Hemophilia A is caused by defects in coagulation factor VIII (FVIII), and nonsense mutations in the FVIII light chain are associated with a particularly high risk of developing inhibitory antibodies during replacement therapy. Singer and colleagues used patient-derived induced pluripotent stem cell–based endothelial models to investigate how different FVIII light-chain variants are processed intracellularly and how this affects protein secretion and degradation. They found that specific variants show divergent intracellular fates, with some being preferentially targeted. to proteasomal degradation while others retain partial secretory potential, providing a mechanistic explanation for their different immunogenicity and inhibitor risk.

The management of acute leukemia and high-grade myeloid neoplasms in Jehovah’s Witnesses is particularly challenging because patients decline blood transfusions. Zarka and colleagues describe patient-centered clinical strategies and supportive care approaches designed to treat these patients while minimizing or avoiding transfusion support. They show that carefully tailored treatment regimens combined with proactive blood conservation measures can allow effective leukemia therapy with acceptable outcomes.