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Hemolytic anemia due to drugs and toxins

Author
Stanley L Schrier, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Drugs are an uncommon cause of hemolytic anemia, but when a patient develops hemolytic anemia in the setting of a drug, it is important to determine whether the drug is responsible. Additional challenges in patient management include identifying which drug is most likely to be the cause of the anemia, and whether any additional interventions besides stopping the drug will benefit the patient.

This topic discusses types of drug-induced hemolysis and hemolytic anemia, the patient evaluation, and management interventions. Separate topic reviews address the general approach to evaluating anemia in adults, the diagnosis of hemolytic anemia, and causes of hemolytic anemia other than drugs.

Anemia evaluation (child) – (See "Approach to the child with anemia".)

Anemia evaluation (adult) – (See "Approach to the adult patient with anemia".)

Hemolytic anemia diagnosis (child) – (See "Overview of hemolytic anemias in children".)

                                           
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Literature review current through: Nov 2017. | This topic last updated: Oct 02, 2017.
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References
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  1. Misra HP, Fridovich I. The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 1972; 247:6960.
  2. Hebbel RP, Eaton JW. Pathobiology of heme interaction with the erythrocyte membrane. Semin Hematol 1989; 26:136.
  3. Chiu D, Lubin B. Oxidative hemoglobin denaturation and RBC destruction: the effect of heme on red cell membranes. Semin Hematol 1989; 26:128.
  4. Darling R, Roughton F. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol 1942; 137:56.
  5. Chan TK, Chan WC, Weed RI. Erythrocyte hemighosts: a hallmark of severe oxidative injury in vivo. Br J Haematol 1982; 50:575.
  6. Yoo D, Lessin LS. Drug-associated "bite cell" hemolytic anemia. Am J Med 1992; 92:243.
  7. Low FM, Hampton MB, Winterbourn CC. Peroxiredoxin 2 and peroxide metabolism in the erythrocyte. Antioxid Redox Signal 2008; 10:1621.
  8. Hebbel RP. Auto-oxidation and a membrane-associated 'Fenton reagent': a possible explanation for development of membrane lesions in sickle erythrocytes. Clin Haematol 1985; 14:129.
  9. Harris JW. Studies on the mechanism of a drug-induced hemolytic anemia. J Lab Clin Med 1954; 44:809.
  10. Johnson ST, Fueger JT, Gottschall JL. One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia--a new paradigm. Transfusion 2007; 47:697.
  11. Garratty G. Immune hemolytic anemia associated with drug therapy. Blood Rev 2010; 24:143.
  12. Arndt PA, Garratty G. The changing spectrum of drug-induced immune hemolytic anemia. Semin Hematol 2005; 42:137.
  13. Garbe E, Andersohn F, Bronder E, et al. Drug induced immune haemolytic anaemia in the Berlin Case-Control Surveillance Study. Br J Haematol 2011; 154:644.
  14. Mayer B, Bartolmäs T, Yürek S, Salama A. Variability of Findings in Drug-Induced Immune Haemolytic Anaemia: Experience over 20 Years in a Single Centre. Transfus Med Hemother 2015; 42:333.
  15. Worlledge SM, Carstairs KC, Dacie JV. Autoimmune haemolytic anaemia associated with alpha-methyldopa therapy. Lancet 1966; 2:135.
  16. Lo Buglio AF, Jandl JH. The nature of the alpha-methyl-dopa red-cell antibody. N Engl J Med 1967; 275:658.
  17. Petz LD, Fudenberg HH. Coombs-positive hemolytic anemia caused by penicillin administration. N Engl J Med 1966; 274:171.
  18. Logue GL, Boyd AE III, Rosse WF. Chlorpropamide-induced immune hemolytic anemia. N Engl J Med 1970; 83:900.
  19. Salama A, Mueller-Eckhardt C. The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N Engl J Med 1985; 313:469.
  20. Salama A, Mueller-Eckhardt C. On the mechanisms of sensitization and attachment of antibodies to RBC in drug-induced immune hemolytic anemia. Blood 1987; 69:1006.
  21. Salama A, Santoso S, Mueller-Eckhardt C. Antigenic determinants responsible for the reactions of drug-dependent antibodies with blood cells. Br J Haematol 1991; 78:535.
  22. Arndt PA, Leger RM, Garratty G. Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia. Transfusion 2012; 52:602.
  23. Radin AI, Buckley P, Duffy TP. Interferon therapy for agnogenic myeloid metaplasia complicated by immune hemolytic anemia. Hematol Pathol 1991; 5:83.
  24. Stavroyianni N, Stamatopoulos K, Viniou N, et al. Autoimmune hemolytic anemia during alpha-interferon treatment in a patient with chronic myelogenous leukemia. Leuk Res 2001; 25:1097.
  25. Cauli C, Serra G, Chessa L, et al. Severe autoimmune hemolytic anemia in a patient with chronic hepatitis C during treatment with peginterferon alfa-2a and ribavirin. Haematologica 2006; 91:ECR26.
  26. Gentile I, Viola C, Reynaud L, et al. Hemolytic anemia during pegylated IFN-alpha2b plus ribavirin treatment for chronic hepatitis C: ribavirin is not always the culprit. J Interferon Cytokine Res 2005; 25:283.
  27. Kazuta Y, Watanabe N, Sagawa K, et al. A case of autoimmune hemolytic anemia induced by IFN-beta therapy for type-C chronic hepatitis. Fukushima J Med Sci 1995; 41:43.
  28. Manzler AD, Schreiner AW. Copper-induced acute hemolytic anemia. A new complication of hemodialysis. Ann Intern Med 1970; 73:409.
  29. Eastwood JB, Phillips ME, Minty P, et al. Heparin inactivation, acidosis and copper poisoning due to presumed acid contamination of water in a hemodialysis unit. Clin Nephrol 1983; 20:197.
  30. Steindl P, Ferenci P, Dienes HP, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113:212.
  31. Robitaille GA, Piscatelli RL, Majeski EJ, Gelehrter TD. Hemolytic anemia in Wilson's disease. A report of three cases with transient increase in hemoglobin A2. JAMA 1977; 237:2402.
  32. Forman SJ, Kumar KS, Redeker AG, Hochstein P. Hemolytic anemia in Wilson disease: clinical findings and biochemical mechanisms. Am J Hematol 1980; 9:269.
  33. Kraut JR, Yogev R. Fatal fulminant hepatitis with hemolysis in Wilson's disease. Criteria for diagnosis. Clin Pediatr (Phila) 1984; 23:637.
  34. Kiss JE, Berman D, Van Thiel D. Effective removal of copper by plasma exchange in fulminant Wilson's disease. Transfusion 1998; 38:327.
  35. Valsami S, Stamoulis K, Lydataki E, Fountoulaki-Paparizos L. Acute copper sulphate poisoning: a forgotten cause of severe intravascular haemolysis. Br J Haematol 2012; 156:294.
  36. Yang CC, Wu ML, Deng JF. Prolonged hemolysis and methemoglobinemia following organic copper fungicide ingestion. Vet Hum Toxicol 2004; 46:321.
  37. Sansinanea AS, Cerone SI, Elperding A, Auza N. Glucose-6-phosphate dehydrogenase activity in erythrocytes from chronically copper-poisoned sheep. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 1996; 114:197.
  38. Walsh FM, Crosson FJ, Bayley M, et al. Acute copper intoxication. Pathophysiology and therapy with a case report. Am J Dis Child 1977; 131:149.
  39. Walshe JM. The acute haemolytic syndrome in Wilson's disease--a review of 22 patients. QJM 2013; 106:1003.
  40. Sacchi S, Kantarjian H, O'Brien S, et al. Immune-mediated and unusual complications during interferon alfa therapy in chronic myelogenous leukemia. J Clin Oncol 1995; 13:2401.
  41. Takase K, Nakano T, Hamada M, et al. Hemolytic anemia provoked by recombinant alpha-interferon. J Gastroenterol 1995; 30:795.
  42. Salama A, Mueller-Eckhardt C, Kiefel V. Effect of intravenous immunoglobulin in immune thrombocytopenia. Lancet 1983; 2:193.
  43. Nakamura S, Yoshida T, Ohtake S, Matsuda T. Hemolysis due to high-dose intravenous gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura. Acta Haematol 1986; 76:115.
  44. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986; 26:410.
  45. Brox AG, Cournoyer D, Sternbach M, Spurll G. Hemolytic anemia following intravenous gamma globulin administration. Am J Med 1987; 82:633.
  46. Comenzo RL, Malachowski ME, Meissner HC, et al. Immune hemolysis, disseminated intravascular coagulation, and serum sickness after large doses of immune globulin given intravenously for Kawasaki disease. J Pediatr 1992; 120:926.
  47. Schumacher MJ, Schmidt JO, Egen NB, Dillon KA. Biochemical variability of venoms from individual European and Africanized honeybees (Apis mellifera). J Allergy Clin Immunol 1992; 90:59.
  48. Williams ST, Khare VK, Johnston GA, Blackall DP. Severe intravascular hemolysis associated with brown recluse spider envenomation. A report of two cases and review of the literature. Am J Clin Pathol 1995; 104:463.
  49. Murray LM, Seger DL. Hemolytic anemia following a presumptive brown recluse spider bite. J Toxicol Clin Toxicol 1994; 32:451.
  50. Blackall DP. Transfusion medicine illustrated: intravascular hemolysis with brown recluse spider envenomation. Transfusion 2004; 44:1543.
  51. McDade J, Aygun B, Ware RE. Brown recluse spider (Loxosceles reclusa) envenomation leading to acute hemolytic anemia in six adolescents. J Pediatr 2010; 156:155.
  52. Raza S, Shortridge JR, Kodali MK, et al. Severe haemolytic anaemia with erythrophagocytosis following the bite of a brown recluse spider. Br J Haematol 2014; 167:1.
  53. Elbahlawan LM, Stidham GL, Bugnitz MC, et al. Severe systemic reaction to Loxosceles reclusa spider bites in a pediatric population. Pediatr Emerg Care 2005; 21:177.
  54. Anderson PC. Spider bites in the United States. Dermatol Clin 1997; 15:307.
  55. Lane DR, Youse JS. Coombs-positive hemolytic anemia secondary to brown recluse spider bite: a review of the literature and discussion of treatment. Cutis 2004; 74:341.
  56. Tambourgi DV, Morgan BP, de Andrade RM, et al. Loxosceles intermedia spider envenomation induces activation of an endogenous metalloproteinase, resulting in cleavage of glycophorins from the erythrocyte surface and facilitating complement-mediated lysis. Blood 2000; 95:683.
  57. Tambourgi DV, De Sousa Da Silva M, Billington SJ, et al. Mechanism of induction of complement susceptibility of erythrocytes by spider and bacterial sphingomyelinases. Immunology 2002; 107:93.
  58. Chaves-Moreira D, Chaim OM, Sade YB, et al. Identification of a direct hemolytic effect dependent on the catalytic activity induced by phospholipase-D (dermonecrotic toxin) from brown spider venom. J Cell Biochem 2009; 107:655.
  59. Harvey AL, Hider RC, Khader F. Effect of phospholipase A on actions of cobra venom cardiotoxins on erythrocytes and skeletal muscle. Biochim Biophys Acta 1983; 728:215.
  60. Gibly RL, Walter FG, Nowlin SW, Berg RA. Intravascular hemolysis associated with North American crotalid envenomation. J Toxicol Clin Toxicol 1998; 36:337.
  61. León G, Rodríguez MA, Rucavado A, et al. Anti-human erythrocyte antibodies in horse-derived antivenoms used in the treatment of snakebite envenomations. Biologicals 2007; 35:5.
  62. Angus BJ, Chotivanich K, Udomsangpetch R, White NJ. In vivo removal of malaria parasites from red blood cells without their destruction in acute falciparum malaria. Blood 1997; 90:2037.
  63. Newton PN, Chotivanich K, Chierakul W, et al. A comparison of the in vivo kinetics of Plasmodium falciparum ring-infected erythrocyte surface antigen-positive and -negative erythrocytes. Blood 2001; 98:450.
  64. Jauréguiberry S, Ndour PA, Roussel C, et al. Postartesunate delayed hemolysis is a predictable event related to the lifesaving effect of artemisinins. Blood 2014; 124:167.
  65. Centers for Disease Control and Prevention (CDC). Published reports of delayed hemolytic anemia after treatment with artesunate for severe malaria--worldwide, 2010-2012. MMWR Morb Mortal Wkly Rep 2013; 62:5.
  66. Rolling T, Agbenyega T, Issifou S, et al. Delayed hemolysis after treatment with parenteral artesunate in African children with severe malaria--a double-center prospective study. J Infect Dis 2014; 209:1921.
  67. Bell MD. Sudden death due to intravascular hemolysis after bladder irrigation with distilled water. J Forensic Sci 1992; 37:1401.
  68. Aepli R. [Physiopathology of accidental drowning]. Schweiz Med Wochenschr 1975; 105:161.
  69. Conn AW, Miyasaka K, Katayama M, et al. A canine study of cold water drowning in fresh versus salt water. Crit Care Med 1995; 23:2029.
  70. Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA 1980; 243:1909.
  71. Safrin S, Finkelstein DM, Feinberg J, et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group. Ann Intern Med 1996; 124:792.
  72. Beutler E. G6PD deficiency. Blood 1994; 84:3613.
  73. Wason S, Detsky AS, Platt OS, Lovejoy FH Jr. Isobutyl nitrite toxicity by ingestion. Ann Intern Med 1980; 92:637.
  74. Bogart L, Bonsignore J, Carvalho A. Massive hemolysis following inhalation of volatile nitrites. Am J Hematol 1986; 22:327.
  75. Romeril KR, Concannon AJ. Heinz body haemolytic anaemia after sniffing volatile nitrites. Med J Aust 1981; 1:302.
  76. Beaupre SR, Schiffman FJ. Rush hemolysis. A 'bite-cell' hemolytic anemia associated with volatile liquid nitrite use. Arch Fam Med 1994; 3:545.
  77. Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia. Treatment issues. Drug Saf 1996; 14:394.
  78. Brandes JC, Bufill JA, Pisciotta AV. Amyl nitrite-induced hemolytic anemia. Am J Med 1989; 86:252.
  79. Rodriguez LF, Smolik LM, Zbehlik AJ. Benzocaine-induced methemoglobinemia: report of a severe reaction and review of the literature. Ann Pharmacother 1994; 28:643.
  80. Ferraro-Borgida MJ, Mulhern SA, DeMeo MO, Bayer MJ. Methemoglobinemia from perineal application of an anesthetic cream. Ann Emerg Med 1996; 27:785.
  81. Collins JF. Methemoglobinemia as a complication of 20% benzocaine spray for endoscopy. Gastroenterology 1990; 98:211.
  82. Marcovitz PA, Williamson BD, Armstrong WF. Toxic methemoglobinemia caused by topical anesthetic given before transesophageal echocardiography. J Am Soc Echocardiogr 1991; 4:615.
  83. Karim A, Ahmed S, Siddiqui R, Mattana J. Methemoglobinemia complicating topical lidocaine used during endoscopic procedures. Am J Med 2001; 111:150.
  84. Guertler AT, Pearce WA. A prospective evaluation of benzocaine-associated methemoglobinemia in human beings. Ann Emerg Med 1994; 24:626.
  85. Nathan DM, Siegel AJ, Bunn HF. Acute methemoglobinemia and hemolytic anemia with phenazopyridine: possible relation to acute renal failure. Arch Intern Med 1977; 137:1636.
  86. Fincher ME, Campbell HT. Methemoglobinemia and hemolytic anemia after phenazopyridine hydrochloride (Pyridium) administration in end-stage renal disease. South Med J 1989; 82:372.
  87. Siddiqui MA. Chronic severe hemolytic anemia from phenazopyridine. Ann Intern Med 1995; 122:156; author reply 157.
  88. Ward KE, McCarthy MW. Dapsone-induced methemoglobinemia. Ann Pharmacother 1998; 32:549.
  89. Coleman MD. Dapsone toxicity: some current perspectives. Gen Pharmacol 1995; 26:1461.
  90. Sin DD, Shafran SD. Dapsone- and primaquine-induced methemoglobinemia in HIV-infected individuals. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12:477.
  91. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990; 323:776.
  92. Jahoor F, Jackson A, Gazzard B, et al. Erythrocyte glutathione deficiency in symptom-free HIV infection is associated with decreased synthesis rate. Am J Physiol 1999; 276:E205.
  93. SPRIGGS AI, SMITH RS, GRIFFITH H, TRUELOVE SC. Heinz-body anaemia due to salicylazosulphapyridine. Lancet 1958; 1:1039.
  94. Neunert CE, Paranjape GS, Cameron S, Rogers ZR. Intravascular hemolysis following low dose daily rifampin. Pediatr Blood Cancer 2008; 51:821.
  95. Ahrens N, Genth R, Salama A. Belated diagnosis in three patients with rifampicin-induced immune haemolytic anaemia. Br J Haematol 2002; 117:441.
  96. Fowler BA, Weissberg JB. Arsine poisoning. N Engl J Med 1974; 291:1171.
  97. Kleinfeld MJ. Arsine poisoning. J Occup Med 1980; 22:820.
  98. McCarthy LJ, Danielson C, Houseworth J, et al. Transfusion medicine illustrated. Black plasma resulting from inhalation of arsine gas. Transfusion 2006; 46:1267.
  99. Blair PC, Thompson MB, Bechtold M, et al. Evidence for oxidative damage to red blood cells in mice induced by arsine gas. Toxicology 1990; 63:25.
  100. Winski SL, Barber DS, Rael LT, Carter DE. Sequence of toxic events in arsine-induced hemolysis in vitro: implications for the mechanism of toxicity in human erythrocytes. Fundam Appl Toxicol 1997; 38:123.
  101. Ng LL, NaiK RB, Polak A. Paraquat ingestion with methaemoglobinaemia treated with methylene blue. Br Med J (Clin Res Ed) 1982; 284:1445.
  102. Casey PB, Buckley BM, Vale JA. Methemoglobinemia following ingestion of a monolinuron/paraquat herbicide (Gramonol). J Toxicol Clin Toxicol 1994; 32:185.
  103. Danielson C, Houseworth J, Skipworth E, et al. Arsine toxicity treated with red blood cell and plasma exchanges. Transfusion 2006; 46:1576.
  104. GOLUBOFF N, WHEATON R. Methylene blue induced cyanosis and acute hemolytic anemia complicating the treatment of methemoglobinemia. J Pediatr 1961; 58:86.
  105. Harvey JW, Keitt AS. Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia. Br J Haematol 1983; 54:29.
  106. Coleman MD, Scott AK, Breckenridge AM, Park BK. The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man. Br J Clin Pharmacol 1990; 30:761.
  107. Coleman MD, Rhodes LE, Scott AK, et al. The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients. Br J Clin Pharmacol 1992; 34:244.
  108. Rosen PJ, Johnson C, McGehee WG, Beutler E. Failure of methylene blue treatment in toxic methemoglobinemia. Association with glucose-6-phosphate dehydrogenase deficiency. Ann Intern Med 1971; 75:83.
  109. Goldstein GM, Doull J. Treatment of nitrite-induced methemoglobinemia with hyperbaric oxygen. Proc Soc Exp Biol Med 1971; 138:137.