Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

Thrombotic risk associated with gender-affirming hormone therapy.

Transgender and gender-expansive (TG) people-those who identify with a gender other than their assigned sex at birth-frequently experience gender dysphoria, which is associated with negative health outcomes. One key strategy for improving gender dysphoria is the use of gender-affirming hormone therapy (GAHT): estrogen for feminization and testosterone for masculinization. Estrogen use in cisgender women is associated with well-established changes in hemostatic parameters, including increases in prothrombotic factors and decreases in inhibitors of coagulation. Cisgender women using estrogen have an increased risk of thrombosis. Studies of thrombosis risk associated with estrogen GAHT in TG people are less robust, with some studies limited by the use of hormones and hormone management strategies that are no longer recommended. However, TG women using estrogen appear to be at increased risk of both arterial and venous thrombosis, which may increase with longer time on estrogen. Testosterone use in both cisgender and transgender men is associated with increases in hemoglobin and hematocrit, which can lead to erythrocytosis and thus increased risk of thrombosis. The results of studies evaluating thrombosis risk in the setting of testosterone use are mixed. This review presents an overview of alterations in hemostatic parameters and thrombosis risk associated with use of exogenous estrogen and testosterone. Understanding what is known and unknown about thrombosis risk associated with use of these hormones is essential for hematologists who may be asked to evaluate TG people and provide guidance on management of those who may be at increased risk of thrombosis.

Hemoglobin concentration and body mass index are determinants of plasma von Willebrand factor and factor VIII levels.

BACKGROUND: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. VWD is characterized by an abnormal quantity or quality of von Willebrand Factor (VWF). Anemia is often found at presentation for a bleeding disorder evaluation due to chronic blood loss. OBJECTIVES/HYPOTHESIS: We hypothesized that anemia is associated with elevations in both VWF and factor VIII (FVIII) over baseline. We also hypothesized that obesity would be associated with increased levels of VWF. METHODS: We conducted a single-center review of the electronic health record for patients that had proximal von Willebrand profiles and Hb data. RESULTS: We identified 4552 unique subjects with VWF studies and a CBC within 24 h. We found that decreasing hemoglobin inversely correlated with VWF antigen, VWF ristocetin cofactor activity, and FVIII activity. We also found that obesity and Black race were independently associated with increased VWF antigen, activity, and FVIII activity. Hb, race, and body mass index (BMI) continued to be determinants of VWF and FVIII levels in multivariable analysis. CONCLUSION: Our study demonstrates that anemia, race, and BMI were found to be associated with elevation of VWF antigen, VWF activity, and FVIII levels. As many individuals with anemia present for evaluation for a bleeding disorder, these variables need to be considered. KEY POINTS: - Anemia was found to be associated with elevation of VWF antigen, VWF activity and FVIII levels. - Testing von Willebrand factor at times of anemia may mask a diagnosis of von Willebrand Disease.