CHAPTER 63 HEMOLYTIC ANEMIA DUE TO - CHEMICAL AND PHYSICAL AGENTS ERNEST BEUTLER Uby inleracting with sulfhydryl groups. Lead inhibits ey of red cell enzymes, including several eitzyince iia metaboliom and pyrimidine’’-nucleotdase. miathat it produces is usually not primarily hemo. nature. Copper inhibits a number of red cell ene ant catalyses. the oxidation of #8 anda varity of toxins have been associated with red cell Btn. Hemolyss tha results when certain drugs are administered Bath deficient in glucose-6-phosphate dehydrogenase or with {Netdoglobins is discussed in Chaps. 45 and 48. Immune Eiin8 iy also play a role in drug- or toxin-induced hemolytic b Sue heinolytic anemias are discussed in Chap. 57. Microan. t chapter deals with drugs, toxiis, and other physical ‘aise ed cell destruction by other mechanisms, or by mth are not understood at present. eof arsine gas (rsenie hyde, Ast) is a well-recog- hemolytic anemia. Arsine is formed during many ses. Most commonly it result from the reaction of generated by the action of acid on metal, with Eten. The arsenic is usally present as a contaminant GFE 25 or the metal, so thatthe contact with aseni com. Bp) be apparent from the history. Exposure to sufcient Fei will lead wo severe anemia, janice, and hemoglo- Be mechanism of hemolysis is not clearly understood, al- Bsns taper inh chap ica: ALA amine imatmineeeic cis; GR, gluon sedate: OS, iH O-69D, coe 6 phosphate debytrogenaes NADPH fpeoee deacon pepe ‘hough the well-known reactions of arsenic compounds wth sulfhydryl ‘soups in the cell membrane may play an important role ‘LEAD {Lead poisoning (plumbism) has been recognized since antiquity. The ingestion of beverages containing lead leached from highly soluble lead glazes or earthenvare containers has been blamed for the dectine and fall of the Roman aristocracy and is even now an occasional cause of lead intoxication,’ The distillation of alcobol in leaded flasks is ‘anothee rare cause of plumbism in certain areas, although the practice ‘was prohibited in 1723 by the Massachusetts Bay Colony afte it wes noticed that consumption of rum so disiled resulted in abvlominal Pain known as the “dry gripes.” Among the earliest published de- Seriptions of lead poisoning isa letter writen in 1786 by Benjamin ‘Franklin who had leamed as a printer that working over small furs iaces of melted metal or drying racks of wet type in front ofa fire ‘ight cause pain in the hands. Today, lead intoxication in children generally results from ingestion of flaking lead pint or from chewing lead-painted articles. In adults, it occurs primarily as the result cf inhalation of lead compounds used or produced in industrial processes? 4s in battery manufacture," but poisoning may occur as a result of leaching from pottery or dishes that come in contact with food. Restoring tapestries and producing pottery and ties!" have also ‘caused lead poisoning. Most patients with lead poisoning manifest ‘somae degree of anemia, although anemia s only rarely the predominant clinical manifestation. However, examination ofthe blood often pro. Vides the key diagnostic clue, and thus the hemstologic findings are ‘of special interest, Modest shorting of red cell lifespan sa relatively Constant feature of the disorder. In vitro treatment of re cells wth lead prodiuces measurable membrane damage: lead interferes withthe cation pump possibly in inhibiting membrane ATPase." [es not at all clear, however; thatthe hemolysis observed in lead poisoning is due to these changes. In some children with lead poisoning, clectrophoretically fast moving hemoglobin indistinguishable. from hemoglobin A, comprises approximately 15 percent of the total pigment. ‘The anemia of lead intoxication is not usually due primarily to hemolysis. Lead apparently interferes with the nocmal production of erythrocytes, probably through a combination of mechanisms, Heme Synthesis markedly abnormal in patients with lead poisoning. Several ccazymes of heme synthesis are inhibited, including 8aminolevulini acid (ALA) synthetase, ALA dchydase, heme synthetase, porphyrino- en deaminase, uroporphyiinogen decarboxylase, and coproperphy. Finogen oxidase": 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,” but its sensitivity at low blood lead levels has been questioned.” Increased ‘amounts of é-aminolevulinic acid and coproporphyrin are found in the urine." and the free protoporphyrin levels of the erythrocytes are ‘tikingly increased, presumably as a result of inhibition ofthe heme biosyathetic en2ymes. Marked inhibition of the enzyme pyrimidine ‘S/-mucleotdase is also observed." In the absence of this enzyme, Pyrimidine nucleotides accumulate inthe red cells and normal depo. lymerization of reticulocyte ribosomal RNA does not occur. In heredi- ‘ary pyrimidine 5'-nucleotidase deficiency. basophilic stippling of ceothrocytes.is a characteristic finding (Chap. 45), and it has been suggested that inbibition of pyrimidie-s'-nucieotidase by lead may be responsible:for the basophilic stippling of erythrocytes that oceurs in plumbism (see below). Inhibition of acdvity ofthe hexase mono Phosphate shunt has been documented: Synthesis of @- and f-globin chains seems to be defective in lead poisoning,” 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 injetion of lead in an attempt to treat malignant disease were published in 1928.” Distortion of real cells was observed both in blood films and in wet preparations made immediately after infusion of lead. This was characterized by a "fold, ing’ that made the cells appear as semicircles, clumping, and the Presence of “ite cells” The anemia of chronic lead poisoning ts Usually mi in the adult but i Frequently’ more severe in childrew, A ‘relatively close relationship exists between blood lead tevels and the hematocrit." The red cells are normocytic and slightly hypochromie ‘The hypochromia may be duc to Goexisting iron deficiency.” Base, philic stippling of the erythrocytes may be fine oF coarse, and the ‘number of granules seen in each cell may be quite variable. Wher blood is collected in ethylenediaminetetraacetic acid (EDTA; “purple "0p" tube), asi commonly done the tipping may disappear ® Young polychromatophiliccells are most likely tobe stippled. Electron micro Scopic studies have demonstrated thatthe basophilic granules repre. Sent abnormally aggregated ribosomes. In the marréw, ringed sider. blasts (Chap. 22) are frequently found, Iron-taden mitochondria are Present” but do not appear to contribute to the basophilic stipling that is observed on light microscopy. It may be presumed thet ion entering the developing erythroblat fails to be incorporated inte heme ‘ta normal rate, either because of lea-induced impairment of heme synthesis or because of the direct ‘effect of lead on mitochondrn ‘Meso 2,3-dimercaptosuecinic acid, an orally administered chelat ing agent has been used to treat lead poisoning = COPPER Hemolysis ha also resulted from ingestion of copper sulfate in suicide ‘attempts and from accumulation of toxic amounts from hemodialysis ‘uid contaminated by copper pipes." Hemolysis in Wilson disease has been attributed to the elevated plasma copper levels characteristic of that disorder.%*™ and hemolytic anemia,may be the presenting symptom.” The pathogenesis of this hemolytic anemia may be related ‘oxidation of intracellular GSH, hemoglobin, and NADPH and inh tion of glucose-6-phosphate dehydrogenase (G-6PD) by copper. However, the amouat of copper required to inhibit G-6-PD is lage, ‘and copper in much lower concentrations inhibits pyruvate Kinase! hexokinase, phosphogluconate dehydrogenase, phosphofructokinase, and phosphoglycerate kinase." Plasma exchange fas been used suc cessfully o teat the hemolytic anemia of Wilson discase # CHLORATES 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 brescription errors in which sodium chlorate was dispensed instead of sodium chloride. 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 methemoglobin. emia“ Leaching of formaldehyde from plastic used in a water filter ‘employed for hemodialysis is also a cause of hemolytic anemia, It Was suggested thatthe 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. ARTY THe gn TABLE 53:1 DRUGS AND CHEMICALS THAT HAVE BEEN REPORTED: CAUSE CLINICALLY SIGNIFICANT HEMOLYTIC ANEMIA Gnescats Aniline” Apia Dichiorprop herbicide) Fomldehyde™ Hydroxylamines™ Dar Minecal spirits" Nittobenzene™ Resor" Amy aiite™ Mephenesin™ Methylene bive” Omeprarae Pentachoropienot® Phenazopyridine (Pyridiamn Salcylanosulfepyridine (Avafiine MISCELLANEOUS DRUGS AND CHEMICALS There are also isolated rejors of hemolytic anemia oc the administration ofa variety of other substances, listed i Ti Hemolytic anemia produced by phenazopyridine is of sted with “bite cells” and “blister cell” When large of distiled water gain access to the systemic circulation, i intravenous injection or when used a6 an irigating soli surgery, hemolysis will occur Severe hemolysis may also Water inhalation in near-drowning.® OXYGEN Hemolytic anemia has been observed in astronauts expe erent oxygen; a redaction of red ell volume als cae ©, tension is maintained at normal atmosphere ves belived tobe due in some unknown way to meighee least one patient, hyperbaric oxygenation was associated hemolysis." It was suggested that hemolysin this stances been dv to abnormal peroxidation of iid in the ant evidence supporting this view was inect and equveed 8 INSECT, SPIDER, AND SNAKE VENOMS : ee” and wasp” stings have been associated with ever and sider or sompion bites ave oceasionlly been al Iytic anemia and hemoglobinuria" The spiders usta be responsible are Lasoscles lov and Loxoseles unknown vty some patents suffer hemolysis after iset sees do ot. Ako snake venom may cause beni by converting lecithin to isolcthin (See Chap 27), ke nt often res from snake bites." and wht dos represent microagiopthichemolyie ani asaciaed ll tion abmommaties induced bythe venom HEAT temperatures above 47°C (L17°F) rapidly produces visible enythrocytes. The sequence of events has been defined in ‘damaged by heating not only show morphologic ehanges:Datient as part of treatment,” Aisorders that are common RADIATION SkAM Namer R. Hap &, Coin R:Barhenivare containers as a Tre Conpen hd Deisong. N Eat J Med ts ae The Complete Works of Reman Frankin cited by Bigelow, Putnam, New York, 1888, 2s Toe: Peianin aki: Pyscie et medio sama 236557, 1976 cia ra, Roth VS: Oscpaianl ad pong Fam Phys- From, Krsta-Boneh F Henbasat Ashkanaz , Ribak I: Predictive Conan atmos of rnc ppomtyin fa ee od lead atin, Wallace Sass, tat Lead poisoning fm at restoration Pade nore wns exposure source andes a JExsiron Pathol Toxicol Oncol 11:7, W995" neh Cote SA, Laue G, eta: Extensive tat exposure in inant MP. Poze E Eis LD, Jensen WY: Conesttons ofead Rang it Pumbism. W Engl J Med 271346, toon Khalil Manesh F, Tartaglia 1, Gone snd anettopaiy IV. 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Cer Opin Pedr 173,197, tena, DIDHrocii aid DMA) Sn water-soluble Kan Wel hy. Ae Med Be Sa or ori Met EN. Pie AR: Act copes oe hazard Maemosialyis. Arch ism Med 129598 ton uzler AD, Schein AW: Coperindead ee homolytic anemia, Menge metetion of betils ame Ic segs 1970 ment Cink HM, Lev A Comings NG ee Hemolytic Danna evens ese N Engl J Med Mesto ss Deiss A, Lee GR, Catwrisht GE, Hemolytic anemia in Wilson's disease ‘Ann Inter Med 73:413, 4090 maattn PB: Wilson's disease prescaig with severe merelyticanas- mia. Ugeskr Laeger 1501229" tose moto N- hibeshi Hema Hi t a Falminane epatc faite Cane ied ina pregnant woman wi Wiese Gastroenterol Jpn 2669, 19h, ence 181463, 1973, Gaeron BS, Savio B, Raik B, Couts D, Mahony J: Heinz body