Drug induced Hemolytic Anemia - Clinicals, Diagnosis, and Management

Hematology

Clinicals - History

Fact Explanation
History of drug use Hemolytic Anemia is a condition where there is a destruction of red blood cells prematurely leading to anaemia with release of bilirubin in to the circulation. There are main 2 types of haemolytic anaemia: acquired and hereditary. There are also different types of acquired haemolytic anaemia such as immune mediated, infection induced, microangiopathic haemolytic anaemia and hereditary haemolytic anaemia such as glucose 6 phosphate deficiency, pyruvate kinase deficiency, hereditary spherocytosis and haemoglobinopathies. Drug induced haemolytic anaemia can be immune mediated where there is formation of autoantibodies against the red blood cell membrane after penicillin or immune complex formation after quinine therapy. It may be drug-dependent or drug-independent. Anaemia can be triggered by drugs such as primaquine, sulfonamide and aspirin in people with glucose 6 phosphate deficiency. Drugs also can trigger the anaemia in auto immune haemolytic anaemia. Eg:-Penicillin produces large amounts of penicillin antibodies , third-generation cephalosporins methyldopa, β-lactamase inhibitors nonsteroidal anti-inflammatory agents, levaquin, oxaliplatin History of drug use
Hemolytic Anemia is a condition where there is a destruction of red blood cells prematurely leading to anaemia with release of bilirubin in to the circulation. There are main 2 types of haemolytic anaemia: acquired and hereditary. There are also different types of acquired haemolytic anaemia such as immune mediated, infection induced, microangiopathic haemolytic anaemia and hereditary haemolytic anaemia such as glucose 6 phosphate deficiency, pyruvate kinase deficiency, hereditary spherocytosis and haemoglobinopathies. Drug induced haemolytic anaemia can be immune mediated where there is formation of autoantibodies against the red blood cell membrane after penicillin or immune complex formation after quinine therapy. It may be drug-dependent or drug-independent. Anaemia can be triggered by drugs such as primaquine, sulfonamide and aspirin in people with glucose 6 phosphate deficiency. Drugs also can trigger the anaemia in auto immune haemolytic anaemia. Eg:-Penicillin produces large amounts of penicillin antibodies , third-generation cephalosporins methyldopa, β-lactamase inhibitors nonsteroidal anti-inflammatory agents, levaquin, oxaliplatin
Past history and family history of similar episodes Glucose 6 phosphate dehydrogenase deficiency is a main red blood cell enzyme defect with X linked inheritance. In G6PD deficiency, people are mostly asymptomatic and develop anaemia during an oxidative stress. They develop symptoms after above mentioned drugs as production of the glutathione is declining. In cold autoimmune haemolytic anaemia, the episodes can be triggered by infections such as mycoplasma and Epstein bar virus, and certain diseases like SLE, lymphoma and leukaemia. IgM antibodies bind at <4Centigrades, causing activation of red cell surface compliment. Past history and family history of similar episodes
Glucose 6 phosphate dehydrogenase deficiency is a main red blood cell enzyme defect with X linked inheritance. In G6PD deficiency, people are mostly asymptomatic and develop anaemia during an oxidative stress. They develop symptoms after above mentioned drugs as production of the glutathione is declining. In cold autoimmune haemolytic anaemia, the episodes can be triggered by infections such as mycoplasma and Epstein bar virus, and certain diseases like SLE, lymphoma and leukaemia. IgM antibodies bind at <4Centigrades, causing activation of red cell surface compliment.
Shortness of breath Exertional dyspnoea can occur due to the anaemia especially in people with heart disease. Shortness of breath
Exertional dyspnoea can occur due to the anaemia especially in people with heart disease.
Lethargy and malaise Anaemia causes reduced blood oxygenation, leading to reduced supply of oxygen to the energy production. Therefore they feel lack of energy. Lethargy and malaise
Anaemia causes reduced blood oxygenation, leading to reduced supply of oxygen to the energy production. Therefore they feel lack of energy.
Right hypochondrial pain May be present due to associated gallstones due to high level of bilirubin in the blood. Right hypochondrial pain
May be present due to associated gallstones due to high level of bilirubin in the blood.
Dark urine Suggestive of intravascular haemolysis. Dark urine
Suggestive of intravascular haemolysis.
History of diabetes mellitus Methformin can cause hemolysis after 9 to 14 days of starting the treatment. This may be due to the formation of an antibody against the erythrocyte-drug complex. History of diabetes mellitus
Methformin can cause hemolysis after 9 to 14 days of starting the treatment. This may be due to the formation of an antibody against the erythrocyte-drug complex.
Intravenous Rh (D) immune globulin This is used for the treatment of immune thrombocytopenic purpura and it can cause mild hemolysis. Intravenous Rh (D) immune globulin
This is used for the treatment of immune thrombocytopenic purpura and it can cause mild hemolysis.

Clinicals - Examination

Fact Explanation
Pallor Haemogloin level goes down during an attack, patient develops anaemia due to red cell destruction. Pallor
Haemogloin level goes down during an attack, patient develops anaemia due to red cell destruction.
Jaundice Haemolysis of red blood cells releases bilirubin in to the blood causing elevation of unconjugated bilirubin. This accumulated bilirubin causes yellowish discolouration of eyes and mucous membranes. Jaundice
Haemolysis of red blood cells releases bilirubin in to the blood causing elevation of unconjugated bilirubin. This accumulated bilirubin causes yellowish discolouration of eyes and mucous membranes.
Right hypochondrial tenderness If associated with gall stones due to high level of bilirubin in the blood. Right hypochondrial tenderness
If associated with gall stones due to high level of bilirubin in the blood.
Splenomegaly Autoimmune haemolytic anaemia causes extravascular haemolysis causing splenomegaly. Splenomegaly
Autoimmune haemolytic anaemia causes extravascular haemolysis causing splenomegaly.
Dyspnea Patients can develop progressive dyspnea. This can even ends up with fatal respiratory arrests. Dyspnea
Patients can develop progressive dyspnea. This can even ends up with fatal respiratory arrests.

Investigations - Diagnosis

Fact Explanation
Full blood count Anaemia causes lowering of haemoglobin level, pack cell volume and red cell count. Mean corpuscular volume and mean corpuscular haemoglobin is normal as it is a normocytic normochromic anaemia. Blood film may show leucopenia and eosinophilia in certain occasions. Full blood count
Anaemia causes lowering of haemoglobin level, pack cell volume and red cell count. Mean corpuscular volume and mean corpuscular haemoglobin is normal as it is a normocytic normochromic anaemia. Blood film may show leucopenia and eosinophilia in certain occasions.
Blood picture Red cells are normal in size as this causes normocytic normochromic type of a blood picture. Glucose 6 phosphate dehydrogenase deficiency is the most common form of haemolytic anaemia induced by the drugs. There will be abnormal red blood cells in G6PD deficiency like blister cells and bite cells. Blood picture
Red cells are normal in size as this causes normocytic normochromic type of a blood picture. Glucose 6 phosphate dehydrogenase deficiency is the most common form of haemolytic anaemia induced by the drugs. There will be abnormal red blood cells in G6PD deficiency like blister cells and bite cells.
Reticulocyte count Reticulocyte count is increased. Haemolysis causes ineffective erythropoiesis. Reticulocyte count
Reticulocyte count is increased. Haemolysis causes ineffective erythropoiesis.
Unconjugated bilirubin Haemolysis of red blood cells releases bilirubin in to the blood causing elevation of unconjugated bilirubin. Unconjugated bilirubin
Haemolysis of red blood cells releases bilirubin in to the blood causing elevation of unconjugated bilirubin.
Direct coomb’s test Positive in autoimmune haemolytic anaemia and negative in other drug induced haemolytic anaemias. Direct coomb’s test
Positive in autoimmune haemolytic anaemia and negative in other drug induced haemolytic anaemias.
Enzyme assay Glucose 6 phosphate dehydrogenase enzyme can be assessed after 8 weeks of attack, it is not done during the acute attack as false normal results can be there due to the young red blood cells already there in the circulation. Enzyme assay
Glucose 6 phosphate dehydrogenase enzyme can be assessed after 8 weeks of attack, it is not done during the acute attack as false normal results can be there due to the young red blood cells already there in the circulation.
Free IgG antipenicillin antibody This is found in most patients who developed haemolysis following penicillin therapy. Free IgG antipenicillin antibody
This is found in most patients who developed haemolysis following penicillin therapy.

Investigations - Management

Fact Explanation
Full blood count Haemoglobin level is monitored with the time to see the clinical improvement after avoiding the offending agent. Full blood count
Haemoglobin level is monitored with the time to see the clinical improvement after avoiding the offending agent.
Direct coomb's test Will become less strongly positive with the avoidance of the precipitating cause/drug. Direct coomb's test
Will become less strongly positive with the avoidance of the precipitating cause/drug.
Full blood count Sometimes, haemolysis is triggered by the infections such as parvovirus B19, mycoplasma and Epstein bar virus and other. They will have elevated lymphocytes in viral infections. Full blood count
Sometimes, haemolysis is triggered by the infections such as parvovirus B19, mycoplasma and Epstein bar virus and other. They will have elevated lymphocytes in viral infections.
Fluorescent spot test, the spectrophotometric assay, and the cytochemical assay Patients should be screened for G6PD deficiency before treatment with antimaarial drugs and other haemolytic agents where possible. Some of these tests use to screen are fluorescent spot test, the spectrophotometric assay, and the cytochemical assay. Fluorescent spot test is good at detecting hemizygous males and homozygous females, but is unreliable for the detecting heterozygous females. Fluorescent spot test, the spectrophotometric assay, and the cytochemical assay
Patients should be screened for G6PD deficiency before treatment with antimaarial drugs and other haemolytic agents where possible. Some of these tests use to screen are fluorescent spot test, the spectrophotometric assay, and the cytochemical assay. Fluorescent spot test is good at detecting hemizygous males and homozygous females, but is unreliable for the detecting heterozygous females.
Thick and thin films for malaria There can be haemoglobinuria causing black water fever in malaria. Thick and thin films for malaria
There can be haemoglobinuria causing black water fever in malaria.

Management - Supportive

Fact Explanation
Supportive treatment Patient has to be kept warm in cold autoimmune haemolytic anaemia. Red cell transfusion may be needed in some occasions with severe aanemia. Supportive treatment
Patient has to be kept warm in cold autoimmune haemolytic anaemia. Red cell transfusion may be needed in some occasions with severe aanemia.
Avoidance of precipitants Drugs causing hemolysis such as penicillin, primaquine, sulfonamide and aspirin have to be avoided where possible. Penicillin can be replaced by drugs like erythromycin where possible. Avoidance of precipitants
Drugs causing hemolysis such as penicillin, primaquine, sulfonamide and aspirin have to be avoided where possible. Penicillin can be replaced by drugs like erythromycin where possible.
Screening before the hemolytic agents Patients should be screened for G6PD deficiency before treatment with antimalarial drugs and other haemolytic agents where possible. Some of these tests use to screen are fluorescent spot test, the spectrophotometric assay, and the cytochemical assay. Screening before the hemolytic agents
Patients should be screened for G6PD deficiency before treatment with antimalarial drugs and other haemolytic agents where possible. Some of these tests use to screen are fluorescent spot test, the spectrophotometric assay, and the cytochemical assay.

Management - Specific

Fact Explanation
Steroids/immunosuppressants These drugs can be used to treat warm autoimmune haemolytic anaemia. Methylprednisolone 1 mg kg–1 can be used to treat the autoimmune haemolytic anaemia. Steroids/immunosuppressants
These drugs can be used to treat warm autoimmune haemolytic anaemia. Methylprednisolone 1 mg kg–1 can be used to treat the autoimmune haemolytic anaemia.
Chlorambucil Used for the treatment of cold autoimmune haemolytic anaemia. This is an alkylating agent used for the autoimmune conditions. Chlorambucil
Used for the treatment of cold autoimmune haemolytic anaemia. This is an alkylating agent used for the autoimmune conditions.
Plasmapheresis and IV immunoglobulin Can be used in autoimmune hemolytic anaemia. Plasmapheresis and IV immunoglobulin
Can be used in autoimmune hemolytic anaemia.
Anti B cell therapy Rituximab , a chimeric anti CD20 monoclonal antibody, can be used to lower the progression of hemolytic process, through its inhibitory action on B lymphocytes. This is used in refractory autoimmune hemolysis and may lead to long lasting remission. Anti B cell therapy
Rituximab , a chimeric anti CD20 monoclonal antibody, can be used to lower the progression of hemolytic process, through its inhibitory action on B lymphocytes. This is used in refractory autoimmune hemolysis and may lead to long lasting remission.

Concise, fact-based medical articles to refresh your knowledge

Access a wealth of content and skim through a smartly presented catalog of diseases and conditions.

  1. AGARWAL A, NAYAK M. D, PATIL A, MANOHAR C. Glucose 6 Phosphate Dehydrogenase Deficiency Unmasked by Diabetic Ketoacidosis: An Underrated Phenomenon J Clin Diagn Res [online] 2013 Dec, 7(12):3012-3013 [viewed 06 August 2014] Available from: doi:10.7860/JCDR/2013/6159.3892
  2. ALWAR V, SHANTHALA DA, SITALAKSHMI S, KARUNA RK. Clinical Patterns and Hematological Spectrum in Autoimmune Hemolytic Anemia J Lab Physicians [online] 2010, 2(1):17-20 [viewed 22 September 2014] Available from: doi:10.4103/0974-2727.66703
  3. FLEGEL KM. Symptoms and signs of malaria. Can Med Assoc J [online] 1976 Sep 4, 115(5):409-410 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1878692
  4. GUPTA S, SZERSZEN A, NAKHL F, VARMA S, GOTTESMAN A, FORTE F, DHAR M. Severe refractory autoimmune hemolytic anemia with both warm and cold autoantibodies that responded completely to a single cycle of rituximab: a case report J Med Case Reports [online] :156 [viewed 22 September 2014] Available from: doi:10.1186/1752-1947-5-156
  5. JOHNSON CD. Upper abdominal pain: Gall bladder BMJ [online] 2001 Nov 17, 323(7322):1170-1173 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1121646
  6. LANGLEY GR, TODD FR, BISHOP AJ. Glucose-6-phosphate dehydrogenase deficiency in Canadian Negroes. Can Med Assoc J [online] 1969 Jun 7, 100(21):973-977 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1945957
  7. LAURENTI L, VANNATA B, INNOCENTI I, AUTORE F, SANTINI F, PICCIRILLO N, ZA T, BELLESI S, MARIETTI S, SICA S, EFREMOV DG, LEONE G. Chlorambucil plus Rituximab as Front-Line Therapy in Elderly/Unfit Patients Affected by B-Cell Chronic Lymphocytic Leukemia: Results of a Single-Centre Experience Mediterr J Hematol Infect Dis [online] , 5(1):e2013031 [viewed 22 September 2014] Available from: doi:10.4084/MJHID.2013.031
  8. MAKADIA D, SIDDAIAHGARI SR, LATHA MS. Anti B cell targeted therapy for autoimmune hemolytic anemia in an infant Indian J Pharmacol [online] 2013, 45(5):526-527 [viewed 06 August 2014] Available from: doi:10.4103/0253-7613.117755
  9. MINTZER DM, BILLET SN, CHMIELEWSKI L. Drug-Induced Hematologic Syndromes Adv Hematol [online] 2009:495863 [viewed 06 August 2014] Available from: doi:10.1155/2009/495863
  10. MIR-REZA S, TABATABAEIYAN M, DOOSTI R, OWJI M, MOGHADASI AN. Is anemia a probable cause of fatigue in patients with multiple sclerosis? Iran J Neurol [online] 2013, 12(1):35-36 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829269
  11. PACKER CD, HORNICK TR, AUGUSTINE SA. Fatal hemolytic anemia associated with metformin: A case report J Med Case Reports [online] :300 [viewed 06 August 2014] Available from: doi:10.1186/1752-1947-2-300
  12. PALLA AR, KHIMANI F, CRAIG MD. Warm Autoimmune Hemolytic Anemia with a Direct Antiglobulin Test Positive for C3 and Negative for IgG: A Case Study and Analytical Literature Review of Incidence and Severity Clin Med Insights Case Rep [online] :57-60 [viewed 22 September 2014] Available from: doi:10.4137/CCRep.S11469
  13. PALOMBI M, NISCOLA P, PERROTTI AP, DE FABRITIIS P. Cold autoimmune hemolytic anemia resolved by rituximab Asian J Transfus Sci [online] 2010 Jul, 4(2):136-137 [viewed 22 September 2014] Available from: doi:10.4103/0973-6247.67027
  14. PALOMBI M, NISCOLA P, TRAWINSKA MM, SCARAMUCCI L, GIOVANNINI M, PERROTTI A, DE FABRITIIS P. Long-lasting remission induced by rituximab in two cases of refractory autoimmune haemolytic anaemia due to cold agglutinins Blood Transfus [online] 2009 Jul, 7(3):235-236 [viewed 22 September 2014] Available from: doi:10.2450/2008.0066-08
  15. PETERS AL, VAN NOORDEN CJ. Glucose-6-phosphate Dehydrogenase Deficiency and Malaria: Cytochemical Detection of Heterozygous G6PD Deficiency in Women J Histochem Cytochem [online] 2009 Nov, 57(11):1003-1011 [viewed 06 August 2014] Available from: doi:10.1369/jhc.2009.953828
  16. RISITANO AM, ROTOLI B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents Biologics [online] 2008 Jun, 2(2):205-222 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721357
  17. SARKAR RS, PHILIP J, MALLHI RS, JAIN N. Drug-induced immune hemolytic anemia (Direct Antiglobulin Test positive) Med J Armed Forces India [online] 2013 Apr, 69(2):190-192 [viewed 06 August 2014] Available from: doi:10.1016/j.mjafi.2012.04.017
  18. UZ B, ÖZDEMIR E, AKSU S, AKYOL TK, JONES R. Successful Treatment of Autoimmune Hemolytic Anemia with Steroid, IVIg, and Plasmapheresis in a Haploidentical Transplant Recipient Turk J Haematol [online] 2012 Jun, 29(2):199-200 [viewed 06 August 2014] Available from: doi:10.5505/tjh.2012.78055
  19. WHITE JM, BROWN DL, HEPNER GW, WORLLEDGE SM. Penicillin induced Haemolytic Anaemia Br Med J [online] 1968 Jul 6, 3(5609):26-29 [viewed 06 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1989488
  20. WORLLEDGE SM, BRAIN MC, COOPER AC, HOBBS JR, DACIE JV. Immmunosuppressive drugs in the treatment of autoimmune haemolytic anaemia. Proc R Soc Med [online] 1968 Dec, 61(12):1312-1315 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211603
  21. ÖZSOYLU Ş. Megadose Methyl-Prednisolone (MDMP) for Autoimmune Hemolytic Anemia Turk J Haematol [online] 2013 Jun, 30(2):228-229 [viewed 22 September 2014] Available from: doi:10.4274/Tjh.2013.0052