HEMATOPOIETIC ACUTE RADIATION SYNDROME (BONE MARROW SYNDROME, APLASTIC ANEMIA): MOLECULAR MECHANISMS OF RADIATION TOXICITY

HEMATOPOIETIC ACUTE RADIATION SYNDROME (BONE MARROW SYNDROME, APLASTIC ANEMIA): MOLECULAR MECHANISMS OF RADIATION TOXICITY

Hematopoietic Acute Radiation Syndrome.Dmitri Popov, PhD, Advanced Medical Technology and Systems Inc. , Canada.Jeffrey Jones , Professor, Baylor School Of Medicine, Houston, Texas.Maliev Slava, Professor, Vladicaucasian Research Center of Russian Academy of Science.

Acknowledgements

Carlos Montesinos, Kedar Prasad, Michael Epperly, Joel Greenberger.Aplastic AnemiaAplastic anemiais a disease in which thebone marrow, and theblood stem cellsthat reside there, are damaged. This causes a deficiency of all three blood cell types (Pancytopenia):Red Blood Cells- RBC - (anemia),White Blood Cells WBC-(leukopenia),Platelets(Thrombocytopenia). [ Kasper 2005, Merck Manual ]Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005).Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill.ISBN978-0-07-140235-4.Merck Manual, Professional Edition, Aplastic Anemia (Hypoplastic Anemia)

4Aplastic AnemiaAplastic Anemia is a disorders of the pluripotential stem cells involve a decrease in the number of cells of Myeloid,Erythroid and Megakaryotic lineage [Segel et al.2000 ]EtiologyEtiology of Aplastic Anemia include idiopathic cases and secondary Aplastic Anemia after exposure to drugs, toxins, chemicals, Viral Infections, Lympho-prolipherative Diseases, Radiation, Genetic Causes, MyelodisplasticSyndromesandHypoplastic Anemias,Thymomas, Lymphomas.[Brodsky et al. 2005., Modan et al. 1975., Szklo et al. 1975].Hematopoietic Acute Radiation Syndrome or Radiation Acquired Aplastic Anemia.Hematopoietic Acute Radiation Syndrome(or Bone marrow syndrome, orRadiation Acquired Aplastic Anemia )the Acute Toxic Syndrome usually occurs with adose of irradiation between 0.7 and 10Gy (70 1000 rads).[ Waselenko e tal., 2004].Forms of H ARS.Hematopoietic (Bone Marrow) Acute Radiation Syndrome. Different forms of Hematopoietic Acute Radiation Syndrome occur at dose > 0.7 Gy (> 70 rads)(mild symptoms may occur as low as 0.3 Gy or 30 rads)Forms of Hematopoietic ARS include Moderate form of H- ARSSevere form of H ARSExtremely Severe form of H ARSLethal form of H ARS.death may occur in some individuals at 1.2 Gy (120 rads).

Andrews lymphocyte depletion curves

Dainiak N, Gent RN, et al.First Global Consensus for Evidence-Based Management of the Hematopoietic Syndrome Resulting From Exposure to Ionizing Radiation. Disaster Med Public Health Prep. 2011 Oct;5(3):202-212. [PubMed Citation]Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman CN, Seed T, Lowry P, Armitage JO, Dainiak N; Strategic National Stockpile Radiation Working Group.Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Annals of Internal Medicine 2004; Vol. 140:1037-51. [PubMed Citation]

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Radiation Effects On Blood Counts.Fliedner.Reversible hematopoietic injury (H1-3 patterns):a sufficiently large residual viable population of hematopoietic stem cells (HSCs) remains to repopulate the bone marrow. As a consequence, victims will require observation and/or supportive care but are likely not candidates for HSC transplant.

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology10Radiation Effects on Blood CountIndicators of H1 injury:Lymphocytes remain in the normal range (1.5-3.5) x 109cells/liter; single lymphocyte counts as low as 1.0 x 109may be seen.Granulocytes remain in normal range (4-9) x 109cells/liter; a single granulocyte count below normal range may occur but never below 1.0 x 109cells/liter.Platelets usually remain in the normal range (150-350) x 109cells/liter; a single platelet count around 100 x 109cells/liter may be seen, with a potential drop between days 25 and 35 to the lower border of normal.

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology11Radiation Effects On Blood CountIndicators of H2 injury:Lymphocytes decline from the normal range of (1.5-3.5) x 109cells/liter within 2 days and remain between (0.5-1.5) x 109cells/liter.Granulocyte levels increase in the first few days, followed by a drop. Then there is an abortive rise up to the lower limit of normal. Then cell counts decline slowly to nadir below 1.0 x 109cells/liter from day 20-30, followed by a variable rate of rise after days 30-35.Platelets remain on low side of normal (100-150) x 109cells/liter until days 10-12, then nadir to about 50.0 x 109cells/liter about day 22 for 5-10 days, with regeneration between days 30 and 32.

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology12Radiation Effects On Blood CountIndicators of H3 injury:Lymphocytes drop within the first 48 hours and remain between (0.25-1.0) x 109cells/liter.Granulocytes may increase within 1-3 days then decrease until day 5. An abortive rise may start at around day 5, keeping levels about 1.0 x 109cells/liter for about 5-8 days. Then counts drops to below 0.5 x 109cells/liter around days 10-15 and remain at this nadir for about 20 days, with gradual or rapid increase beginning around days 30-35.Platelet counts remain at or above the lower border of the normal range between (100-150) x 109cells/liters until days 5-10. There is a further drop to a nadir of about (0-50) x 109cells/liter at about day 16-18. The nadir lasts for 12-15 days, with recovery at variable rate beginning after days 35-40.

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology13Radiation Effects On Blood CountIrreversible hematopoietic injury (H4 pattern):an insufficient residual population of HSCs remains to repopulate the bone marrow either "ever" or within a short enough time period to withstand the likely radiation-induced complications from hypoplasia/aplasia of the blood elements. Supportive care alone will not salvage this injury, and these victims are potential candidates for HSC transplantation.

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology14Radiation Effect On Blood CountIndicators of H4 injury:Lymphocytes decline within first 24 hours and remain between (0.1-0.25) x 109cells/liter for weeks.Granulocytes may increase within 48 hours, then counts decline rapidly reaching values of 0.5 x 109cells/liter, with this nadir persisting.Platelets decline over the first 10 days and remain low.Although victims with H4 injury should be evaluated for potential HSC transplant, transplant efficacy after severe radiation accidents, such as Chernobyl, has not yet been proven to improve survival. As techniques for this complex therapeutic intervention continue to improve, some victims may derive potential benefit from this therapy. It is strongly suggested that patients be treated on approved clinical Hematopoietic Stem Cell transplant protocols

Fliedner TM, Friesecke I, Beyrer K.Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. (METREPOL) (PDF - 970 KB) (originally published by Oxford: British Institute of Radiology15

Moderate and high doses of radiation induces necrosis of radiosensitive cells with the subsequent formation of radiation toxins (radiomimetics) and their induced acute inflammatory processes.Radiation Toxins are playing an important role as the trigger mechanism for inflammation, cell lysis, and damage to vital cellular structures such as mitochondria, DNA, ion channels and cell membranesHematopoietic Acute Radiation Syndrome blood cells, stem cells apoptosis or/and necrosis.

Radiation acquired ApoptosisApoptosis may occur as the result of many signals, among which include: various types of lympholytic agents, different chemical agents, and physical factors which include ionizing radiation.Apoptosis does not induce Inflammation.Necrosis always induce Inflammation.

Radiation acquired Inflammation.Acute Radiation Disease (ARD) or Acute Radiation Syndromes (ARS) are defined as the collective toxic clinical states observed from the acute pathological processes in various doses of irradiated mammals; to include: systemic inflammatory response syndrome (SIRS), toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMODS), and finally, toxic multiple organ failure (TMOF).Etiology and PathogenesisAfter irradiation the number of marrow CD34+ cells multi-potential hematopoietic progenitors and colony forming unit-granulocyte-macrophage (CFU-GM) and burst forming unit granulocyte macrophage (BFU-E) reduced significantly and depend on doses of irradiation. Mechanisms responsible for radiation acquired marrow cell failure include direct toxicity to hematopoietic multi-potential cells. Radiation Acquired Aplastic AnemiaHematopoietic Acute Radiation Syndrome developed after significant doses of radiation and demonstrated a disorder of blood formation in the marrow. The number of marrow cD34+ cells multipotential hematopoietic progenitors and their derivative colony forming unit granulocyte macrophage ( CFU-GM) and burstforming unit erythroid (BFU-E) reduced markedly. [Kagan WA et al. , Segel et al., Scopes J, et al.]Experiments:Administration of Haemotopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg produced specific toxic reactions with symptoms of the hematological form of ARS.Hematotoxin of SRD-4 isolated from L.S. of irradiated animals with Hematopoetic form of ARS after single doseinjection with doses 5 mg/kg, 10 mg/kg, 15 mg/kg, 30 mg/kg activate hematotoxic reactions with destruction of red blood cells and lysis oof white blood cell and activation of apoptosis/necrosis of hematopoietic cells progenitors.

HematotoxinsIs it possible that Acute Radiation Hematopoietic Syndrome could be induced without radiation?Yes ! Hematotoxic Radiation Toxins induce development of Acute Hematopoietic Acute Radiation Syndrome.HematoToxinsThe Hemotopoietic Radiation Toxins (SRD-4) were administered to radiation naive animals in doses of 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg and 30 mg/kg. Injection of SRD-4 to experimental animals resulted in erythrocytopenia,lymphocytopenia, leukocytopenia, and thrombocytopenia within days to weeks after injection.

Radiation Hematotoxins.The development of clinical features of the Acute Hemotopoietic Syndrome depended on the dose of SRD-4 Hematopoietic Radiation Toxins injected to radiation nave animals. Autopsy of those animals that died after injections oof SRD showed acute or chronic hematotoxic reactions.Radiation HematotoxinsThe clinical signs were: short-term agitation within 2 hours after administration accompanied by a short-term leukocytosis which gave way to a progressive, profound leukopenia, mainly attributable to a decrease in the absolute number of leukocytes and lymphocytes, the minimal levels of which were measured between days 7 and 15 after injection. Blood counts exhibited thrombocytopenia accompanied by progressive erythrocytopenia, which developed into profound anemia.HematotoxinsAn extensive blood analysis of the peripheral blood of the cattle showed that the processes induced by the SRD-4 injection and the processes occurring after irradiation were nearly identical. Analysis of the clinical reaction to SRD-4 administration, which was assessed on the basis of body temperature, and heart and respiration rate, established that all experimental animals showed reactions of the same type for all the tested doses and that sheep and horses were more sensitive to the administered preparation.Radiation HematotoxinsPostmortem examination of the animals that died showed changes characteristic of acute radiation sickness, accompanied by marked hemorrhage. Death often will occur secondary to overwhelming bacterial or fungal sepsis. Some sheep showed areas of skin epilation on the back and abdomen.Radiation HematotoxinsCase# 1 . Species- sheep. Hematoxin, SDR-4, isolated from irradiated mammals with the Hematopoietic form of ARS, was injected via single dose to non-irradiated mammals. The SRD-4 RT induced significant changes in white blood cells (WBC) and red cells profile (RBC).Hematoxin injected to non-irradiated sheep in doses 5 mg/kg, 10 mg/kg, 30 mg/kg activated a complex reaction which included general inflammation, vascular endothelial cell injury, apoptosis and necrosis of blood progenitor/ stem cells.Radiation HematotoxinsThe levels of sheep erythrocytes, leukocytes, lymphocytes, thrombocytes significantly increased in first hours and day after single injection of radiation hematotoxin and could be a result of general inflammation reactions and stimulation of immune system. However the levels of erythrocytes, leukocytes, lymphocytes, thrombocytes significantly decreased after 72 hours after hematoxin administration and the minimal level of erythrocytes, leukocytes, lymphocytes were measured after 168- 360 hours following a single dose injection of the radiation-induced hematoxin.Radiation HematotoxinsRadiation toxin SRD-4 (hematotoxin) induces development of red cell lysis and apoptosis / necrosis of white blood cell and red cell progenitors.Thrombocytopenia, lymphocytopenia, granulocytopenia , ecchymosis, hemorrhage and coagulopathy were important clinical signs of the mimicked hematopoietic acute radiation syndrome.Other clinical indicators of the Radiation Toxins (RT) included cutaneous system involvement: including: cutaneous edemas, blustering, desquamation, hair loss, ulcer and necrosis.Radiation HematotoixinsHematopoetic RT are strong hematotoxins.Hematopoetic RT can destroy red blood cells and initiate hemolysis, disrupt the blood clotting system and cause multi-organ degeneration and tissues damages. Hematopoietic RT possess important activity against pluripotent stem cells and blood marrow.Radiation Acquired Aplastic AnemiaACUTE RADIATION SYNDROME IN HUMANS RONALD E. GOANS, PhD, MD*; DANIEL F. FLYNN, MS, MDGusev IA , Guskova AK , Mettler FA Jr, editors. Medical Management of Radiation Accidents, 2 nd ed., New York : CRC Press, Inc.; 2001.Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman CN, Seed T, Lowry P, Armitage JO, Dainiak N; Strategic National Stockpile Radiation Working Group. Medical managenent of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group . Annals of Internal Medicine 2004; Vol. 140:1037-51.Dainiak N, Ricks RC.The evolving role of hematopoietic cell transplantation in radiation injury: potentials and limitations. BJR Suppl. 2005; 27:169-74.