Evidence of disseminated intravascular coagulation in a porcine model following radiation exposure

Abstract

Recent evidence has suggested that disseminated intravascular coagulation (DIC) plays an integral role in death at the LD50 dose of either gamma or solar particle event (SPE)-like proton radiation in ferrets. In these studies, Yucatan minipigs were evaluated to determine whether they were susceptible to the development of radiation induced DIC. Yucatan minipigs were exposed to a dose of 2.5 Gray (Gy) with x-rays and monitored over the course of 30 days. Evidence of DIC was evaluated by way of thromboelastometry parameters, platelet counts, fibrinogen concentration, and the d-dimer assay. Pigs exposed to x-rays developed signs of DIC within 2 days post-irradiation. The development of DIC was exacerbated over the course of the studies, and one of the pigs died at day 14 and another had to be euthanized on day 16 post-irradiation. For both of these pigs, DIC was evident at the time of death. The following observations were indicated or were suggestive of DIC: whole blood clotting was impaired (as evidenced by thromboelastometry alterations), there were decreased platelet counts, elevated d-dimer concentrations in the blood, and/or hemorrhaging and the presence of fibrin in tissues observed during post-mortem examination. The extrapolation of data from these studies, in combination with other published data, have led to the hypothesis that there could be a correlation between the propensity to develop DIC, as indicated by hemorrhaging at death at relatively low doses of radiation, and the LD50 for a particular species. Our data suggest that the development of DIC may contribute to death at the LD50 dose in large mammals.

Minipigs as models in drug discovery

“…Though recent attempts to develop the minipig as an animal model for ARS have progressed satisfactorily, the relative radiosensitivity of the Göttingen minipig raises concerns. A recent study suggests that radiation-induced disseminated intravascular coagulation may be a contributing factor to the radiosensitivity of minipigs [19]. Though the referred study has been conducted using X-rays, it is believed that the findings are comparable for X-rays, γ-rays, and solar particle event radiation.…”

A Review of Radiation-Induced Coagulopathy and New Findings to Support Potential Prevention Strategies and Treatments

“…Findings from our work indicate that radiation activates the coagulation cascade and induces changes in hemostasis resulting in hemorrhage and RIC. We recently published the results of numerous experiments indicating that radiation exposure can result in bleeding and ultimate death in ferrets and minipigs at doses near the LD 50 ; the evidence suggests that the early changes related to RIC can progress to death resulting from a coagulopathy [(1–5); reviewed in (6)]. It is expected that changes similar to those observed in ferrets and pigs also occur in other large mammals, including humans, irradiated at or near their respective LD 50 levels (3, 5, 6).…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…Further, it has been recently suggested that the minipig's high radiosensitivity and early death patterns following acute irradiation are not necessarily due to a failure of function of either the hematopoietic or gastrointestinal systems per se, but perhaps mediated largely by DIC. Specifically, recent reports have indeed demonstrated that DIC induced by irradiation may be a promoting factor for the radiosensitivity of minipigs (Krigsfeld et al 2014a(Krigsfeld et al , 2014b. It needs to be noted that the latter study was conducted using an X-ray source and not c-ray source.…”

“…disseminated intravascular coagulation (DIC) may be a significant, contributing factor leading to ferret death at the LD 50 dose of radiation (Krigsfeld et al 2014a). DIC is a serious and life-threatening condition in which the coagulation mechanism is over activated, causing bleeding and clotting to occur at the same time (Krigsfeld et al 2014b). This condition may be the major mechanism by which relatively low doses of radiation causes death in large mammals.…”

“…The low LD 50/30 value of the minipig, 1.73 Gy (Moroni et al 2011b), has been suggested to be due to the abnormally high radiosensitivity of its vascular/endothelial cells. Recent studies suggest that radiation-induced DIC may be a contributing factor to the radiosensitivity of minipigs (Krigsfeld et al 2014a(Krigsfeld et al , 2014b. It is important to note that the study being referred to was conducted using X-rays; however, it is believed that the findings would be comparable for c-rays as well.…”