Drug-induced hemolytic anemia
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Drug-induced hemolytic anemia Presented by Onnicha Chaisetsumpan, MD. December 24, 2021
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Drug-induced hemolytic anemia
- 1. Drug-induced Hemolytic Anemia Onnicha Chaisetsumpan, MD Division of Allergy, Immunology and Rheumatology unit, Department of Pediatrics King Chulalongkorn Memorial Hospital
- 2. Overview •Introduction •Mechanism of drug-induced hemolytic anemia •Diagnosis and investigation •Management
- 3. Definition
- 4. Drug allergy, Middleton’s Allergy: Principle and practice, 9th edition
- 5. Altered peptide Repertoire model Pharmacologic – interaction model Hapten/Prohapten model Drug allergy, Middleton’s Allergy: Principle and practice, 9th edition Immunopathologic features of drug allergy
- 6. Gell and Cooombs classification Drug allergy, Middleton’s Allergy: Principle and practice, 9th edition
- 7. Introduction •Drug-induced immune hemolytic anemia (DIIHA) •Incidence is unknown •Estimated incidence about 1 per million of population •Drug-induced hemolytic anemia is quite rare • Drug-induced immune thrombocytopenia is more common, 10-18 cases per million • Neutropenia 2-15 cases per million Garratty G. Blood Rev. 2010;24(4-5143-50.
- 8. Introduction 1953 1956 1967 1989 2007 Snapper • Mephenytoin • Pancytopenia with hemolytic anemia with positive DAT Harris First to document history and serology of immune hemolytic anemia due to stibophen Dausset and Contu • Review literature on DIIHA • 34 cases due to 15 drugs 50 drugs well- documented as causes of IHA 125 drugs with reasonable evidence to suggest DIIHA Garratty G. Blood Rev. 2010;24(4-5143-50.
- 9. Introduction Arndt PA. Immunohematology. 2014;30(2):44-54. PMID: 25247622.
- 10. Drug-induced hemolytic anemia Drug-induced hemolytic anemia Immune-mediated Non-Immune-mediated Oxidant injury Methemoglobinemia Drug-dependent Drug-independent Garratty G. Blood Rev. 2010;24(4-5143-50.
- 11. Drug-induced immune hemolytic anemia • Immune destruction of RBC • Generally antibody-mediated Garratty G. Blood Rev. 2010;24(4-5143-50.
- 12. Drug-depended immune- mediated DIIHA •Hapten reaction •Immune complex formation •Protein adsorption Garratty G. Blood Rev. 2010;24(4-5143-50. Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9
- 13. Hapten reaction IgG antibody against drug Hemolysis by complement or phagocytosis Drug • Penicillin type • Drug remains present on RBC surface • Required for antibody binding • Limitation: most drugs do not form stable bond with RBC Garratty G. Blood Rev. 2010;24(4-5143-50. Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9
- 14. Immune complex • Drugs cause formation of immune complex • Bind to RBC and cause complement activation • Quinidine Drug Antibody against drug Carrier protein C3b receptors Hemolysis by complement Garratty G. Blood Rev. 2010;24(4-5143-50.
- 15. Passive adsorption •Nonimmunologic protein adsorption (NIPA) •Drugs modified the RBC membrane •Plasma proteins were adosrbed nonimmunologically •Cephalothin was the prototype drug for this mechanism Garratty G. Blood Rev. 2010;24(4-5143-50.
- 16. Nonimmunologic protein adsorption (NIPA) Garratty G. Blood Rev. 2010;24(4-5143-50.
- 17. • Autoimmune model • Drug induced autoantibody reacted with normal RBC • Similar to reactivity seen with autoantibodies found in idiopathic IgG warm AIHA • e.g. methyldopa Drug independent immune-mediated DIIHA Normal RBC antigen Hemolysis by phagocytosis Garratty G. Blood Rev. 2010;24(4-5143-50.
- 19. Proposed unifying hypothesis • Antibody to drug • Penicillin antibody • Antibody to mainly membrane components • May not need drug to be added to detect antibody • Drug-independent autoantibody • Antibody to drug and membrane components • Only react with neoantigen composed of drug and membrane protein Garratty G. Blood Rev. 2010;24(4-5143-50.
- 20. Drug-induced hemolytic anemia Drug-induced hemolytic anemia Immune-mediated Non-Immune-mediated Oxidant injury Methemoglobinemia Drug-dependent Drug-independent Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.
- 21. Oxidant injury • RBCs can be affected by oxidant injury from drugs • Interaction with hemoglobin and oxygen, leading to intracellular formation of H2O2 and other oxidizing radicals • G6PD deficiency • RBCs protected from oxidant injury by NADPH • G6PD deficiency increased susceptibility to oxidant drugs • Hemoglobin H disease G6PD deficiency Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.
- 22. Methemoglobinemia Decreased tissue oxygenation • Ferric heme cannot bind oxygen • Left-shifted hemoglobin-oxygen dissociation curve Hemolysis • Not directly harmful to RBC • Large oxidative stress, coverted to hemichromes à formation of Heinz bodies • Removal of membrane-attached Heinz bodies can produce hemolysis Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.
- 23. Diagnosis • First step in evaluating suspected drug- induced hemolytic anemia is to recognize signs and symptoms of hemolysis • Review history of exposure with focus on new medication, other possible drug or chemical exposures • Review medical record to determine timing of hemolysis (relative to initiation of new medicines) Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.
- 24. Diagnosis •Does the patient have hemolytic anemia? •Does the patient have a positive DAT? •Positive for IgG or C3 (or both) close to the time of observed hemolysis •If not tested until weeks later, DAT may be weak or negative •What drug(s) is (are) the patient taking now or recently? •Is there a temporal relationship between drug administration and hemolytic anemia? Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 25. Diagnosis • Peripheral blood smear • Determine likely causes and appropriate laboratory testing • Spherocytes or microspherocyte, MAHA blood pictures, bite cells • G6PD testing • If suspected oxidative hemolysis • May be negative in setting of severe hemolysis, repeat testing following recovery may be warranted Robert A, et al. Drug-induced hemolytic anemia. Uptodate 2021.
- 26. Direct coombs test • Positive DAT is consistent with immune hemolysis • No distinguish between DIIHA, AIHA unrelated to drug or alloimmune hemolysis • Negative DAT in massive acute intravascular hemolysis or transfusions before DAT is performed • Anti-IgG, anti-C3 Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 27. Drug-induced immune hemolytic anemia testing Drug-independent • Serologic reactivity without drug being present • Indistinguishable from idiopathic IgG warm autoantibiodies React with drug- treated RBCs React with untreated RBCs in the presence of solution of drug Best to follow techniques used in relevant report Useful to avoid future drug-induced hemolytic anemia and especially helpful in patients with acute-onset, unexplained hemolytic anemia Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 28. Drug-induced immune hemolytic anemia testing Sample from patient • Prefer sample from first observed in vivo hemolysis • Second sample (2-3 days after drug stopped) to detect true autoantibody reactivity or drug antibody reacting with a circulating drug • True autoantibody: persisent autoantibody • Drug-immune complex: autoantibody reactivity disappears when drug has cleared from patient’s circulation (1-2 days after drug stopped) Sample from drug • Drug under investigation should not be dissolved before sending • Caution in pediatric oral suspension formula due to hemolyze RBC • Isotonic solution of drug for use with RBCs (PBS, pH 7.1-7.4) Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 29. DIIHA testing: drug-treated RBCs • Negative control: • Normal serum (pooled or several individual serum and PBS) • Positive control whenever available • Drugs known to cause NIPA: positive control is tested at dilution of ≥ 1:20 1 drop of drug-treated RBCs or control untreated RBCs 2 drops of patient’s serum and control • Incubated at 37 oC for 1 hour • examined for hemolysis and agglutination 40 mg/ml Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 30. DIIHA testing: drug-treated RBCs Interpretation of results Definitive drug antibody • Reactivity of patient’s serum and eluate with drug-treated RBCs and no reactivity with untreated-RBCs • No reactivity of normal serum and PBS control • Reactivity of positive control, if available, with only the drug-treated RBCs Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 31. DIIHA testing: drug-treated RBCs Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 32. DIIHA testing: drug-treated RBCs Positive control: drug truly bounded to test RBCs Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 33. DIIHA testing: drug-treated RBCs Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 34. DIIHA testing: drug-treated RBCs Antiglobulin reactivity: NIPA (undiluted and diluted 1:20) Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 35. DIIHA testing: drug-treated RBCs • Direct agglutination of drug-treated RBCs, but not untreated- RBCs à low-titer antibody to drug • Widespread use of antibiotics in agriculture and environmental contamination = source of exposure to many drugs Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 36. Testing in the presence of the soluble drug • Testing untreated RBCs in the presence of a solution of the drug • Piperacillin and some second- and third-generation cephalosporins react by this method • 1 mg/ml solution of drug in PBS, pH 7 to be compatible with RBCs Untreated or enzyme- treated RBCs Drug Patient’s serum + Fresh normal serum for source of complement Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 37. Testing in the presence of the soluble drug Interpretation of results: Definitive drug antibody • Reactivity in the tests with patient’s serum plus drug and not reactivity in the control tests of patient’s serum plus PBS or with complement source without serum • No reactivity in any tests indicates no drug antibody is present Leger RM, et al. Immunohematology. 2014 Jan 1;30(2):85-94.
- 38. KCMH หลักการ Antigen-antibody detection ตรวจหา antibody ใน plasma คนไข้ โดยการทําปฏิกิริยากับ 1%cell ของเลือด group O ทีx coat ด้วยยาทีxสนใจใน gel test
- 39. KCMH DIIHA (lab hemato med) 1. ปัZนแยก Plasma ของคนไข้ออกมาเก็บไว้ และนํา RBC ของคนไข้ไปทําการล้างเซลล์ เพืZอกําจัด สิZงรบกวนออก 2. นํา RBC ของคนไข้มาทําเป็น 1% cell 3. ตรวจ direct antiglobulin test (DAT test) 4. เตรียม 1% cell group O ทีZ coat ด้วยยา • RBC group O ปัxนล้าง และนํามาผสมกับยาตัวทีxสนใจ + PBS • Incubate ทีx 37 oC 1 ชัxวโมง • นํามาปัxนตกและนํา RBC ทีx coat ยา มาทําเป็น 1% cell Drug e.g. Ceftriaxone 40mg/ml RBC group O Drug-treated RBC
- 40. KCMH DIIHA (lab hemato med) 5. เตรียม Eluate (ใช้ PRC ล้างเซลล์ทีZเหลือ นํามาทํา Elution เพืZอให้ได้ Eluate) 6. ใส่ Patient’s plasma, eluate, last wash, PBS, pooled normal plasma และ patient’s plasma (autoimmune) ผสมกับ 1% cell group O ทีZ coat ด้วย ยา และ untreated RBC 7. Incubate 37oC เป็นเวลา 15 นาที หลังจากนั‚นปัZน ด้วยเครืZอง ID-centrifuge 6S 10 นาที 8. อ่านผลจาก ID-cards และลงระดับความแรงของ ปฏิกิริยา
- 41. Drug-induced immune hemolytic anemia (DIIHA) test with Ceftriaxone • Patient’s plasma + Ceftriaxone coated RBCs = Positive 4+ • Eluate + Ceftriaxone coated RBCs = Positive 1+ • PBS + Ceftriaxone coated RBCs = negative • Pool normal plasma + Ceftriaxone coated RBCs = negative • Patient’s plasma + Patient’s RBC = negative
- 42. Drug-induced immune hemolytic anemia (DIIHA) test with Ceftriaxone
- 43. Characteristics of common DIIHAs • 42% anti-mircrobials • 16% NSAIDs, 13% anti-neoplastics, 6% anti-hypertensive/diuretics • Most commonly associated with fatal hemolysis was cefotetan (8%) and ceftriaxone (6%), particularly in young children Garratty G. Blood Rev. 2010;24(4-5143-50.
- 44. Cephalosporin •First generation cephalosporins caused positive DATs but rarely caused drug-induced immune hemolytic anemia • Cephalothin, cephalexin and cefazolin •Second and third generation cephalosporins caused DIIHA • Cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid, cefotetan, cefmetazole • Cefotaxime, cefoperazone, ceftriaxone, cefixime •No reports of DIIHA due to fourth generation cephalosporins Garratty G. Blood Rev. 2010;24(4-5143-50.
- 45. Cefotetan • Most common cause of drug- induced immune hemolytic anemia • Associated with prophylactic use of cefotetan (60% with surgery) • Only 18% documented history of previous cefotetan Garratty G. Blood Rev. 2010;24(4-5143-50.
- 46. Ceftriaxone •Second most common drug cause DIIHA •Acute and severe hemolytic anemia in children, 50% fatality •History of previous ceftriaxone therapy Garratty G. Blood Rev. 2010;24(4-5143-50.
- 47. Ceftriaxone-induced immune hemolytic anemia • Comprehesive literature review according to PRISMA • CIIHA: new onset or exacerbation of hemolytic anemia associated with administration of ceftriaxone and at least 1 of the following • New seroconversion from negative to positive DAT • Presence of drug-dependent anti-ceftriaxone antibody • Exclusion of other possible triggers such as other drugs known to cause hemolytic anemia Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.
- 48. Ceftriaxone-induced immune hemolytic anemia •Demographic data • Median age was 10 years (0.66-80 years), 70% children • 30% case fatality (27% children, 64% of children were fatal) •Ceftriaxone exposure • Previous ceftriaxone exposure 65% • 3% no prior exposure to ceftriaxone • Median number of ceftriaxone doses received during current episode = 4 • Elapsed time from initiation of trigger dose and symptoms was 40 minutes and 1 hours (range 5 minutes to 5.6 hours) Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.
- 49. Complication 32% presented with an initial, brief, self- limited hemolytic episode associated with earlier dose of ceftriaxone Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.
- 50. Frequency of laboratory findings • Anti-ceftriaxone antibody were positive 68% of cases • Not reported in 32% • 5 cases negative both DAT and antibody Neuman G, et al. Ann Pharmacother. 2014;48(12):1594-604.
- 51. Kapur G, et al. Pediatric blood & cancer. 2008 Jan;50(1):139-42.
- 52. Serologic characteristics 79 patients suspected DIIHA due to ceftriaxone, 1987-2010 Cases were screened via telephone to exclude those that did not fit possible DIIHA • No hemolysis • Hemolysis not temporally related to administration of drug • DAT was negative at time of hemolytic anemia Investigation • DATs: anti-IgG, anti-C3, anti-IgM, anti-IgA • Drug-treated RBC • Untreated or enzyme-treated RBC in presence of drug solution Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.
- 53. Drug-treated RBC Untreated RBC in the presence of drug solution Group O donor RBC Ceftriaxone 40 mg/ml prepared either PBS or sodium barbital buffer Incubate 40 1-2 hours at 37 oC 2 drops of patient’s serum One drop of treated or untreated RBC Incubate 1 hour 37 oC Test for hemolysis and agglutination Negative control= pool normal plasma Patient’s serum ± pool fresh plasma (complement) Ceftriaxone Untreated RBC 2 drops of patient’s serum 2 drops of ceftriaxone (1mg/ml in PBS) One drop of untreated group O RBC Incubate 1-2 hour 37 oC Test for hemolysis and agglutination Parallel test • PBS added to serum instead of ceftriaxone • Fresh normal serum instead of patient’s serum Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.
- 54. Results • Antibody to ceftriaxone were detected 25/79 (32%) of patients suspected of DIIHA caused by ceftriaxone • DATs • Performed 19/25 patients • 100% reacted with anti-C3 agent • 47% also reacted with anti-IgG • 22% reacted with anti-IgM, 6% reacted with anti-IgA (18/25 patients) Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.
- 55. • Drug-treated RBCs • 7/25 patients were tested against drug-treated RBCs • All either non-reactive (n=4) or equivalent reactivity (n=3) with untreated RBCs • Untreated RBCs in presence of ceftriaxone • 25/25 patients tested in presence of 1mg/ml ceftriaxone 100% ceftriaxone antibodies detected • Untreated RBC with no ceftriaxone added • 64% (16/25) patients’s serum reacted without ceftriaxone 50% weakly reactive, 50% stronger (2-4+) • Presences of circulating drug or drug-antidrug immune complexes in patient’s blood • Immunoglobulin • 9/14 IgM agglutinin, 2/14 additional IgG, 5/14 non-reactive or very weakly reactive Complement can usually be detected on patient’s RBC and IgM antibody detected in patient’s serum Arndt PA, et al. Transfusion. 2012 Mar;52(3):602-12.
- 56. Piperacillin • Piperacillin is often used in combination with tazobactam, beta- lactamase inhibitor (Tazocin, Zosyn) • Reactivity for two reasons • Antibody to piperacillin • Nonimmunologic protein adsorption due to BI component • Not reported: Antibody to BI component (tazobactam) Garratty G. Blood Rev. 2010;24(4-5143-50.
- 57. Other drugs reported DIIHA •Purine nucleoside analogues • Fludarabine and cladribine •Hydrocortisone • Case report of DIIHA due to hydrocortisone •DIIHA following transplantation • No definite data to support suggestions Garratty G. Blood Rev. 2010;24(4-5143-50.
- 58. Management •Discontinuation of presumed offending drug • Most cases, eliminating exposure to implicated drug is sufficient for management • Rate of recovery depends on rate of clearance of drug •Supportive treatment • Blood production transfusion in severe and symptomatic anemia • Hydration and dialysis • Presumptive treatment of other possible causes until the results of definitive diagnosis available Garratty G. Blood Rev. 2010;24(4-5143-50.
- 59. Drug discontinuation • 8/9 (89%) Children with ceftriaxone-induced hemolytic anemia whose ceftriaxone was stopped immediately, survived • Children without cessation of ceftriaxone treatment had mortality of 50% • Ceftriaxone therapy was continued in 8 patients • 4/8 patients died • 1 patients with repeated cardiorespiratory arrests, 1 patient with severe renal failure requiring 14 days of hemodialysis and 1 patient with severe neurological deficit Stop suspicious drug immediately 23 ceftriaxone-induced hemolytic anemia Leicht HB, et al. BMC Pharmacol Toxicol. 2018;19(1):67.
- 60. Management • Steroid • No proven benefit and no recommendation for steroid therpy • In general, reports of successful use of steroids are confounded by withdrawal of responsible drug at the same time • In case of drug-independent antibodies (autoantibodies), steroid therapy can be tried • IVIG • Evidence of intravascular hemolysis, like treatment of warm-type AIHA • Successfully used in child with severe ceftriaxone- induced hemolytic anemia • Plasmapheresis or plasma exchange • Remove drug-induced antibodies from serum • Drug adsorption-type DIIHA, severe renal failure • Eculizumab • Immune complex-type due to complement- mediated intravascular hemolysis • Complement inhibitor, hinder formation of membrane attack complex could be helpful • No report of the use of eculizumab in patients with DIIHA Leicht HB, et al. BMC Pharmacol Toxicol. 2018;19(1):67.
- 61. Re-exposure and cross-reactivity •Absolute contraindication for re-exposure of responsible drug for patient’s lifetime •Implicated drug should be clearly noted in patient’s medical record •Application of drugs of same substance class should be considered very carefully •Interactions of drug-dependent antibody, cross-reactivity •Interactions to drug or drug metabolite (more probable cross-reaction to drugs of same substance class) Garratty G. Blood Rev. 2010;24(4-5143-50.
- 62. Cross-reactivity Garratty G. Hematology Am Soc Hematol Educ Program. 2009:73-9
- 63. Antibodies • 7 cefotetan antibodies to react with cefotetan-treated RBCs and untreated RBCs in the presence of cefotetan • 1 ceftriaxone antibody to react with untreated RBCs in the presence of ceftriaxone Drug • Cefotetan disodium • Ceftriaxone sodium • Cephalothin sodium • Cefazolin sodium • Cefamandole nafate • Cefoxitin sodium • Cefotaxime sodium • Cefoperazone sodium • Penicillin G potassium • Ceftazidime • Cefepime hydrochloride Antibody detection • Drug-treated RBC • Immune complex method • Hapten-inhibiton studies Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.
- 64. • Cephalothin, cefoxitin-treated RBCs (all) • Weak reactivity with penicillin-treated RBCs Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.
- 65. • Cefotetan • 1 sample of cetotetan antibody showed reactivity in antiglobulin test with cephalothin • Ceftriaxone • Hemolyzed only in the presence of cefotaxime • Weak agglutination/antiglobulin test in the presence of cetotaxime, cefamandole and cefoperazone Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.
- 66. •Serum samples containing cefotetam antibodies showed • Cross-reactivity with cephalothin and cefoxitin • Much lesser extent with penicillin and ceftazidime •Ceftriaxone antibodies showed • Very weak cross-reactivity with cefotaxime, cefamandole and cefoperazone •No data to determine in vivo reactivity Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.
- 67. • One reported negative reactions with cefotaxime-coated RBCs, 3 reported negative reactions with cefazolin • Single reports of positive reactions with cefadroxil, cephalexin, ceftriaxone, cephalothin • Two reports of positive and two reports of negative reactions with penicillin Arndt PA, et al. American journal of clinical pathology. 2002 Aug 1;118(2):256-62.
- 68. Cross-reactivity of ceftriaxone-DIIHA • Cross-reactivity in structurally similar structures of cephalosporins • Antibody appeared to cross-react with cefotaxime and cefopodoxime proxetil • Serological work-up must include tests to determine cross-reactivity of ceftraxone-dependent antibodies to avoid hemolysis due to administration of structually realted cephalosporins in affected patients Seltsam A, et al. Intensive care medicine. 2000 Sep;26(9):1390-4.
- 69. Take home messages • Drug-induced immune hemolytic anemia (DIIHA) is rare but life-threatening condition • Drug-dependent, drug-independent • The most frequent drugs associated with DIIHA are cefotetan, ceftriaxone and piperacillin • Early and correct diagnosis of DIIHA is crucial • Withdrawal of causative drug is essential for patient prognosis