Apohemoglobin-Haptoglobin Complex is a Therapeutic Against Vaso-Occlusive Crisis: Scavenging of Hemoglobin and Heme

Sickle cell disease (SCD) leads to vaso-occlusive episodes (VOEs) releasing cell-free hemoglobin (Hb) and heme that drive oxidative stress, inflammation, and microvascular dysfunction. Current treatments for VOEs remain limited with no targeted therapies addressing these hemolytic byproducts. This study investigated the potential of an apohemoglobin-haptoglobin (ApoHb-Hp) complex (protein scavenger of both Hb and heme) versus haptoglobin (Hp) (scavenger of only Hb), in transgenic SCD mice exposed to hypoxia-reoxygenation. Briefly, HbSS-Townes mice instrumented with a dorsal skinfold window chamber received ApoHb-Hp (150 mg/kg), Hp alone (150 mg/kg), or an equal volume of saline vehicle, groups were compared to HbAA controls. At the same dose ApoHb-Hp had reduced Hb-binding capacity compared to Hp alone, but it possessed heme-binding capacity from the associated apoHb moiety. Despite the reduced Hb-binding capacity, ApoHb-Hp produced significantly greater protective effects than Hp alone. During hypoxia, ApoHb-Hp preserved >90% of baseline arteriolar and venular flow, while untreated and Hp-treated mice exhibited >50% reductions. Functional capillary density (FCD) at 72 hours post-hypoxia declined by 80% in untreated mice and 44% in Hp-treated mice, but only 27% in ApoHb-Hp-treated mice. Pulmonary inflammation was significantly lower in ApoHb-Hp-treated mice compared to Hp-treated mice, with reduced numbers of macrophages (15 ± 2 vs. 18 ± 3), neutrophils (5 ± 1 vs. 7 ± 1), and lymphocytes (18 ± 4 vs. 20 ± 3). The increased effectiveness of ApoHb-Hp, is due to its unique dual-scavenging mechanism. This addresses both Hb and heme toxicity, which each contribute to the pathophysiology of SCD. These findings indicate that the ApoHb-Hp complex is a promising therapeutic option for SCD.