Brain Anomalies in Children with Severe Factor VIII Deficiency- a Pilot Study

Introduction: Bleeding resulting from factor VIII deficiency (hemophilia A) can occur in any tissue including the brain. While significant progress has been made in prevention and treatment of hemophilia-related joint and muscle disease with prophylaxis, there is a paucity of research to understand, treat, or prevent brain disease in hemophilia patients. People with hemophilia are recognized to be at risk for neuropsychiatric and neurocognitive disorders even when treated with factor VIII (FVIII) primary prophylaxis. This is especially problematic given that brain injury is difficult to detect early, and consequences are often delayed. Therefore, our study aims to evaluate brain structure and cognitive function in pediatric patients with severe FVIII deficiency in order to improve outcomes.

Methods: After IRB approval, a single-center pilot study enrolled seven pediatric subjects with severe FVIII deficiency and 23 healthy controls to evaluate brain structure and function. Inclusion criteria included males aged 6 - 16 years. All subjects with severe hemophilia A had a FVIII level of less than 1% completed at the Iowa Hemophilia and Thrombosis Center. Any subject was excluded due to a known diagnosis of traumatic brain injury, brain tumor, major chromosomal anomalies, or intellectual disability. Subjects with a known diagnosis of intracranial hemorrhage or FVIII inhibitor were excluded. Neurocognitive assessments included the Behavioral Regulation Index of Executive Function (BRIEF) which measures executive function. Magnetic resonance imaging sequences included T1, T2, and diffusion tensor imaging. Freesurfer and Brain Research: Analysis of Images, Networks, and Systems (BRAINS2) software were used to preprocess imaging and generate volumetric data.

Results: Mean age for PWH was 10.4 years and 11.8 years for controls (p = 0.24). Both groups had similar height, weight, and socioeconomic status. Despite normal IQ, PWH demonstrate impaired behavior regulation and globally impaired executive composition compared to controls (p = 0.001 and p = 0.038, respectively). Volumetric brain quantification revealed subjects with hemophilia had decreased whole brain volumes compared to controls (p = 0.019). Our analysis suggests that these differences are in discrete regions. Future analysis will investigate if volumetric differences correlate with neurocognitive assessments.

Conclusions: PWH demonstrated abnormal brain structure and function compared to healthy controls. Further evaluation is warranted to understand why and how FVIII deficiency and its treatment alter neurological outcomes.