Purpose: The hemorrhagic syndrome is a major cause of morbidity and mortality associated with the acute radiation syndrome (ARS) . We previously characterized the dose-response relationship for total body irradiation (TBI)-induced ARS in the New Zealand White (NZW) rabbit. Thrombocytopenia, hemorrhage, and anemia were strongly associated with morbidity/mortality during the first three weeks post-TBI. The objective of the current study was to further characterize the natural history of thrombocytopenia, hemostatic dysfunction and hemorrhage in the rabbit model at a TBI dose range to induce ARS.

Methods: Fifty male NZW rabbits were randomized to receive 7.0 or 7.5 Gy of 6MV-derived TBI. Sham-irradiated controls (n = 6) were included as a comparator. Animals were treated with minimal supportive care including pain medication, antibiotics, antipyretics for temperature >104.8 °F, and fluids for signs of dehydration. Animals were culled at pre-determined timepoints post-TBI, or for signs of imminent mortality based on pre-defined euthanasia criteria. Hematology parameters, serum chemistry, viscoelasticity of whole blood, coagulation tests, and coagulation factor activities were measured. A gross exam of vital organs was performed at necropsy.

Results: Findings in this study include severe neutropenia during the first week post-TBI followed by thrombocytopenia and severe acute anemia with petechial hemorrhages of the skin and hemorrhage of the vital organs during the second to third weeks post-TBI. Abnormalities in whole blood viscoelastometry were observed concurrent with thrombocytopenia and hemorrhage. Antithrombin activity was significantly elevated in animals after exposure to 7.5 Gy, but not 7.0 Gy TBI.

Conclusions: The hemorrhagic syndrome in the rabbit model of TBI recapitulates the pathogenesis described in humans following accidental or deliberate exposures. The rabbit may present an alternative to the rodent model as a small animal species for characterization of the full spectrum of multiorgan injury following TBI and early testing of promising medical countermeasures.

目的：出血综合征是与急性放射综合症（ARS）相关的发病率和死亡率的主要原因。我们以前表征了新西兰白（NZW）兔体内全身照射（TBI）诱导的ARS的剂量反应关系。TBI后的前三周，血小板减少症，出血和贫血与发病率/死亡率密切相关。本研究的目的是进一步表征在TBI剂量范围内诱发ARS的兔模型中血小板减少，止血功能障碍和出血的自然史。

方法：将50只NZW雄性兔子随机分为7.0或7.5 Gy的6MV TBI。假对照组（n = 6）作为对照。用最少的支持护理治疗动物，包括止痛药，抗生素，温度> 104.8°F的退热药和出现脱水迹象的液体。在TBI后的预定时间点对动物进行扑杀，或根据预定的安乐死标准对即将死亡的动物进行扑杀。测量血液学参数，血清化学，全血粘弹性，凝血试验和凝血因子活性。尸检时对重要器官进行了大体检查。

结果：这项研究的发现包括TBI后第一周出现严重的中性粒细胞减少，随后的血小板减少和严重急性贫血，TBI后第二至第三周出现皮肤的瘀斑和重要器官出血。观察到全血粘度弹力测定异常，并伴有血小板减少症和出血。暴露于7.5 Gy的TBI后，动物的抗凝血酶活性显着提高。

结论： TBI兔模型中的出血综合症概括了人类意外或故意暴露后的发病机理。兔子可能是啮齿动物模型的替代品，它是一种小型动物，用于表征TBI后的多器官损伤的全谱以及有希望的医学对策的早期测试。