PRINCIPLES OF TOXICOLOGY - Biology East Borneo

4.3 THE MYELOID SERIES 93to contract. The contraction stimulates the release of ADP (adenine diphosphate), serotonin, and otherlocally active compounds that initiate the clotting cascade mechanism, which culminates with theformation of a fibrin clot. Thus, platelets serve two purposes: (1) they create a physical barrier viaformation of a plug to seal a vascular break, and (2) they initiate the intrinsic and extrinsic clottingmechanism involving proteins (clotting factors) synthesized by the liver. Platelet activation is normallya life-saving process. However, in the presence of atherosclerotic plaques (fatty, fibrous, calcifiedlesions in the arterial endothelium), repeated rupture of the blood vessel may lead to thickening andclosure of the arterial lumen (strokes and hypertension). This can result in sudden death if a plateletclot occludes the coronary artery (myocardial infarction, starving downstream heart tissue of oxygen).Cigarette smoke–induced arteriosclerosis is a chemical toxicity that indirectly involves the platelets.In atherosclerosis accelerated by cigarette smoking, plaques, composed of a complex mixture of lipids(e.g., cholesterol), form underneath the normal smooth endothelial lining of the artery/arterioles. If theplaque ruptures, which it can do unpredictably, the connective tissue underneath the endothelial liningbecomes exposed, and this event triggers platelet aggregation. If the platelet aggregation and fibrindeposition progresses to the point of occluding the blood vessel, an infarct occurs, and all tissue distalto the occlusion (platelet clot) dies from anoxia. The muscle that dies downstream of the clot (infarctor inclusion) is replaced by scar tissue, and hence the efficiency of the cardiac muscle is compromised.The scar may also impact normal electrical conduction pathways in the heart. Hence, platelets areinvolved in the final stages of cigarette-induced atherosclerosis, a condition that can lead to vasculardisease, strokes, angina, and heart attacks.Overall, few toxicologically effects result from direct stimulation of platelet aggregation. On theother hand, aspirin and inhibitors of prostaglandin synthetase, such as ibuprofen, inhibit plateletaggregation and can prolong bleeding times. In individuals with bleeding disorders, inhibition ofplatelet aggregation can lead to excessive blood loss. However, the impairment of clotting is actuallybeneficial to individuals who are at risk of strokes, angina (ischemia of the cardiac muscle, causingpain and potential arrhythmias), and heart attacks (myocardial infarction).The most common platelets toxicity involves suppression of normal platelet number (thrombocytopenia).Alkylating agents used in the treatment of cancer are notorious for causing thrombocytopenia.For many of these cancer chemotherapeutics, their dosages are limited by potentially life-threateningthrombocytopenia, which can lead to hemorrhaging and death. The oncologist will frequently regulatethe dose of alkylating agents based on the patient’s platelet count. As one would anticipate, hemorrhagingfrom the mucous membranes of the mouth, nose, and kidneys often reveals the onset of adeficiency in platelet-controlled clotting. Sometimes it is necessary to administer platelets or wholeblood to treat a cancer patient who develops serious thrombocytopenia.Granulocytes or Neutrophils, Monocytes or Macrophages, Eosinophils, and BasophilsDifferentiation pathways similar to RBCs exist for neutrophils, basophils, eosinophils, and monocytes(which mature into macrophages after leaving the bloodstream). Neutrophils provide the first line ofdefense against bacterial invasion. They are also commonly referred to as polymononuclear neutrophils(or PMNs) because they possess a multilobed nucleus. They generally amplify in number in responseto infectious agents, which gives the physician a diagnostic endpoint to suspect an infection; specifically,PMNs exceeding 10,000 mm 3 in blood may indicate an infectious process.Neutrophils spend less than a day in circulation before attaching to vascular epithelial cells andmigrating to extravascular locations in response to foreign invasion. Monocytes circulate in the bloodfor 3–4 days before migrating to reticuloendothelial tissues, such as the liver, spleen, and bone marrow,where they set up residence as fixed macrophages. Macrophages are recruited into an area of infectionor injury and remove cellular debris and phagocytize pathogens. Macrophages may also act as antigenpresenting cells (APCs) by presenting a digested antigen to T lymphocytes in order to activate cellularimmunity (the immune response mediated by T lymphocytes). Overall, granulocytes (includingneutrophils, eosinophils, and basophils) and monocytes or macrophages can act as phagocytic cells byphysically attaching to foreign particles via receptor recognition. Following attachment, the macro-