A Gottingen minipig model of radiation-induced coagulopathy

Karla D. Thrall,¹ Saikanth Mahendra,² Keven Jackson¹

¹Altasciences Preclinical Seattle, Everett, WA; ²Northwest Medical Physics Center, Lynnwood, WA

International Journal of Radiation Biology, 96, 12 (2020).

Purpose:  Total body irradiation of the Gottingen minipig results in a characteristic hematopoietic response, including anemia, neutropenia, lymphocytopenia, and thrombocytopenia. Currently, there are no well-characterized large or small animal models for radiation-induced thrombocytopenia. The study described here using the Gottingen minipig was focused on understanding which aspects of the coagulation cascade leads to radiation-induced coagulopathy. In this study, multiple clinical pathology parameters were determined prior to and for 45-days following total body irradiation using a 6 MV photon linear accelerator.

Materials and methods:  Following irradiation, frequent analyses of conventional hematology and coagulation parameters provided time-course information on the onset and recovery of thrombocytopenia. In addition, thromboelastography (TEG) was utilized to monitor coagulation dysfunction, namely clotting time, clot formation time, clot strength, and fibrinolysis. Coagulation factor activity levels were measured for factors II, V, VII, VIII, IX, X, XI, XII, XIII, Protein C, fibrin monomers, antiplasmin and D-dimer using a Siemen’s coagulation analyzer to provide time course information of changes in activity post irradiation exposure.

Results:  These analyses revealed that in total body irradiated minipigs, TEG tracings demonstrate long R (time to initial clot formation) and K (time to achieve a certain clot strength) times, and low alpha-angle (rate of clot formation) and MA (overall stability of the clot) during onset of thrombocytopenia (typically post irradiation day 10–15). Low alpha-angle and MA directly correlated with decreased platelet counts. A long R time is suggestive of a deficiency in clotting factors and was compared to measured activity levels of individual coagulation factors. The data indicates that coagulation factors are significantly changed early after irradiation exposure prior to thrombocytopenia and factors VIII, XI, XII and XIII are markedly altered during the critical point of thrombocytopenia.

Conclusion:  These data support the continued use of multiple approaches to evaluate the coagulation cascade in order to provide the most meaningful interpretation of the hematopoietic changes that occur post irradiation.