Hematotoxicology: Blood and Blood-Forming Tissues

• Hematotoxicology studies the adverse effects of drugs, nontherapeutic chemicals, and other agents on blood and blood-forming tissues.
• Blood transports oxygen from the lungs to the body and carbon dioxide from the cells to the lungs for exhalation.
• Blood and hematopoietic tissue are considered sensitive target organs due to their vital functions and high proliferative and regenerative capacity, making them susceptible to intoxication.
• Blood contains many elements, including bone marrow (site of hematopoiesis), spleen (clearance of defective cells), and lymph nodes.
• Bone marrow contains stem cells that are immature precursors for erythrocyte (red blood cell), leukocyte (white blood cell), and thrombocyte (platelet).
• Erythrocytes, leukocytes, and thrombocytes are produced at approximately 1-3 million/sec.
• Red blood cells (RBCs) have a lifespan of 120 days.
• A decrease in RBCs leads to anemia.
• A decrease in white blood cells (WBCs) leads to leucopenia.
• A decrease in platelets (thrombocytes) leads to thrombocytopenia.
• Hematotoxicity can be primary, directly affecting blood components, or secondary, resulting from other tissue injury or disturbances.
• Primary toxicity is considered among the serious effects of xenobiotics, especially drugs.
• Xenobiotics can affect the production, function, and survival of erythrocytes.
• Erythrocytes (red blood cells [RBCs]) comprise 40% to 45% of the circulating blood volume.
• Erythrocytes transport oxygen from the lungs to peripheral tissues and carbon dioxide from tissues to the lung.
• Erythrocytes act as carriers or pools for drugs and toxins.
• Two general mechanisms can lead to anemia: decreased production or increased destruction of erythrocytes.
• Erythrocyte production is a continuous process dependent on frequent cell division and a high rate of hemoglobin synthesis.
• Adult hemoglobin (hemoglobin A) is a tetramer composed of two α-globin chains and two β-globin chains, each with a heme residue.

Mechanisms of Alteration in RBC Production

• An imbalance between α- and β-chain production of Hb causes congenital thalassemia syndromes, leading to decreased hemoglobin production and microcytosis.
• Heme synthesis requires iron incorporation into a porphyrin ring.

Iron Deficiency

• Iron deficiency usually results from dietary deficiency or increased blood loss.
• Iron deficiency may increase the risk of iron deficiency anemia.
• Drugs that contribute to blood loss, like NSAIDs, may potentiate the risk of iron deficiency anemia due to increased risk of gastrointestinal ulceration and bleeding.

Defects in Porphyrin Ring Synthesis

• Defects in the synthesis of the porphyrin ring of heme can lead to sideroblastic anemia, with iron accumulation in bone marrow erythroblasts.
• Accumulated iron precipitates within mitochondria, causing intracellular injury.
• Xenobiotics associated with sideroblastic anemia include ethanol, isoniazid, cycloserine, chloramphenicol, zinc, and lead intoxication.
• Hematopoiesis requires active DNA synthesis and frequent mitoses.
• Folate and vitamin B12 are necessary to maintain thymidine synthesis for DNA incorporation.
• Folate and/or vitamin B12 deficiency results in megaloblastic anemia.
• Several xenobiotics may contribute to vitamin B12 and/or folate deficiency, leading to megaloblastic anemia.