6/22/2020
Blood toxicity lab 7
Blood Basics
Blood is a specialized body fluid. It has four main components:
plasma, red blood cells, white blood cells, and platelets.
Blood has many different functions, including:
1-Transporting oxygen and nutrients to the lungs and tissues 2-Forming blood clots to prevent excess blood loss
3-Carrying cells and antibodies that fight infection
4-Bringing waste products to the kidneys and liver, which filter and clean the blood 5-Regulating body temperature
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Hematology: is the science or study of blood, blood-forming organs and blood diseases. In the medical field, hematology includes the treatment of blood disorders and malignancies, including types of hemophilia, leukemia, lymphoma and sickle-cell anemia. Hematotoxicology : is the study of adverse effects of drugs, nontherapeutic chemicals, and other chemicals in our environment on blood and blood-forming tissues.
Each of the various blood cells (erythrocytes, granulocytes, and platelets) is produced at a rate of approximately one to three million/s in a healthy adult and several times that rate in conditions where demand for these cells is high, as in hemolytic anemia or suppurative inflammation.
The hematopoietic tissue is also susceptible to : 1-The secondary effects of toxic agents that affect the supply of nutrients, such as iron
2- The clearance of toxins and metabolites, such as urea
3- The production of vital growth factors, such as erythropoietin and granulocyte colony- stimulating factor(G-CSF).
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The consequences of direct or indirect damage to blood cells and their precursors are predictable and potentially life-threatening.
They include hypoxia, hemorrhage, and infection. These effects may be subclinical and slowly progressive or acute and fulminant, with dramatic clinical presentations.
Hematotoxicity may be regarded :
Primary :where one or more blood components are directly affected, is regarded as among the more common serious effects of xenobiotics, particularly drugs. Secondary :where the toxic effect is a consequence of other tissue injury or systemic disturbances. It is more common, due to the tendency of blood cells to reflect a wide range of local and systemic effects of toxicants on other tissues.
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hematopoiesis
Hematopoiesis : it is the production of all of the cellular components of blood and blood plasma. It occurs within the hematopoietic system, which includes organs and tissues such as the bone marrow, liver, and spleen. Simply, hematopoiesis is the process through which the body manufactures blood cells.
The bone marrow is the principal site of hematopoiesis in humans and most laboratory and domestic animals, it produces the main blood cells of the body - red cells, white cells, and platelets. Anemia is a condition characterized by the low levels of circulating, red blood cells. Red blood cells are released from the marrow into the bloodstream where they travel throughout the body delivering oxygen to tissue.
A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of the skin (pallor), lightheadedness and additional findings.
TOXICOLOGY OF THE ERYTHRON Erythrocytes (red blood cells [RBCs]) make up 40% to 45% of the circulating blood volume.
Erythrocytes are involved in : 1-Red blood cells contain hemoglobin, which helps carry oxygen from the lungs to the rest of the body and then returns carbon dioxide from the body to the lungs so it can be exhaled.
2-Maintenance of a constant pH in blood.
3-Regulation of blood flow to tissues. 4- Help modulate the inflammatory response through clearance of immune complexes containing complement components.
5- As a carrier and/or reservoir for drugs and toxins.
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RBCS start as immature cells in the bone marrow and after seven days of maturation are released into the bloodstream.
red blood cells have no nucleus and can easily change shape, helping them fit through the various blood vessels in your body ,the lack of a nucleus makes a red blood cell more flexible, it also limits the life of the cell The RBC survives on average only 120 days. The effect of xenobiotics on erythrocytes has been extensively evaluated, because of both : 1-They readily access to the tissue .
2- The frequency with which xenobiotics cause changes in this critical tissue.
Xenobiotics may affect the production, function, and/or survival of erythrocytes. These effects are most frequently manifest as a change in the circulating red cell mass, usually resulting in (anemia).
Alterations in Red Cell Production Synthesis of heme requires incorporation of iron into a porphyrin ring , iron deficiency is usually the result of dietary deficiency or increased blood loss.
Drugs that contribute to blood loss, such as NSAID, with their increased risk of gastrointestinal ulceration and bleeding, may potentiate the risk of developing iron deficiency anemia. sideroblastic anemia are a group of inherited and acquired bone marrow disorders characterized by pathological iron accumulation in the mitochondria of bone marrow erythroblast as a result
In both acquired and congenital sideroblastic anemia, heme synthesis is impaired due to the inability to incorporate iron into protoporphyrin IX, leading to the formation of ringed sideroblasts.
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A number of xenobiotics can interfere with one or more of the steps in erythroblast heme synthesis and result in sideroblastic anemia. include :
1- Alcoholism.
2- Lead poisoning, zinc overdose, copper or pyridoxine ( B6) deficiency . 3- Congenital sideroblastic anemias (CSA).
4-Drugs (eg, chloramphenicol, cycloserine, isoniazid, linezolid, pyrazinamide)
5-Toxins (including ethanol and lead)
Megaloblastic anemia
Megaloblastic anemia is a condition in which the bone marrow produces large, structurally abnormal, immature red blood cells (megaloblasts). Megaloblastic anemia has several different causes - deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most common causes. These two vitamins serve as building blocks and are essential for the production of healthy cells .Without these essential vitamins DNA synthesis is hampered.
Symptoms in individuals : 1-GI abnormalities including diarrhea, nausea, and loss of appetite. Some affected individuals may develop a sore, reddened tongue.
2-Mild enlargement of the liver (hepatomegaly) and a slight yellowing of the skin or eyes (jaundice) may also occur.
3-Neurological symptoms. The initial neurological symptom may be tingling or numbness in the hands or feet.
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Drug-induced aplastic anemia Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells. occurs because of damage to stem cells inside bone marrow causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.
The condition leaves you fatigued and more prone to infections and uncontrolled bleeding. A rare and serious condition, aplastic anemia can develop at any age. Factors that can injure bone marrow and affect blood cell production include:
1-Radiation and chemotherapy treatments.
2-Exposure to toxic chemicals. Toxic chemicals, such as some used in pesticides and insecticides, and benzene, an ingredient in gasoline
3-Use of certain drugs. Some medications, such as those used to treat rheumatoid arthritis and some antibiotics, can cause aplastic anemia.
Treatment for aplastic anemia might include blood transfusions or a stem cell transplant, also known as a bone marrow transplant.
Pure red cell aplasia is a syndrome in which the decrease in bone marrow production is limited to maturation arrest that occurs in the formation of erythrocytes; however, white blood cell and platelet production are normal.
It is an uncommon disorder that may be due to genetic defects, infection (parvovirus B19), immunemediated injury, myelodysplasia, drugs, or other toxins. The drugs mostly implicated include isoniazid, phenytoin, and azathioprine. The mechanism of drug-induced pure red cell aplasia is unknown
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Alterations in the Respiratory Function of Hemoglobin
The ability of hemoglobin to safely and efficiently transport oxygen is dependent on both intrinsic (homotropic) and extrinsic (heterotropic) factors that affect the performance of this system. Homotropic Effects
One of the most important homotropic properties of oxyhemoglobin is the slow but consistent oxidation of heme iron Fe2+ (ferrous) state to the ferric state (Fe3+) to form methemoglobin .
Methemoglobin is not capable of binding and transporting oxygen. the normal erythrocyte has metabolic mechanisms for reducing heme iron back to the ferrous state; these mechanisms are normally capable of maintaining the concentration of methemoglobin at less than 1% of total hemoglobin.
A failure of these control mechanisms leads to increased levels of methemoglobin, or methemoglobinemia.
The most common cause of methemoglobinemia :
1- Therapeutic agents :dapsone,,topical anesthetics (benzocaine, lidocaine, and prilocaine), Primaquine,Sulfonamide,Nitric oxide,Phenazopyridine,Quinones,Methylene blue
2- Environimental agents: Nitrites,Nitrobenzenes,Aniline dyes ,,Potassium chlorate,Gasoline additives,Aminobenzenes Symptoms of methemoglobinemia may vary depending on which type you have. The main symptoms are:
Cyanosis, which describes a bluish color of the skin, especially the lips and fingers
Chocolate-brown colored blood Headache ,shortness of breath, nausea ,rapid heart rate,fatigue and lethargy, loss of consciousness
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Heterotropic Effects
Major heterotropic effectors of hemoglobin function: pH, and temperature
pH : adecrease in pH (eg,lactic acid, carbon dioxide) lowers the affinity of hemoglobin for oxygen, that is, it causes a right shift in the oxygen dissociation facilitating the delivery of oxygen to tissues
Temperature :The oxygen affinity of hemoglobin decreases as the body temperature increases .This facilitates delivery of oxygen to tissues during periods of extreme exercise and febrile illnesses associated with increased temperature.
The respiratory function of hemoglobin may also be impaired by blockade with carbon monoxide( CO).
The major sources of carbon monoxide are smoking and burning of fossil fuels (including automobiles),particularly in enclosed spaces.
Heavy smoking during pregnancy may result in significant levels of carboxyhemoglobin in fetal blood and diminished oxygenation of fetal tissues. Symptoms of carbon monoxide toxicity, such as dizziness, shortness of breath,and headache,
The key to therapy is removal from the source of carbon monoxide and provision of an adequate supply of oxygen.
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Alterations in Erythrocyte Survival Mechanical Injuries March hemoglobinuria (The presence of free hemoglobin in the urine, which may make the urine look dark.) is an episodic disorder characterized by destruction of RBCs during vigorous exercise or marching . The erythrocytes appear to be destroyed by mechanical trauma in the feet. Sufficient hemoglobin may be released to cause hemoglobinuria.
Major thermal burns are also associated with a hemolytic process. The erythrocyte membrane becomes unstable as the temperature increases with major burns there can be significant heat dependent lysis of erythrocytes. Small RBC fragments break off, with resealing of the cell membrane.
Infectious Diseases
A variety of infectious diseases may be associated with significant hemolysis, by either direct effect on the erythrocyte or development of an immune-mediated hemolytic process .
The most common agents that directly cause hemolysis include malaria,,clostridial infections, and bartonellosis.
Oxidative Hemolysis
A number of xenobiotics particularly compounds containing aromatic amines (example, hydroxylamine, and phenolic compound), Example of drugs that cause oxidative injury :Nitrofurantoin ,Nalidixic acid Sulfanilamide are capable of inducing oxidative injury in erythrocytes.
The interaction between these xenobiotics and hemoglobin leads to the formation of free radicals that denature critical proteins, including hemoglobin, thiol-dependent enzymes, and components of the erythrocyte membrane.
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Non oxidative Chemical-Induced Hemolysis
Exposure to some xenobiotics is associated with hemolysis without significant oxidative injury example :
Arsenic hydride is a gas that is formed during several industrial processes. Inhalation of the gas can result in severe hemolysis, with anemia, jaundice, and hemoglobinuria. Lead poisoning is associated with defects in heme synthesis and a shortening of erythrocyte survival.
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