PRINCIPLES OF TOXICOLOGY - Biology East Borneo

92 HEMATOTOXICITY: CHEMICALLY INDUCED TOXICITY OF THE BLOODin which inherited defects in cytoskeletal membrane proteins predispose RBCs to hemolysis anddestruction by the spleen; proxysmal nocturnal hemoglobinuria involving nighttime episodes ofhemolysis; autoimmune-induced RBC destruction; chemical-induced RBC damage or destruction;infectious diseases such as malaria; and hypersplenism. Many of the underlying pathological conditionsthat give rise to the various types of anemia can be quite complex and require careful clinicalassessment. Anemias may present with different RBC morphology (shape or appearance). The typesof anemia and information regarding specific anemias are listed in Table 4.3.An essential characteristic of RBCs is their ability to undergo reversible shape changes ordeformations as they travel through the narrow capillary beds. The reversible deformability involvesa highly organized submembrane cytoskeletal scaffolding system. In this system, spectrin chains areattached to the membrane via ankyrin and further controlled by actin and numerous other cytoskeletalmembrane proteins. Not surprisingly, if these cytoskeletal membranes are damaged by active oxygen(the high oxygen environment of the erythrocyte or redox cycling caused by chemicals, as discussedbelow) or by some other chemically induced perturbation or hereditary disease, the deformability ofthe erythrocyte is lost, and bizarre shape changes may ensue. Alterations in the normal cytoskeletalprotein structure may also impart fragility to the RBC, inducing it to burst (hemolyze) under stressfulconditions. In hereditary hemolytic anemias, familial mutations in various cytoskeletal membraneproteins induce premature destruction of the red blood cells. Chemical-induced hemolytic anemia isa similar condition in which exposure to certain chemicals results in damage to the cytoskeletalmembrane proteins and the ultimate destruction of RBCs.Platelets (or Thrombocytes)Platelets are formed in a similar manner to erythrocytes, originating from the same myeloid stem cells.Platelets are actually cell fragments that pinch off the megakaryocyte. Mature platelets are the smallestcells found in circulation, and once a platelet is formed, its circulating life span is only 9 days.Circulating platelets provide the first line of defense against blood loss by monitoring the integrityof the endothelial lining of arteries and veins. If a blood vessel ruptures, the connective tissueunderneath the normally smooth, continuous, and nonreactive endothelial lining is exposed. Theexposed collagen has a strong negative charge and is one of the most powerful inducers of plateletaggregation. Platelets bind to the collagen and to other platelets, and then the aggregated platelets beginTABLE 4.3 AnemiasTypesMicrocytic hypochromic anemia;small RBCsDescriptionResults when red blood cells are formed having a low hemoglobincontent (this occurs when red cells are produced rapidly in response torapid blood loss); frequently an iron deficiency coincides with aninability to meet the demand of increased erythrocyte production,thereby causing a reduction in hemoglobin, hence hypochromic orreduced red pigmentation; iron-deficient diets may also producehypochromic anemia; genetic diseases such as thalassemia result inabnormal hemoglobin production and microcytic anemiaMacrocytic; large RBCs This anemia involves two different types: (1) megaloblastic and (2)nonmegaloblastic—it is an anemia resulting from a defect in DNAsynthesis possibly secondary to folic acid or vitamin B12 deficiency;other etiologies may include liver disease and hypothyroidism thatresult in destruction of recticulocytes (reticulocytosis), or themyelodysplastic syndromeNormocytic; normal-sized RBCs Early stages of microcytic and macrocytic anemia may present asnormocytic; causes of normocytic anemia may be primary bonemarrow failure such as aplastic anemia, hemorrhage, hemolytic anemia(immune or drug-induced), and mild hypothyroidism