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Study of adverse effects on blood and blood forming tissues
hematoxicology4
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Production of blood cells
hematopoiesis
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Totipotent stem cells
- can be transformed into any cell
- embryonic stem cell
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Pluripotent stem cell
- can be transformed into multiple types of cells but not all types
- ex. bone marrow
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Xenobiotics
compounds that are non-native to the body
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Anemia
- decreased RBC production
- increased RBC destruction
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Erythrocytosis
increased RBC count
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Adult Hemoglobin structure
- MW = 68Kd
- 2 alpha and 2 beta globin chains, each with heme
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alpha hemoglobin chain has ____ amino acids while beta chain has ____ amino acids.
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Methemoglobin reductase reactivates hemoglobin by
reducing the iron center from Fe3+(ferric) to Fe2+(ferrous) (active state).
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Normal concentrations of hemoglobin
- men: 13.5-16.5 g/dl
- women: 12.1-15.1 g/dl
- children: 11-16 g/dl
- pregnancy: 11-12 g/dl
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fetal hemoglobin consists of
2 alpha and 2 gamma chains
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Adult hemoglobin A
- 95% of hemoglobin in the body
- 2 alpha and 2 beta chains
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Adult hemoglobin A2
- 1.5-3.5% of hemoglobin in the body
- 2 alpha and 2 delta chains
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hemoglobin F
- rare
- fetal hemoglobin
- 2 alpha chains and 2 gamma chains
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Hemoglobin H
- seen in alpha thalassemia
- 4 beta chains
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Hemoglobin S
- seen in sickel cell anemia
- 2 alpha chains and 2 beta-S chains
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Hemoglobin C
- mild chronic hemolytic anemia
- 2 alpha chains and 2 beta C chains
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Heme and hemoglobin synthesis
- In Mitochondria: glycine + succinyl-CoA
- In Cytoplasm: coproporphyrinogen III
- Back to mitochondria: + Fe2+ => Heme
- Back to cytoplasm: +Globin => hemoglobin
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Sideroblastic Anemia
- any situation that inhibits heme synthesis
- can be caused by ethanol, chloramphenicol, isoniazid, copper chelation, pyrazinamide, zinc and lead
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Megaloblastic anemia
- distruction of RBCs
- normal life span is 120 days
- Vitamin B12 deficiency
- Folate deficiency
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Vitamin B12 deficiency can result from
- colchicine
- neomycin
- ethanol
- zidovudine
- omeprazole
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Folate deficiency can result from
- phenytoin
- promidone
- carbamazepine
- phenobarbitol
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Aplastic anemia characterized by
- peripheral blood pancytopenia
- reticulocytopenia
- bone marrow hypoplasia
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Aplastic anemia may be caused by
chloramphenicol, gold, PCN/methycillin, mefloquine, indomethacin, mepazin, bismuth, streptomycin, sulfonamides, mercury, allopurinol, benezne, amphotericin B, pyrimithime
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Methemoglobin
- iron in Fe3+ state (ferric)
- we can survive with up to 10% of methemoglobin
- decreased oxygen binding affinity
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3 major extinsic factors that influence oxygen binding affinity of heme
- pH (direct correlation)
- 2,3-biphosphoglycerate (increases efficiency)
- temperature (inverse correlation)
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Non-immune hemolytic anemia
- microangiopathic anemia
- infectios diseases
- oxidative hemolysis
- nonoxidative chemical induced hemolysis
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Microangiopathic anemia
- fragmented RBCs in blood
- caused by doxorubicin or hemangiosarcoma in dog
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Infectios diseases resulting in non-immune hemolytic anemia
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Oxidative hemolysis results from
- too many oxidative free radicles that destroy RBCs
- acetanalide, napthalene, phenylhydrazine, nitrobenzene, methylene blue
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Non-oxidative chemical induced hemolysis results from
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Immune hemolytic anemia causes
- penicillin: binds to hapten = RBC lysis
- quinidine: binds RBC = conformation change
- alpha-mehtyldopa: autoantibody = RBC destruction
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Granular leukocytes
- basophils
- neutrophils
- eosinophils
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Drugs that effect granulocyte function
- methotrexate
- cytosine
- arbinoside
- daunorubicin
- cisplatin
- cyclophosphamide
- nitrosureas
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Drugs that effect granulocyte function
- ethanol & glucocorticoids: inhibit phagocytosis
- Iohexol and loxaglate: inhibit superoxide production
- zinc, heroin and methadone: inhibit chemotaxis
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Acute leukemia
- acute lymphoblastic leukemia (ALL)
- acute myelogenous leukemia (AML)
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Chronic leukemia
- chronic lymphocytic leukemia (CLL)
- Chronic myelogenous leukemia (CML)
- myelodisplastic syndromes (mds)
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Agents that may cause leukemia
- alkylating agnets (MDS, AML)
- benzene
- topoisomerase-II inhibitors, etoposide & teniposide (AML)
- High dose gamma or x ray irradiation (ALL, AML, CML)
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important for haemostatic plug after vascular injury
platelets
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decreased production or increased destruction of platelets
thrombocytopenia
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mechanism of thrombocytopenia
- penicillin-hapten antibody
- changes in protein conformation
- change in conformation of coagulation factors
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Thrombocytopenia agents
- PLA2/COX inhibitors (NSAIDS)
- interference with agonist and receptor (antibiotics, ticlodipine)
- calcium channel blockers
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Heparin binds factor ___
4
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factors that are dependant on vitamin K for synthesis
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Conditions associated with abnormal synthesis of vitamin k dependant coagulation factors
- warfarin
- rodenticides
- broad spectrum antibiotics
- dietary deficiency
- cholestyramine resin
- malabsorption syndromes
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Xenobiotics that influence factor 5
- streptomycin/gentamicin
- PCN/cephalosporins
- topical bovine thrombin
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Xenobiotics that can interfere with factor 8
- PCN/ampicillin/chloramphenicol
- phenytoin
- methyldopa
- nitrofurazone
- phenylbutazone
- isoniazid
- procainamide
- practolol
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common side effects with warfarin
- bleeding
- loss of bone density
- skin necrosis
- congenital abnormalities in fetus
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common side effects with heparin
- heparin induced thrombocytopenia
- elevation of aminotransferase levels
- hyperkalemia
- rare: alopecia & osteoporosis
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