Is Disseminated Intravascular Coagulation the Major Cause of Mortality from Radiation at Relatively Low Whole Body Doses?

Krigsfeld, Gabriel; Kennedy, Ann R.

doi:10.1667/rr3321.1

Cited by 20 publications

(17 citation statements)

References 25 publications

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“…The survival curves for γ-ray irradiated ferrets were comparable to those for the proton-irradiated animals, and both the proton and γ-ray irradiated ferrets displayed signs of distress including ecchymosis, petechiae, and hemorrhaging. It was hypothesized that the ferrets were dying of DIC in these studies (224), which was confirmed by additional evidence collected (142). …”

Section: Acute Radiation Effectssupporting

confidence: 62%

Biological effects of space radiation and development of effective countermeasures

Kennedy

2014

Life Sciences in Space Research

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150

117

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As part of a program to assess the adverse biological effects expected from astronaut exposure to space radiation, numerous different biological effects relating to astronaut health have been evaluated. There has been major focus recently on the assessment of risks related to exposure to solar particle event (SPE) radiation. The effects related to various types of space radiation exposure that have been evaluated are: gene expression changes (primarily associated with programmed cell death and extracellular matrix (ECM) remodeling), oxidative stress, gastrointestinal tract bacterial translocation and immune system activation, peripheral hematopoietic cell counts, emesis, blood coagulation, skin, behavior/fatigue (including social exploration, submaximal exercise treadmill and spontaneous locomotor activity), heart functions, alterations in biological endpoints related to astronaut vision problems (lumbar puncture/intracranial pressure, ocular ultrasound and histopathology studies), and survival, as well as long-term effects such as cancer and cataract development. A number of different countermeasures have been identified that can potentially mitigate or prevent the adverse biological effects resulting from exposure to space radiation.

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Section: Acute Radiation Effectssupporting

confidence: 62%

Biological effects of space radiation and development of effective countermeasures

Kennedy

2014

Life Sciences in Space Research

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150

117

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“…The results from our previous studies have indicated that radiation-induced coagulopathy (RIC) can result in bleeding/hemorrhage/ microvascular thrombosis, organ damage and death from multi-organ failure (MOF) [from disseminated intravascular coagulation (DIC)], which can occur at doses near the LD 50 , with RIC-associated hemorrhage occurring well before the expected decline in peripheral platelet counts (1–6). It has also been observed in irradiated dogs (7) as well as the individuals exposed to radiation from the atomic bomb (8) that bleeding often occurs in the absence of a drop in platelet counts.…”

Section: Introduction/background Informationmentioning

confidence: 99%

“…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).…”

Section: Introduction/background Informationmentioning

confidence: 99%

“…There are no known studies in which it has been concluded that human populations exposed to significant doses of radiation develop DIC, but markers for the presence of DIC (including the hallmark of DIC, hemorrhage) have been observed and reported in irradiated humans, as discussed elsewhere (1, 3, 5, 6). There is extensive evidence that widespread hemorrhages occurred in the Hiroshima and Nagasaki A-bomb casualties, even in those exposed to the lowest doses (25).…”

Section: Introduction/background Informationmentioning

confidence: 99%

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

2016

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Results from our recent studies have led to the novel hypothesis that radiation-induced coagulopathy (RIC) and associated hemorrhage occurring as part of the acute radiation syndrome (ARS) is a major cause of death resulting from radiation exposure in large mammals, including humans. This article contains information related to RIC, as well as potential strategies for the prevention and treatment of RIC. In addition, new findings are reported here on the occurrence of RIC biomarkers in humans exposed to radiation. To determine whether irradiated humans have RIC biomarkers, blood samples were obtained from radiotherapy patients who received treatment for different types of malignancies. Blood samples from allogeneic hematopoietic cell transplantation (allo-HCT) patients obtained before, during and after irradiation indicated that exposure led to prolonged clot formation times, increased levels of thrombin-antithrombin III (TAT) complex and increased circulating nucleosome/ histone (cNH) levels, which suggest potential coagulopathies in the allo-HCT patients. Since these allo-HCT patients received chemotherapy prior to radiotherapy, it is possible that the chemical agents could have influenced the observed results. Frozen plasma samples from radiotherapy patients with prostate, lung and breast cancer were also obtained for analyses of cNH levels. The results indicated that some of these patients had very high cNH blood levels. Analysis of cNH levels in plasma samples from irradiated ferrets also indicated increased cNH levels compared to preirradiation baseline levels. The results from irradiated animals and some radiotherapy patients suggest the possibility that anti-histone antibodies, which block the toxic effects of elevated cNH levels in the blood, might be useful as therapeutic agents for adverse biological radiation-induced effects. The detection of increased levels of cNH in some radiotherapy patient blood samples demonstrates its potential as a biomarker for diagnosing and/or predicting the propensity for developing coagulopathies/hemorrhage, offering possible treatment options with personalized medicine therapies for cancer patients.

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“…We have recently reported that DIC was the most likely cause of death in ferrets exposed to doses near the LD 50 level (19). One of the major drawbacks of the ferret model, as well as most other animal model systems, for studies of DIC is the lack of availability of assays specific to this species to monitor the progression of DIC in a living animal.…”

Section: Discussionmentioning

confidence: 99%

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

Krigsfeld

Shah

Sanzari

et al. 2014

Life Sciences in Space Research

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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.

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Is Disseminated Intravascular Coagulation the Major Cause of Mortality from Radiation at Relatively Low Whole Body Doses?

Cited by 20 publications

References 25 publications

Biological effects of space radiation and development of effective countermeasures

Biological effects of space radiation and development of effective countermeasures

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

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

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