1. Hematopoietic Acute RadiationSyndrome. Dmitri Popov, PhD, Advanced Medical Technologyand Systems Inc. , Canada. Jeffrey Jones , Professor, Baylor School Of Medicine,Houston, Texas. Maliev Slava, Professor, Vladicaucasian ResearchCenter of Russian Academy of Science.

2. Acknowledgements Carlos Montesinos, Kedar Prasad, Michael Epperly,Joel Greenberger. 3. Aplastic Anemia Aplastic anemia is a disease in which the bonemarrow, and the blood stem cells that reside there, aredamaged. 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 ] 4. Aplastic Anemia Aplastic Anemia is a disorders of the pluripotentialstem cells involve a decrease in the number of cells ofMyeloid,Erythroid and Megakaryotic lineage [Segel et al. 2000 ] 5. Etiology Etiology of Aplastic Anemia include idiopathic casesand secondary Aplastic Anemia after exposure todrugs, toxins, chemicals, Viral Infections, Lympho-prolipherativeDiseases, Radiation, Genetic Causes,Myelodisplastic Syndromes and HypoplasticAnemias, Thymomas, Lymphomas. [Brodsky et al. 2005., Modan et al. 1975., Szklo et al.1975]. 6. Hematopoietic Acute RadiationSyndrome or Radiation AcquiredAplastic Anemia. Hematopoietic Acute Radiation Syndrome(or Bonemarrow syndrome, or Radiation Acquired AplasticAnemia ) the Acute Toxic Syndrome usually occurswith a dose of irradiation between 0.7 and 10 Gy (70 1000 rads). [ Waselenko e tal., 2004]. 7. Forms of H ARS. Hematopoietic (Bone Marrow) Acute Radiation Syndrome. Different forms of Hematopoietic Acute RadiationSyndrome 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- ARS Severe form of H ARS Extremely Severe form of H ARS Lethal form of H ARS. death may occur in some individuals at 1.2 Gy (120 rads). 8. Andrews lymphocyte depletioncurves 9. Radiation Effects On Blood Counts.Fliedner. Reversible hematopoietic injury (H1-3 patterns): asufficiently large residual viable population ofhematopoietic stem cells (HSCs) remains torepopulate the bone marrow. As a consequence,victims will require observation and/or supportive carebut are likely not candidates for HSC transplant. 10. Radiation Effects on Blood Count Indicators of H1 injury: Lymphocytes remain in the normal range (1.5-3.5) x109 cells/liter; single lymphocyte counts as low as 1.0 x109 may be seen. Granulocytes remain in normal range (4-9) x109 cells/liter; a single granulocyte count below normalrange may occur but never below 1.0 x 109 cells/liter. Platelets usually remain in the normal range (150-350) x109 cells/liter; a single platelet count around 100 x109 cells/liter may be seen, with a potential drop betweendays 25 and 35 to the lower border of normal. 11. Radiation Effects On Blood Count Indicators of H2 injury: Lymphocytes decline from the normal range of (1.5-3.5) x109 cells/liter within 2 days and remain between (0.5-1.5) x109 cells/liter. Granulocyte levels increase in the first few days, followed by adrop. Then there is an abortive rise up to the lower limit ofnormal. Then cell counts decline slowly to nadir below 1.0 x109 cells/liter from day 20-30, followed by a variable rate ofrise after days 30-35. Platelets remain on low side of normal (100-150) x109 cells/liter until days 10-12, then nadir to about 50.0 x109 cells/liter about day 22 for 5-10 days, with regenerationbetween days 30 and 32. 12. Radiation Effects On Blood Count Indicators of H3 injury: Lymphocytes drop within the first 48 hours and remainbetween (0.25-1.0) x 109 cells/liter. Granulocytes may increase within 1-3 days then decrease untilday 5. An abortive rise may start at around day 5, keepinglevels about 1.0 x 109 cells/liter for about 5-8 days. Then countsdrops to below 0.5 x 109 cells/liter around days 10-15 andremain at this nadir for about 20 days, with gradual or rapidincrease beginning around days 30-35. Platelet counts remain at or above the lower border of thenormal range between (100-150) x 109 cells/liters until days 5-10. There is a further drop to a nadir of about (0-50) x109 cells/liter at about day 16-18. The nadir lasts for 12-15 days,with recovery at variable rate beginning after days 35-40. 13. Radiation Effects On Blood Count Irreversible hematopoietic injury (H4 pattern): aninsufficient residual population of HSCs remains torepopulate the bone marrow either "ever" or within ashort enough time period to withstand the likelyradiation-induced complications fromhypoplasia/aplasia of the blood elements. Supportivecare alone will not salvage this injury, and thesevictims are potential candidates for HSCtransplantation. 14. Radiation Effect On Blood Count Indicators of H4 injury: Lymphocytes decline within first 24 hours and remain between (0.1-0.25) x 109 cells/liter for weeks. Granulocytes may increase within 48 hours, then counts declinerapidly reaching values of 0.5 x 109 cells/liter, with this nadirpersisting. Platelets decline over the first 10 days and remain low. Although victims with H4 injury should be evaluated forpotential HSC transplant, transplant efficacy after severeradiation accidents, such as Chernobyl, has not yet beenproven to improve survival. As techniques for this complextherapeutic intervention continue to improve, some victims mayderive potential benefit from this therapy. It is strongly suggestedthat patients be treated on approved clinical HematopoieticStem Cell transplant protocols 15. Hematopoietic Acute Radiation Syndrome blood cells, stem cells apoptosis or/andnecrosis. Moderate and high doses of radiation induces necrosisof radiosensitive cells with the subsequent formationof radiation toxins (radiomimetics) and their inducedacute inflammatory processes. Radiation Toxins are playing an important role as thetrigger mechanism for inflammation, cell lysis, anddamage to vital cellular structures such asmitochondria, DNA, ion channels and cell membranes 16. Radiation acquired Apoptosis Apoptosis may occur as the result of many signals,among which include: various types of lympholyticagents, different chemical agents, and physical factorswhich include ionizing radiation. Apoptosis does not induce Inflammation. Necrosis always induce Inflammation. 17. Radiation acquired Inflammation. Acute Radiation Disease (ARD) or Acute RadiationSyndromes (ARS) are defined as the collective toxicclinical states observed from the acute pathologicalprocesses in various doses of irradiated mammals; toinclude: systemic inflammatory response syndrome(SIRS), toxic multiple organ injury (TMOI), toxicmultiple organ dysfunction syndromes (TMODS),and finally, toxic multiple organ failure (TMOF). 18. Etiology and Pathogenesis After irradiation the number of marrow CD34+ cells multi-potential hematopoietic progenitors and colonyforming unit-granulocyte-macrophage (CFU-GM)and burst forming unit granulocyte macrophage(BFU-E) reduced significantly and depend on doses ofirradiation. Mechanisms responsible for radiation acquiredmarrow cell failure include direct toxicity tohematopoietic multi-potential cells. 19. Radiation Acquired AplasticAnemia Hematopoietic Acute Radiation Syndrome developedafter significant doses of radiation and demonstrateda disorder of blood formation in the marrow. Thenumber of marrow cD34+ cells multipotentialhematopoietic progenitors and their derivative colony forming unit granulocyte macrophage ( CFU-GM)and burstforming unit erythroid (BFU-E) reducedmarkedly. [KaganWA et al. , Segel et al., Scopes J, etal.] 20. 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 producedspecific toxic reactions with symptoms of thehematological form of ARS. Hematotoxin of SRD-4 isolated from L.S. of irradiatedanimals with Hematopoetic form of ARS after singledoseinjection with doses 5 mg/kg, 10 mg/kg, 15 mg/kg, 30mg/kg activate hematotoxic reactions with destruction ofred blood cells and lysis oof white blood cell and activationof apoptosis/necrosis of hematopoietic cells progenitors. 21. Hematotoxins Is it possible that Acute Radiation HematopoieticSyndrome could be induced without radiation? Yes ! Hematotoxic Radiation Toxins inducedevelopment of Acute Hematopoietic AcuteRadiation Syndrome. 22. HematoToxins The Hemotopoietic Radiation Toxins (SRD-4) wereadministered to radiation naive animals indoses of 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kgand 30 mg/kg. Injection of SRD-4 to experimental animals resulted inerythrocytopenia,lymphocytopenia, leukocytopenia,and thrombocytopenia within days to weeks afterinjection. 23. Radiation Hematotoxins. The development of clinical features of the AcuteHemotopoietic Syndrome depended on the dose ofSRD-4 Hematopoietic Radiation Toxins injected toradiation nave animals. Autopsy of those animals that died after injections oofSRD showed acute or chronic hematotoxic reactions. 24. Radiation Hematotoxins The clinical signs were: short-term agitation within 2hours after administration accompanied by a short-termleukocytosis which gave way to a progressive,profound leukopenia, mainly attributable to a decreasein the absolute number of leukocytes andlymphocytes, the minimal levels of which weremeasured between days 7 and 15 after injection. Blood counts exhibited thrombocytopeniaaccompanied by progressive erythrocytopenia, whichdeveloped into profound anemia. 25. Hematotoxins An extensive blood analysis of the peripheral blood ofthe cattle showed that the processes induced by theSRD-4 injection and the processes occurring afterirradiation were nearly identical. Analysis of the clinical reaction to SRD-4administration, which was assessed on the basis ofbody temperature, and heart and respiration rate,established that all experimental animals showedreactions of the same type for all the tested doses andthat sheep and horses were more sensitive to theadministered preparation. 26. Radiation Hematotoxins Postmortem examination of the animals that diedshowed changes characteristic of acute radiationsickness, accompanied by marked hemorrhage.Death often will occur secondary to overwhelmingbacterial or fungal sepsis. Some sheep showed areas ofskin epilation on the back and abdomen. 27. Radiation Hematotoxins Case# 1 . Species- sheep. Hematoxin, SDR-4, isolated from irradiated mammalswith the Hematopoietic form of ARS, was injected viasingle dose to non-irradiated mammals. The SRD-4 RTinduced significant changes in white blood cells(WBC) and red cells profile (RBC). Hematoxin injected to non-irradiated sheep in doses 5mg/kg, 10 mg/kg, 30 mg/kg activated a complexreaction which included general inflammation,vascular endothelial cell injury, apoptosis and necrosisof blood progenitor/ stem cells. 28. Radiation Hematotoxins The levels of sheep erythrocytes, leukocytes, lymphocytes,thrombocytes significantly increased in first hours and dayafter single injection of radiation hematotoxin and could bea result of general inflammation reactions and stimulationof immune system. However the levels of erythrocytes, leukocytes,lymphocytes, thrombocytes significantly decreased after 72hours after hematoxin administration and the minimallevel of erythrocytes, leukocytes, lymphocytes weremeasured after 168- 360 hours following a single doseinjection of the radiation-induced hematoxin. 29. Radiation Hematotoxins Radiation toxin SRD-4 (hematotoxin) inducesdevelopment of red cell lysis and apoptosis / necrosis ofwhite blood cell and red cell progenitors. Thrombocytopenia, lymphocytopenia, granulocytopenia ,ecchymosis, hemorrhage and coagulopathy were importantclinical signsof 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. 30. Radiation Hematotoixins Hematopoetic RT are strong hematotoxins. Hematopoetic RT can destroy red blood cells andinitiate hemolysis, disrupt the blood clotting systemand cause multi-organ degeneration and tissuesdamages. Hematopoietic RT possess important activity againstpluripotent stem cells and blood marrow. 31. Radiation Acquired AplasticAnemia ACUTE RADIATION SYNDROME IN HUMANS RONALD E. GOANS, PhD, MD*; DANIELF. FLYNN, MS, MD Gusev IA , Guskova AK , Mettler FA Jr, editors. Medical Management of RadiationAccidents, 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 NationalStockpile Radiation Working Group. Medical managenent of the acute radiationsyndrome: recommendations of the Strategic National Stockpile Radiation WorkingGroup . Annals of Internal Medicine 2004; Vol. 140:1037-51. Dainiak N, Ricks RC. The evolving role of hematopoietic cell transplantation inradiation injury: potentials and limitations. BJR Suppl. 2005; 27:169-74.