Nplate (Romiplostim) Restores Blood Counts and Accelerates Wound Healing Following Radiation Combined Injury in Mice.

BACKGROUND

Exposure to ionizing radiation (IR), particularly when combined with additional trauma such as skin wounding (referred to as radiation combined injury, RCI), results in a synergistic pathology that significantly increases morbidity and mortality compared to isolated radiation injury (RI). While Nplate (romiplostim), a thrombopoietin (TPO) receptor agonist, is a Food and Drug Administration (FDA)-approved medical countermeasure for haematopoietic acute radiation syndrome (H-ARS), its efficacy on RCI is unclear. This study evaluated the mitigative effects of Nplate on 30-day survival, wound healing, and haematopoietic recovery following RCI.

METHODS

Fourteen-week-old female B6D2F1/J mice were exposed to 60Co γ-radiation (9.0 or 9.5 Gy at 0.4 Gy/min) followed by a full-thickness skin wound within one to two h. A single dose of Nplate (30 µg/kg) or vehicle was administered subcutaneously 24 h post-IR. Survival, body weight, and wound closure were monitored for 30 days. On day 30, survivors were euthanized for blood and tissue analysis, including bone marrow histology, colony-forming unit (CFU) assays, complete blood count (CBC), and splenic assessment.

RESULTS

Nplate significantly improved 30-day survival following 9.5 Gy RI, increasing survival from 30% to 75% (p = 0.0071). In contrast, Nplate provided no significant survival improvement in the RCI groups, with 30-day survival rates of 65% at 9.0 Gy (p = 0.5485) and 15% at 9.5 Gy (p = 0.6044) compared to 75% and 20% in their respective vehicle controls. Despite the lack of survival improvement after RCI, Nplate significantly accelerated wound closure on day 14 after RCI at 9.5 Gy. During the acute phase (Days 1-14), Nplate treatment significantly accelerated healing kinetics, increasing the linear wound healing rate by 54% from 0.124 mm/day to 0.192 mm/day (p = 0.0205). Histological analysis revealed that Nplate enhanced bone marrow cellularity, increased megakaryocyte counts, and suppressed IR-induced adipocyte formation. Furthermore, Nplate treatment significantly strengthened functional haematopoiesis, particularly after 9.0 Gy RCI, and stimulated recovery of the splenic lymphoid compartment after both RI and RCI at 9.5 Gy.

CONCLUSIONS

Nplate is a potent mitigator of H-ARS and a stimulator of multi-lineage haematopoietic and tissue regeneration. However, its efficacy in improving survival is limited in RCI, potentially due to exacerbated systemic physiological stress. These results suggest that while Nplate promotes haematopoietic recovery, managing RCI may require a multi-modal approach to address the unique complexities of combined injury, including gastrointestinal (GI)-ARS, systemic inflammation and endothelial dysfunction.