Hematologic and Immunologic Toxicity

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Hematologic and Immunologic Toxicity

• Dr. Jena Hamra

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Blood Components

• Cellular elements
• Red blood cells
• Carry oxygen and carbon dioxide
• White blood cells
• Lymphocytes
• Neutrophils
• Monocytes/macrophages
• Eosinophils
• Basophils
• Platelets

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Blood Cell Production

• Hematopoiesis
• Where?
• Bone marrow
• Pluripotent hematopoietic stem cells
• Control of hematopoiesis
• Colony stimulating factors
• Interleukins
• Erythropoietin

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Red Blood Cells

• Most abundant blood cells
• Hematocrit
• Percentage of total blood volume that is RBCs
• Anatomy
• Biconcave disk
• Lack nucleus
• No proteins
• Short life
• Contain hemoglobin and enzymes
• No mitochondria
• Glycolysis only

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Erythrocyte Toxicity

• Basic mechanisms
• Altered production of RBCs
• Altered function of hemoglobin
• Alteration in RBC survival

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Altered Production of RBCs

• Mechanisms
• Decreased hemoglobin synthesis
• Iron deficiency anemia
• Sideroblastic anemia
• Lead, zinc
• Ethanol
• Isoniazid
• Chloramphenicol

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Altered Production of RBCs

• Folate or Vitamin B12 deficiency
• Megaloblastic anemia
• Vit. B12 Zidovudine, Neomycin
• Folate Phenytoin, Carbamazepine, Phenobarbital
• Suppression of bone marrow
• Aplastic anemia
• Chloramphenicol, Mefloquine
• Organic arsenicals, Parathion, Chlordane
• Red cell aplasia

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Altered Hemoglobin Function

• Hemoglobin
• Transports oxygen
• Four globular protein chains
• 2 alpha and 2 beta chains (HbA)
• Heme
• Porphyrin ring with Fe center
• Synthesis
• Dietary iron

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Altered Hemoglobin Function

• Mechanisms
• Failure to reduce heme iron to ferrous state
• Methemoglobinemia
• Nitrites, nitrates
• Amy nitrate
• Quinones, Methylene blue
• Alteration of pH
• ? pH ? ? affinity of hemoglobin for oxygen

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Altered Hemoglobin Function

• Mechanisms
• Alteration of 2,3-DPG concentrations
• Binding of DPG to hemoglobin ? ? affinity
• Temperature
• ? temperature ? ? affinity
• Carbon monoxide
• Higher affinity for hemoglobin than oxygen

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Altered RBC Survival

• Hemolytic anemia
• Microangiopathic anemia
• Infectious diseases
• Malaria, Clostridial infections
• Oxidative hemolysis
• Potentiation of normal redox reactions
• Primaquine
• Chlorates
• Nonoxidate chemical-induced hemolysis
• Arsine gas

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Immune System

• Lymphoid tissues
• Primary
• Bone marrow
• Thymus gland
• Secondary
• Spleen
• Lymph nodes
• Diffuse tissues
• Tonsils
• GALT

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Immune Cell Function

• GRANULOCYTES
• Eosinophils
• Fight parasites
• Allergic reactions
• Basophils
• Release histamine, heparin
• Neutrophils
• Ingest and digest bacteria
• Most abundant WBC in blood
• Release pyrogens, mediators of inflammation

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Cell Function

• Lymphocytes
• Secrete antibodies
• Memory cells
• Cytotoxic cells
• Monocytes
• Macrophages in tissue
• Primary scavengers
• Bacteria, tissue
• Antigen presenting cells
• Dendritic cells
• Recognize, capture antigen
• Antigen presenting cells

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Innate Immunity

• Phagocytes
• Macrophages and neutrophils
• Phagocytosis
• Receptor mediated
• Extravasation and diapedesis
• Inflammation
• Cytokines from macrophages
• Acute phase proteins
• Produced by liver
• Released early in immune response

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Acquired Immunity

• Selective reaction to a specific antigen
• Mediated by lymphocytes
• Membrane receptors specific for particular ligand
• Same specificity clones
• Clonal expansion
• First exposure to antigen
• Cells divide new clones
• Produces effector cells and memory cells
• Second exposure to antigen
• Activation of memory cells

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Granulocyte Toxicity

• Mechanisms
• Decreased proliferation
• Methotrexate, cisplatin, nitrosureas
• Impaired phagocytosis
• Ethanol, glucocorticoids
• Neutropenia, nonimmune
• Isoniazid, Allopurinol
• Flurazapam, Phenothiazines
• Neutropenia, immune
• Phenytoin, Nafcillin, Clozapine
• Gold, Quinidine

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Leukemias

• Proliferative disorders of bone marrow
• Acute myelogenous leukemia (AML)
• Most common associated with chemical
• Myelodysplastic syndrome (MDS)/AML
• Alkylating agents
• Benzene
• Radiation

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Immunosuppression

• Mechanisms
• Alteration of cell function
• Alteration of organ structure or function
• Chemicals
• Heavy metals
• PAHs, pesticides
• Narcotics
• Ethanol
• Mycotoxins

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Hemostasis

• Thrombocytes (platelets)
• Small fragments from megakaryocytes
• Smaller than RBCs, no nucleus
• 3 steps
• Vasoconstriction
• Decreases blood flow and pressure
• Formation of platelet plug
• Platelets adhere to exposed collagen
• Become activated and release cytokines
• More vasoconstriction and activate more platelets
• Blood coagulation

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Coagulation

• 2 pathways
• Intrinsic
• Collagen exposure activates plasma proteins
• Cascade
• Extrinsic
• Damaged tissue exposes tissue factor
• Activates plasma proteins
• 2 pathways converge to initiate thrombin
  formation
• End result
• Conversion of fibrinogen to fibrin
• Form clot

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Toxicology of Hemostasis

• Thrombocytopenia
• Decreased production
• Cancer chemotherapeutic agents
• Increased destruction
• Immune mediated
• Penicillin
• Heparin
• Thrombotic thrombocytopenia purpura
• Infectious diseases
• Cocaine, cyclosporine

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Toxicology of Hemostasis

• Alteration of platelet function
• NSAIDs
• b-lactam antibiotics
• Beta-blockers
• Decreased synthesis of coagulation proteins
• Vitamin K dependent (II, VII, IX, X)
• Warfarin
• Rodenticides
• Antibiotics

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Toxicology of Hemostasis

• Increased clearance of coagulation factors
• Antibodies, inhibitors
• Streptomycin, penicillin
• Methyldopa
• Phenytoin
• Griseofulvin
• Pesticides

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Clinical Agents

• Anticoagulants
• Coumadin (Warfarin)
• Heparin
• Fibrinolytic agents
• Streptokinase