Characterization of the hemorrhagic syndrome in the New Zealand white rabbit model following total body irradiation

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.

Keywords:

• Total body irradiation
• acute radiation syndrome
• hemorrhagic syndrome
• rabbit model

Disclosure statement

The authors declare no conflicts of interest related to the data generated within this study.

Additional information

Funding

This project has been funded in whole with federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Department of Health and Human Services under Contract #HHSO100201500009I, Task Order Number HHSO10033001T, entitled “Establishment of a rabbit model of ionizing radiation-induced thrombocytopenia, coagulopathies, and measures of associated vascular and organ injury”.

Notes on contributors

Isabel L. Jackson

Isabel L. Jackson is an Associate Professor, Radiation Biologist, and Deputy Director of the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine. She is the Director of the division’s Medical Countermeasures program.

Ganga Gurung

Ganga Gurung was a Research Associate within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine. She is now practicing medicine in the United Kingdom.

Emmanuel Ayompe

Emmanuel Ayompe was a Research Assistant within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Elena-Rose Fown

Elena Rose-Fown is a Project Coordinator within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Sarah Triesler

Sarah Triesler is a Veterinary Research Specialist within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Buddha Mali

Buddha Mali is a Lead Veterinary Research Specialist within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Andrea Casildo

Andrea Casildo was a Veterinary Research Specialist within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Allison Gibbs

Allison Gibbs is a Research Laboratory Manager within the Division of Translational Radiation Sciences, Department of Radiation Oncology, at the University of Maryland School of Medicine.

Yannick Poirier

Yannick Poirier is an Assistant Professor and board-certified clinical medical physicist in the Department of Radiation Oncology, Division of Medical Physics and Division of Translational Radiation Sciences at the University of Maryland School of Medicine. He oversees the dosimetry and physics of all radiation biological studies of the Division of Translational Radiation Sciences.

Eric P. Cohen

Eric P. Cohen is a Professor of Medicine within the University of Medicine School of Medicine.

Diana Newman

Diana Newman is a Program Director within the Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Medicine School of Medicine.

Zeljko Vujaskovic

Zeljko Vujaskovic is a Professor of Radiation Oncology and Director of the Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Medicine School of Medicine.