Heme Tox C&D 8 Flashcards
11-1. What xenobiotics are associated with sideroblastic anemia (8)?
Ethanol, Isoniazid, Pyrazinamide, Cycloserine, Chloramphenicol, Copper chelation/deficiency, Zinc intoxication, Lead Intoxication
11-2. What laboratory features are associated with megaloblastic anemia (morphology and biochemistry)?
Morphology
Peripheral blood:
Pancytopenia, macrocytosis (increased MCV), oval macrocytes, hypersegmented neutrophils, variation in RBC shape
Bone marrow:
Erythroid hyperplasia, megaloblastic anemia, giant band neutrophils, giant metamyelocytes
Biochemistry Peripheral blood: Decreased B12 and/or folate Increased LD Antiparietal cell antibodies Antibody to intrinsic factor Increased serum iron Hypokalemia
11-3. What xenobiotics are associated with megaloblastic anemia (B12 deficiency and Folate deficiency)?
B12 deficiency (8): Paraminosalicylic acid Cochicine Neomycin Ethanol Omeprazole Hemodialysis Zidovudine Fish tapeworm
Folate deficiency (9): Phenytoin Primidone Carbamazepine Phenobarbital Sulfasalazine Cholestyramine Triamterine Malabsorption syndromes Antimetabolites
11-4. What drugs and other chemicals are associated with the development of aplastic anemia (53)?
Chloramphenicol Methylphenylethylhydantoin Gold Penicillin Methicillin Sulfisoxazole Mefoquine Carbimazole Propylthiouracil Chlorpropamide Indomethacin Meprobramate Mepazine Thiocyanate Bismuth Carbon tetrachloride Azidothymidine Trifluoperazine Organic arsenicals Trimethadione Streptomycin Allopurinol Sulfonamides Sulfamethoxypryridazine Ethosuximide Methylmercaptoimidazole Tolbutamide Carbutamide Carbamazepine Chlorpromazine Methazolamide Mercury Cimetidine Ticlopidine d=Penicillamine Quinacrine Phenylbutazone Benzene Tetracycline Chlortetracycline Amphotericin B Felbamate Potassium perchlorate Pyrimethamine Tripelennamine Diclofenac Chlordiazepoxide Parathion Dinitrophenol Chlordane Metolazone Isoniazid
11-5. What xenobiotics are associated with methhemoglobinemia (therapeutic agents and environmental agents)?
Therapeutic agents (17): Benzocaine Lidocaine Prilocaine Dapsone Amyl nitrate Isobutyl nitrite Nitroglycerine Primaquine Sulfonamide Phenacetin Nitric oxide Phenazopyridine Metoclopramide Flutamide Silver nitrate Quinones Methylene blue
Environmental agents (14): Nitrites Nitrates Nitrobenezenes Aniline dyes and aniline derivatives Butyl nitrite Potassium chlorate Gasoline additives Aminobenzenes Nitrotoluenes Trinitrotoluene Nitroethane ortho-Toluidine para-Toluidine b-Naphthol disulfonate
11-6. What xenobiotics are associated with oxidative injury (21)?
Acetanilide Napthalene Nitrofuarantoin Sulfamethoxypyridazine Aminosalicylic acid Sodium sulfoxone Dapsone Phenazyopyridine Primaquine Chlorates Sulfasalazine Phenylhydrazine Nitrobenzene Phenacetin Phenol Hydroxylamine Methylene blue Toluidine blue Furazolidone Nalidixic acid Sulfanilamide
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage?
Uncommitted (totipotential stem cell)
CFU-S
Stage of development:
Uncommitted (totipotential) stem cell
CFU-S
Disease:
Aplastic anemia
Offending drugs: Chloramphenicol Gold salts Phenylbutazone Phentoin Mephenytoin Carbamazepine
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage? Committed stem cell CFU-G CFU-E BFU-E
Stage of development:
Committed stem cell
CFU-G
CFU-E
BFU-E
Disease and (offending drugs):
Aplastic anemia
(carbamazepine)
Agranulocytosis
(Chlorpromazine, carbamazepine, clozapine)
Pure red cell aplasia
(Phenytoin)
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage?
Morphologically recognizable precursors
Stage of development:
Morphologically recognizable precursors
Disease:
Hypoplastic marrow
Drugs:
Most cancer chemotherapy agents
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage?
Dividing pool:
Promyelocyte
Myelocyte
Stage of development:
Dividing pool:
Promyelocyte
Myelocyte
Disease:
Hypoplastic marrow
Drugs:
Chlorampenicol
Alcohol
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage?
Nondividing pool:
Metamyleocytes, bands
PMNs
Stage of development:
Nondividing pool:
Metamyleocytes, bands
PMNs
Disease:
Agranulocytosis
Drugs:
Clozapine
Phenothiazines
11-7. What are the stages of granulocytopoiesis with site of xenobiotic-induced cellular damage?
Peripheral blood lysis
Metamyleocytes, bands
Stage of development:
Peripheral blood lysis
Metamyleocytes, bands
Disease:
Agranulocytosis
Drugs:
Clozapine, etc
Aminopyrine
11-8. Examples of Toxicants that cause Immune and Nonimmune Idiopathic Neutropenia?
Drugs associated with WBC Antibodies
Drugs associated with WBC Antibodies: Aminopyrine Propylthiouracil Ampicillin Metiamide Dicloxacillin Phenytoin Aprindine Azulfidine Chlorpropamide CPZ/phenothiazines Procainamide Nafcillin Tolbutamide Lidocaine Methimazole Levamisole Gold Quinidine Clozapine
11-8. Examples of Toxicants that cause Immune and Nonimmune Idiopathic Neutropenia?
Drugs NOT associated with WBC Antibodies
Drugs NOT associated with WBC Antibodies: INH Rifampicin Ethambutol Allopurinol Phenothiazines/CPZ Flurazepam HCTZ
11-9. Mechanism of Immune-mediated thrombocytopenia:
Hapten-directed antibody
Prototypic agent:
Penicillin
Antigen/epitope:
Drug
Platelet Effect:
Opsonization
Increased clearance
Clinical Effect:
Bleeding
11-9. Mechanism of Immune-mediated thrombocytopenia:
Acquired antibody to drug-induced epitope
Prototypic agent:
Quinidine
Antigen/epitope:
Drug-GP Ib/IX/V
Drug-GP IIb/IIIa
Platelet Effect:
Opsonization
Increased clearance
Clinical Effect:
Bleeding
11-9. Mechanism of Immune-mediated thrombocytopenia:
Natural antibody to drug-induced epitope
Prototypic agent:
Abciximab
Antigen/epitope:
Drug-GP IIb/IIIa
Platelet Effect:
Opsonization
Increased clearance
Clinical Effect:
Bleeding
11-9. Mechanism of Immune-mediated thrombocytopenia:
Induction of autoimmune antibodies
Prototypic agent:
Gold
Antigen/epitope:
Platelet membrane
Platelet Effect:
Opsonization
Increased clearance
Clinical Effect:
Bleeding
11-9. Mechanism of Immune-mediated thrombocytopenia:
Immune complex
Prototypic agent:
Heparin
Antigen/epitope:
Pf4-heparin complex
Platelet Effect:
Platelet activation
Platelet aggregation
Increased clearance
Clinical Effect:
Thrombosis
11-9. Mechanism of Immune-mediated thrombocytopenia:
Thrombotic thrombocytopenic purpura (TTP)
Prototypic agent:
Ticlopidine
Antigen/epitope:
vWF-cleaving protease
Platelet Effect:
Platelet activation
Platelet aggregation
Increased clearance
Clinical Effect:
Microvascular thrombosis
Microangiopathic hemolytic anemia
11-9. Mechanism of Immune-mediated thrombocytopenia:
Hemolytic-uremic syndrome
Prototypic agent:
Mitomycin
Antigen/epitope:
Unknown
Platelet Effect:
Platelet activation
Platelet aggregation
Increased clearance
Clinical Effect:
Microvascular thrombosis
Microangiopathic hemolytic anemia
11-10. Conditions Associated with Abnormal Synthesis of Vitamin K-dependent coagulation factors
Warfarin and analogs Rodenticides (eg, brodifacoum) Broad-spectrum antibiotics N-Methyl-thiotetrazole cephalosporins Intravenous alpha-tocopherol Dietary deficiency Cholestyramine resin Malabsorption syndrome
11-11. Relationship between Xenobiotics and the development of specific coagulation factor inhibitors:
Coagulation Factor:
Thrombin
Coagulation Factor:
Thrombin
Xenobiotic:
Topical bovine thrombin
Fibrin glue
11-11. Relationship between Xenobiotics and the development of specific coagulation factor inhibitors:
Coagulation Factor:
Factor V
Coagulation Factor:
Factor V
Xenobiotic: Streptomycin Penicillin Gentamicin Cephalosporins Topical bovine thrombin
11-11. Relationship between Xenobiotics and the development of specific coagulation factor inhibitors:
Coagulation Factor:
Factor VIII
Coagulation Factor:
Factor VIII
Xenobiotic: Penicillin Ampicillin Chloramphenicol Phenytoin Methyldopa Nitrofurazone Phenylbutazone
11-11. Relationship between Xenobiotics and the development of specific coagulation factor inhibitors:
Coagulation Factor:
Factor XIII
Coagulation Factor:
Factor XIII
Xenobiotic: Isoniazid Procainamide Penicillin Phenytoin Practolol
11-11. Relationship between Xenobiotics and the development of specific coagulation factor inhibitors:
Coagulation Factor:
von Willebrand factor
Coagulation Factor:
vW Factor
Xenobiotic: Ciprofloxacin Hydroxyethyl starch Valproic acid Griseofulvin Tetracycline Pesticides
11-12. Examples of Problem-driven tests used to characterize hematologic observations in preclinical toxicology
Flow cytometry Heinz body preparation Cell associated antibody assays (erythrocyte, platelet, neutrophil) Erythrocyte osmotic fragility test Erythrokinetic/ferrokinetic analyses Cytochemical/histochemical staining Electron microscopy In vitro hematopoietic clonogenic assays Platelet aggregation Plasma fibrinogen concentration Clotting factor assays Thrombin time Bleeding time
11-13. WHO Grading Criteria for Subacute and Acute Hematotoxicity:
Hematologic Parameters (Adults) at Grade 0
Hematologic Parameters (Adults) at Grade 0:
Hemoglobin g/dL (nmol/L): 11.0 (6.8)
Leukocytes (1000/ul): 4.0
Granulocytes (1000/ul): 2.0
Platelets (1000/ul): 100
Hemorrhage, blood loss: None
11-13. WHO Grading Criteria for Subacute and Acute Hematotoxicity:
Hematologic Parameters (Adults) at Grade 1
Hematologic Parameters (Adults) at Grade 1:
Hemoglobin g/dL (nmol/L): 9.5 - 10.5 (6.5 - 6.7)
Leukocytes (1000/ul): 3.0 - 3.9
Granulocytes (1000/ul): 1.5 - 1.9
Platelets (1000/ul): 75-99
Hemorrhage, blood loss: Petechiae
11-13. WHO Grading Criteria for Subacute and Acute Hematotoxicity:
Hematologic Parameters (Adults) at Grade 2
Hematologic Parameters (Adults) at Grade 2:
Hemoglobin g/dL (nmol/L): 8.0 - 9.4 (4.95 - 5.8)
Leukocytes (1000/ul): 2.0 - 2.9
Granulocytes (1000/ul): 1.0 - 1.4
Platelets (1000/ul): 50-74
Hemorrhage, blood loss: Mild
11-13. WHO Grading Criteria for Subacute and Acute Hematotoxicity:
Hematologic Parameters (Adults) at Grade 3
Hematologic Parameters (Adults) at Grade 3:
Hemoglobin g/dL (nmol/L): 6.5 - 7.9 (4.0 - 4.9)
Leukocytes (1000/ul): 2.0 - 1.9
Granulocytes (1000/ul): 0.5 - 0.9
Platelets (1000/ul): 25-49
Hemorrhage, blood loss: Gross
11-13. WHO Grading Criteria for Subacute and Acute Hematotoxicity:
Hematologic Parameters (Adults) at Grade 4
Hematologic Parameters (Adults) at Grade 4:
Hemoglobin g/dL (nmol/L): 6.5 (4.0)
Leukocytes (1000/ul): 1.0
Granulocytes (1000/ul): 0.5
Platelets (1000/ul): <25
Hemorrhage, blood loss: Debilitating
