CHAPTER 53 HEMOLYTIC ANEMIA DUE TO CHEMICAL AND PHYSICAL AGENTS
CHAPTER 53 HEMOLYTIC ANEMIA DUE TO CHEMICAL AND PHYSICAL AGENTS
Miscellaneous Drugs and Chemicals
Insect, Spider, and Snake Venoms
Arsenic, lead, copper, chlorates, and a variety of other chemicals can cause severe red cell destruction, and hemolytic anemia is a part of the clinical syndrome associated with intoxication by these substances. Arsenic may cause hemolysis by interacting with sulfhydryl groups. Lead inhibits a variety of red cell enzymes, including several enzymes of porphyrin metabolism and pyrimidine-5′-nucleotidase. The anemia that it produces is usually not primarily hemolytic in nature. Copper inhibits a number of red cell enzymes and catalyses the oxidation of intracellular GSH. Chlorates produce methemoglobin and Heinz bodies. There are many drugs that have appeared to cause hemolytic anemia, usually by unknown or poorly defined mechanisms. Animal toxins, such as those elaborated by insects, spiders, and snakes, may also cause hemolytic anemia. Hemolytic anemia is a common accompaniment of severe burns, probably as a result of direct damage to erythrocytes by heat.
Acronyms and abbreviations that appear in this chapter include: ALA, aminolevulinic acid; EDTA, ethylenediaminetetraacetic acid; GR, glutathione reductase; GSH, reduced glutathione; G-6-PD, glucose-6-phosphate dehydrogenase; NADPH, reduced nicotinamide-adenine dinucleotide phosphate.
Many drugs and a variety of toxins have been associated with red cell destruction. Hemolysis that results when certain drugs are administered to patients deficient in glucose-6-phosphate dehydrogenase or with unstable hemoglobins is discussed in Chap. 45 and Chap. 48. Immune mechanisms may also play a role in drug- or toxin-induced hemolytic anemias. Such hemolytic anemias are discussed in Chap. 57. Microangiopathic hemolytic anemias (Chap. 51) may also be caused by drugs such as mitomycin.
The present chapter deals with drugs, toxins, and other physical agents that can cause red cell destruction by other mechanisms, or by mechanisms that are not understood at present.
The inhalation of arsine gas (arsenic hydride, AsH3) is a well-recognized cause of hemolytic anemia.1,2 Arsine is formed during many industrial processes. Most commonly it results from the reaction of nascent hydrogen, generated by the action of acid on metal, with arsenic compounds. The arsenic is usually present as a contaminant of either the acid or the metal, so that the contact with arsenic compounds may not be apparent from the history. Exposure to sufficient amounts of the gas will lead to severe anemia, jaundice, and hemoglobinuria. The mechanism of hemolysis is not clearly understood, although the well-known reactions of arsenic compounds with sulfhydryl groups in the cell membrane may play an important role.
Lead poisoning (plumbism) has been recognized since antiquity. The ingestion of beverages containing lead leached from highly soluble lead glazes or earthenware containers has been blamed for the decline and fall of the Roman aristocracy and is even now an occasional cause of lead intoxication.3 The distillation of alcohol in leaded flasks is another rare cause of plumbism in certain areas, although the practice was prohibited in 1723 by the Massachusetts Bay Colony after it was noticed that consumption of rum so distilled resulted in abdominal pain known as the “dry gripes.”3 Among the earliest published descriptions of lead poisoning is a letter written in 1786 by Benjamin Franklin4,5 who had learned as a printer that working over small furnaces of melted metal or drying racks of wet type in front of a fire might cause pain in the hands. Today, lead intoxication in children generally results from ingestion of flaking lead paint or from chewing lead-painted articles. In adults, it occurs primarily as the result of inhalation of lead compounds used or produced in industrial processes6 as in battery manufacture,7 but poisoning may occur as a result of leaching from pottery or dishes that come in contact with food.8,9 Restoring tapestries and producing pottery and tiles10,11 have also caused lead poisoning. Most patients with lead poisoning manifest some degree of anemia, although anemia is only rarely the predominant clinical manifestation.12 However, examination of the blood often provides the key diagnostic clue, and thus the hematologic findings are of special interest. Modest shortening of red cell life-span is a relatively constant feature of the disorder.13,14 In vitro treatment of red cells with lead produces measurable membrane damage: lead interferes with the cation pump,15,16 possibly in inhibiting membrane ATPase.17,18 It is not at all clear, however, that the hemolysis observed in lead poisoning is due to these changes. In some children with lead poisoning, an electrophoretically fast moving hemoglobin indistinguishable from hemoglobin A3 comprises approximately 15 percent of the total pigment.19
The anemia of lead intoxication is not usually due primarily to hemolysis. Lead apparently interferes with the normal production of erythrocytes, probably through a combination of mechanisms. Heme synthesis is markedly abnormal in patients with lead poisoning. Several enzymes of heme synthesis are inhibited, including d-aminolevulinic acid (ALA) synthetase, ALA dehydrase, heme synthetase, porphyrinogen deaminase, uroporphyrinogen decarboxylase, and coproporphyrinogen oxidase.12,13 ALA dehydrase has been considered particularly sensitive to inhibition, showing decreased activity in erythrocytes at blood lead levels in the upper portions of the normal range,17 but its sensitivity at low blood lead levels has been questioned.20 Increased amounts of d-aminolevulinic acid and coproporphyrin are found in the urine,21 and the free protoporphyrin levels22 of the erythrocytes are strikingly increased, presumably as a result of inhibition of the heme biosynthetic enzymes. Marked inhibition of the enzyme pyrimidine 5′-nucleotidase is also observed.23,24 In the absence of this enzyme, pyrimidine nucleotides accumulate in the red cells and normal depolymerization of reticulocyte ribosomal RNA does not occur. In hereditary pyrimidine 5′-nucleotidase deficiency, basophilic stippling of erythrocytes is a characteristic finding (Chap. 45), and it has been suggested that inhibition of pyrimidine-5′-nucleotidase by lead may be responsible for the basophilic stippling of erythrocytes that occurs in plumbism (see below). Inhibition of activity of the hexose monophosphate shunt has been documented.25 Synthesis of a- and b-globin chains seems to be defective in lead poisoning,26 and this may play a contributory role in the anemia of lead poisoning.
Remarkably complete observations of the acute hematologic changes occurring after the intravenous injection of lead in an attempt to treat malignant disease were published in 1928.27 Distortion of red cells was observed both in blood films and in wet preparations made immediately after infusion of lead. This was characterized by a “folding” that made the cells appear as semicircles, clumping, and the presence of “bite cells.” The anemia of chronic lead poisoning is usually mild in the adult but is frequently more severe in children. A relatively close relationship exists between blood lead levels and the hematocrit.28 The red cells are normocytic and slightly hypochromic. The hypochromia may be due to coexisting iron deficiency.29 Basophilic stippling of the erythrocytes may be fine or coarse, and the number of granules seen in each cell may be quite variable. When blood is collected in ethylenediaminetetraacetic acid (EDTA; “purple top” tube), as is commonly done, the stippling may disappear.30 Young polychromatophilic cells are most likely to be stippled. Electron microscopic studies31 have demonstrated that the basophilic granules represent abnormally aggregated ribosomes. In the marrow, ringed sideroblasts (Chap. 22) are frequently found. Iron-laden mitochondria are present31 but do not appear to contribute to the basophilic stippling that is observed on light microscopy. It may be presumed that iron entering the developing erythroblast fails to be incorporated into heme at a normal rate, either because of lead-induced impairment of heme synthesis or because of the direct effect of lead on mitochondria.
Meso 2,3-dimercaptosuccinic acid, an orally administered chelating agent has been used to treat lead poisoning.32,33
Hemolysis has also resulted from ingestion of copper sulfate in suicide attempts and from accumulation of toxic amounts from hemodialysis fluid contaminated by copper pipes.34,35 Hemolysis in Wilson disease has been attributed to the elevated plasma copper levels characteristic of that disorder,36,37 and 38 and hemolytic anemia may be the presenting symptom.39,40 The pathogenesis of this hemolytic anemia may be related to oxidation of intracellular GSH, hemoglobin, and NADPH and inhibition of glucose-6-phosphate dehydrogenase (G-6-PD) by copper.41 However, the amount of copper required to inhibit G-6-PD is large, and copper in much lower concentrations inhibits pyruvate kinase,42 hexokinase, phosphogluconate dehydrogenase, phosphofructokinase, and phosphoglycerate kinase.43 Plasma exchange has been used successfully to treat the hemolytic anemia of Wilson disease.44
Sodium and potassium chlorate are oxidative drugs which have been known to produce methemoglobinemia, Heinz bodies, and hemolytic anemia. While it might be presumed that the mechanism of hemolysis is similar to that resulting from other oxidative drugs, no cases have been observed in patients deficient in G-6-PD. The rare instances of chlorate poisoning that have been reported usually resulted from prescription errors in which sodium chlorate was dispensed instead of sodium chloride.45 Hemolytic anemia with Heinz body formation has also occurred in patients undergoing dialysis when the tap water used contained a substantial amount of chloramines. Oxidative damage of the red cells of these patients was demonstrated by the presence of Heinz bodies, a positive ascorbate-cyanide test, and methemoglobinemia.46,47 Leaching of formaldehyde from plastic used in a water filter employed for hemodialysis is also a cause of hemolytic anemia. It was suggested that the effect of the low levels of formaldehyde found in the water were not mediated through its fixative effect but rather by inducing metabolic changes in the red cells.48
MISCELLANEOUS DRUGS AND CHEMICALS
There are also isolated reports of hemolytic anemia occurring after the administration of a variety of other substances, listed in Table 53-1.
TABLE 53-1 DRUGS AND CHEMICALS THAT HAVE BEEN REPORTED TO CAUSE CLINICALLY SIGNIFICANT HEMOLYTIC ANEMIA
Hemolytic anemia produced by phenazopyridine is often associated with “bite cells” and “blister cells.”67 When large amounts of distilled water gain access to the systemic circulation, either by intravenous injection or when used as an irrigating solution during surgery, hemolysis will occur.68 Severe hemolysis may also result from water inhalation in near-drowning.69
Hemolytic anemia has been observed in astronauts exposed to 100 percent oxygen; a reduction of red cell volume also occurs when the O2 tension is maintained at normal atmospheric levels, and this is believed to be due in some unknown way to weightlessness.70 In at least one patient, hyperbaric oxygenation was associated with acute hemolysis.71 It was suggested that hemolysis in this instance may have been due to abnormal peroxidation of lipids in the erythrocytes, but evidence supporting this view was indirect and equivocal.
INSECT, SPIDER, AND SNAKE VENOMS
Bee72 and wasp73,74 and 75 stings have been associated with severe hemolysis, and spider or scorpion bites have occasionally been followed by hemolytic anemia and hemoglobinuria.76,77,78,79,80 and 81 The spiders usually thought to be responsible are Loxosceles loeta and Loxosceles reclusus. It is unknown why some patients suffer hemolysis after insect bites whereas others do not. Although snake venom may cause hemolysis in vitro by converting lecithin to lysolecithin (see Chap. 27), hemolysis does not often result from snake bites,82 and when it does occur, it may represent microangiopathic hemolytic anemia associated with coagulation abnormalities induced by the venom.83
It has been known for over a hundred years that heating blood to temperatures above 47°C (117°F) rapidly produces visible damage to erythrocytes. The sequence of events has been defined in detail.84 Cells damaged by heating not only show morphologic changes and increases in osmotic and mechanical fragility but are also removed rapidly after reinjection into the circulation.85 These observations explain the severe hemolytic anemia which occurs in patients with extensive burns. Spherocytosis and increased osmotic fragility are found in many patients, and blood films may show fragmentation, budding, spherocytosis, and severe microspherocytosis. These changes are particularly evident if films are made promptly after the burn occurs. Gross hemoglobinemia was observed in 11 of 40 patients with second- and third-degree burns involving 15 to 65 percent of the body surface.86 It seems likely that the acute hemolytic anemia occurring within the 24 h following a burn is due to the direct effect of heat on circulating erythrocytes. Hemolysis occurring more than 24 h after the burn may sometimes be due to the infusion of isoagglutinins (particularly anti-A) in pooled plasma, when this has been administered to the patient as part of treatment,87 or be the result of infection or coagulation disorders that are common complications of extensive burn injury.
Although reduced red cell survival is a part of the complex series of events occurring after administration of large doses of total body radiation,88 erythrocytes appear to be very resistant to the direct effects of radiation.89 Such shortened red cell survival as may occur after radiation is probably related largely to red cell loss through internal bleeding and to various secondary events such as infection.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn