Abstract

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 6 MV-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.

中文翻译：

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新西兰白兔全身照射后出血综合征的表征

摘要

目的

出血综合征是与急性放射综合征 (ARS) 相关的发病率和死亡率的主要原因。我们之前描述了新西兰白 (NZW) 兔全身照射 (TBI) 诱导的 ARS 的剂量反应关系。在 TBI 后的前三周，血小板减少、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描述在 TBI 剂量范围内诱导 ARS 的兔模型中血小板减少症、止血功能障碍和出血的自然史。

方法

50 只 NZW 雄性兔随机接受 7.0 或 7.5 Gy 的 6 MV 衍生 TBI。假辐照对照 ( n =  6) 被包括作为比较器。动物接受最低限度的支持性护理，包括止痛药、抗生素、温度> 104.8°F的退热剂和脱水迹象的液体。在 TBI 后的预定时间点或基于预定安乐死标准的即将死亡的迹象，动物被扑杀。测量血液学参数、血清化学、全血的粘弹性、凝血试验和凝血因子活性。在尸检时对重要器官进行了大体检查。

结果

本研究的结果包括 TBI 后第一周出现严重中性粒细胞减少，随后出现血小板减少和严重急性贫血，并在 TBI 后第二至第三周出现皮肤点状出血和重要器官出血。在血小板减少和出血的同时观察到全血粘弹性测定异常。动物暴露于 7.5 Gy，但不是 7.0 Gy TBI 后，抗凝血酶活性显着升高。

结论

TBI 兔模型中的出血综合征概括了人类在意外或故意暴露后描述的发病机制。兔子可以作为啮齿动物模型的替代品，作为一种小动物物种，用于表征 TBI 后的全谱多器官损伤和早期测试有希望的医学对策。