the primary therapy for thalassemia but have significant cumulative risks. In 2004, the C enters for D isease C ontrol and P revention ( CDC ) established a national blood safety monitoring program for thalassemia. This report summarizes the population and their previous nonimmune and immune transfusion complications. Study Design and Methods The CDC T halassemia B lood S afety N etwork is a consortium of centers longitudinally following patients. Enrollment occurred from 2004 through 2012. Demographics, transfusion history, infectious exposures, and transfusion and nontransfusion complications were summarized. Logistic regression analyses of factors associated with allo‐ and autoimmunization were employed. Results The race/ethnicity of these 407 thalassemia patients was predominantly Asian or Caucasian. The mean ± SD age was 22.3 ± 13.2 years and patients had received a mean ± SD total number of 149 ± 103.4 units of red blood cells ( RBC s). Multiorgan dysfunction was common despite chelation. Twenty‐four percent of transfused patients had previous exposure to possible transfusion‐associated pathogens including one case of babesia. As 27% were immigrants, the infection source cannot be unequivocally linked to transfusion. Transfusion reactions occurred in 48%, including allergic, febrile, and hemolytic; 19% were alloimmunized. Common antigens were E , K ell, and C . Years of transfusion was the strongest predictor of alloimmunization. Autoantibodies occurred in 6.5% and were associated with alloimmunization (p < 0.0001). Local institutional policies, not patient characteristics, were major determinants of blood preparation and transfusion practices. Conclusion Hemosiderosis, transfusion reactions, and infections continue to be major problems in thalassemia. New pathogens were noted. National guidelines for RBC phenotyping and preparation are needed to decrease transfusion‐related morbidity.

BACKGROUND:Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu-like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission. STUDY DESIGN AND METHODS:Blood specimens obtained from participants of a surveillance system established in federally supported specialized bleeding disorders clinics were used in a B19V seroprevalence study. RESULTS:A total of 1643 specimens from 1043 participants age 2 to 7 years born after B19V NAT screening was implemented were tested. Age-specific prevalence rates were generally higher for subjects exposed to either plasma-derived products alone or in combination with other products compared to subjects with no exposure to antihemophilic products. Overall, compared to participants unexposed to blood or blood products, those exposed to plasma-derived products alone were 1.7 times more likely to have antibodies to B19V (p = 0.002). CONCLUSION:These results are consistent with continued B19V transmission through plasma-derived factor concentrates. Effective viral inactivation and detection processes are needed to protect users of these products from infection with B19V or other new or emerging viruses.

Abstract Abstract 340 Transfusions are the primary therapy for thalassemia (thal) but have significant cumulative risks. The Thalassemia Clinical Research Network recently highlighted the increased rate of alloimmunization in this population1. In 2004, the CDC established a national blood safety monitoring program for thal. The goals of the program were to monitor blood safety and strategies for the management of complications. This report focuses on immune and non-immune transfusion reactions. Methods: The CDC Thalassemia Blood Safety Network is a consortium of thal centers that follow patients longitudinally to determine the transfusion-related complications. Serial demographic, physical, and laboratory data are collected along with blood samples analyzed at the CDC. Data collected includes ethnicity, genotype, phenotype, transfusion data, immunizations, type of red cell product, degree of antigen matching, and chelation therapy. Chronically transfused (CT) patients were defined as requiring at least 8 transfusions annually. Intermittently transfused (IT) patients received less than 8 transfusions annually. Statistical analyses included continuous variables, logistic regression, and multivariant analysis. Results: There were 407 patients including 327 CT patients and 80 IT patients. The genotype of chronically transfused patients included: TM (81%), TI (6%), E-Beta-Thal (6%), and Hemoglobin H/CS (4%). The average age of CT patients was 22.3 years ± 13 and 21.4 years ± 17 in IT patients. The average units CT patients received was 149 ± 103. Hemosiderosis occurred in both patient groups and correlated with transfusion history. The average ferritin (m/L) in each group, respectively, was 2261 and 689. 78% of the total population has received chronic chelation therapy. Multiple organ dysfunction was common in the population, including cardiac disease (13%), gonadal failure (17%), growth hormone deficiency (8%), hypothyroidism (8%), hypoparathyroidism (1.2%), diabetes (10%), and thrombotic events (5.4%). 45% of the population was splenectomized. Transfusion reactions occurred in 48% of patients, including allergic (45%), multiple etiologies (32%), febrile (17%), and hemolytic (5%). Transfusion-associated infection included 58 cases of Hepatitis-C and 4 cases of HIV. Two Hepatitis-C cases occurred after specific blood testing was initiated. Recent cases of bacteremia, malaria, and Babesiosis have been documented. 21% of CT patients and 13% of IT patients developed an alloantibody. The most common antigen specificity included E (25%), Kell (13%), C (9%), Jka (5%), Kpa (4%), HLA (4%), V (3%), c (3%), D (2.5%), WA-1 (2.5%), and S (2.5%). 45% of alloimmunized patients had multiple antibodies. Race, transfusion burden, age and splenectomy predicted alloimmunization. Alloimmunization was found in 31% of splenectomized patients vs. 10% of non-splenectomized patients (p <.0001). The alloimmunization prevalence rose from 10% in young children compared to 54% in older patients. The average units transfused in patients with alloantibodies was 215 ± 104 vs. 126 ± 92 in patients without alloantibodies (p <.0001). Autoantibodies occurred in 6.5% of the population and increased with age and splenectomy. Alloimmunization increased the risk of autoantibodies: 26% of patients with an alloantibody had an autoantibody whereas only 2% of patients without alloantibodies had an autoantibody (p<.0001). Overall, 81% of patients with an autoantibody had an alloantibody. Local institutional policies were the major determinant in the type of units administered. In the last year, 32% of the units were washed and 80% radiated. 40% of patients received standard ABO matching, 47% limited phenotypic matching, and 12% full extended matching. Conclusion: Transfusion-related morbidity is a major problem in thal. Hemosiderosis immunologic and non-immunologic reactions are common. Transfusion-related infections have decreased but new, emerging pathogens have been noted. Disclosures: No relevant conflicts of interest to declare.

Abstract 3378 Background: Parvovirus B19 (B19) is a small, non-enveloped virus that causes a typically benign flu-like illness most commonly in childhood. However, B19 has been associated with arthritis and poses a hazard to the fetus of a pregnant woman. Because infection is common and viremia can occur before symptoms develop, about 1% of blood donations can be contaminated with B19 virus. The virus is resistant to current viral inactivation steps used in the manufacture of plasma-derived (P-D) anti-hemophilic factor concentrates and B19 transmission through these products has been documented. Since 2000, manufacturers have used a B19 nucleic acid test (NAT) to screen plasma pools and withhold from fractionation those with B19 DNA exceeding an established threshold. No study of populations using these products has been conducted to assess the impact of the screening on B19 transmission. Methods: Blood specimens obtained from participants of the CDC-sponsored Universal Data Collection (UDC) surveillance system of persons with bleeding disorders conducted by specialized US bleeding disorders clinics were used in a B19 seroprevalence study. Since B19 NAT screening began in 2000, only participants born after January 1, 2001 were eligible for study. Data collected on treatment products used by participants both prior to and after enrolment in UDC were used to categorize lifetime exposure as 1) no products, 2) recombinant (recomb) products only, 3) P-D products only, or 4) both recomb and P-D products. The proportions of participants with B19 IgG antibodies were compared across age and product exposure categories to determine whether users of products were at higher risk of past infection with B19 compared to those exposed to B19 only by the usual respiratory route. Results: A total of 1,643 specimens from 1,043 participants aged 2 – 7 years were tested. Demographic and clinical characteristics of study participants are shown in Table 1. Compared to subjects with no exposure to products, subjects in nearly every age group exposed to either P-D products alone or to both P-D and recomb products had a higher B19 prevalence (Table 2). In a logistic regression analysis that controlled for differences in the distribution of age, sex, bleeding disorder, treatment type, number of bleeds in previous 6 months, hemophilia inhibitor status, and year specimen obtained, participants exposed to P-D products alone were 1.7 times more likely to have B19 antibodies than those unexposed to blood or factor products (p = 0.002). In addition, there was a significant overall trend of increasing B19 prevalence over time. Discussion/Conclusion: P-D factor products are important therapies for people with VWD, hemophilia inhibitors and rarer factor deficiencies. Although we had no data on clinical illness, these serologic data provide evidence for continued transmission of B19 through these products after implementation of B19 NAT screening. Lowering the B19 threshold for plasma pool rejection should be considered. More importantly, effective viral inactivation processes are needed to protect users of these products not only from infection with B19 but from other as yet unidentified or emerging viruses that would not be detected by B19 NAT. Disclosures: Kessler: Novo Nordisk Inc.: Consultancy.

Technologic advances in diagnostic testing, vaccinations, pathogen inactivation, and vigilant donor screening have greatly reduced the risk of transmitting pathogens through blood transfusion. Nevertheless, transfusion-related infections and fatalities continue to be reported, and emerging pathogens continue to become an increasing threat to the blood supply. This threat is even greater to patients with blood disorders, who are heavily transfused and rely on safe blood products. This article describes some of the emerging and re-emerging transfusion-transmitted pathogens that have increased in incidence in the U.S. in recent years. Peer-reviewed articles and agency websites were the sources of information. The article focuses on the treatment of hereditary blood disorders including hemophilia and thalassemia, and hereditary bone marrow failure. A coordinated approach to addressing blood safety and continued development of sensitive diagnostic testing are necessary to reduce risk in an increasingly globalized society.