A New Zealand White rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome

Abstract

Purpose

The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces the hematopoietic subsyndrome of the acute radiation syndrome (H-ARS).

Methods

Twenty male New Zealand White rabbits were assigned to arms to receive 6-MV of TBI at a dose of 6.5, 7.5, 8.5 or 9.5 Gy. Animals were treated with moderate levels of supportive care including buprenorphine for pain management, antibiotics, antipyretics for rectal body temperature >104.8 °F, and fluids for signs of dehydration. Animals were closelyfollowed for up to 45 days after TBI for signs of major morbidity/mortality. Hematology and serum chemistry parameters were routinely monitored. Hemostasis parameters were analyzed prior to TBI, 2 and 6 hours post-TBI, and at the time of euthanasia.

Results

Animals developed the characteristic signs and symptoms of H-ARS during the first-week post TBI. Animals became thrombocytopenic with signs of severe acute anemia during the second week post TBI. Moribund animals presented with petechia and ecchymosis of the skin and generalized internal hemorrhage. Multiorgan dysfunction characterized by bone marrow failure, gastric ileus, acute renal toxicity, and liver abnormalities were common. Severe abnormalities in coagulation parameters were observed.

Conclusions

The presentation of bone marrow failure and multiorogan injury associated with ARS in the New Zealand White rabbit model is consistent with that described in the canine, swine, non-human primate, and in humans. The hemorrhagic syndrome associated with the ARS in rabbits is characterized by thrombocytopenia and hemostasis dysfunction, which appear to underlie the development of multiorgan dysfunction following TBI to rabbits. Taken together, the rabbit recapitulates the pathogenesis of ARS in humans, and may present an alternative small animal model for medical countermeasure pilot efficacy screening, dose-finding and schedule optimization studies prior to moving into large animal models of TBI-induced ARS.

Keywords:

• Total body irradiation
• acute radiation syndrome
• hematopoietic syndrome
• coagulopathy
• rabbit model

Acknowledgements

The authors gratefully acknowledge our consultants, Dr. Mitchell J. Cohen and Dr. Phillip C. Spinella, whose thoughtful reviews aided in the interpretation of the data generated within this study.

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.

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.

Mathangi Gopalakrishnan

Mathangi Gopalakrishnan is an Assistant Research Professor within the Center for Translational Medicine within the University of Maryland School of Pharmacy.

Eric P. Cohen

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

Terez-Shea Donohue

Terez Shea-Donohue was a Professor of Radiation Oncology and member of the Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Medicine School of Medicine. She is now a Program Director, within the Division of Digestive Diseases and Nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases.

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.