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 [2] , third-generation cephalosporins [3] methyldopa, β-lactamase inhibitors [4] nonsteroidal anti-inflammatory agents, levaquin, oxaliplatin [5]
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. [2] 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 [3] 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. [6]
Right hypochondrial pain May be present due to associated gallstones [7] due to high level of bilirubin in the blood.
Dark urine Suggestive of intravascular haemolysis. [1,2]
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. [3]
Intravenous Rh (D) immune globulin This is used for the treatment of immune thrombocytopenic purpura and it can cause mild hemolysis. [5]
References
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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

Examination

Fact Explanation
Pallor Haemogloin level goes down during an attack, [1] 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. [2] This accumulated bilirubin causes yellowish discolouration of eyes and mucous membranes.
Right hypochondrial tenderness If associated with gall stones [3] due to high level of bilirubin in the blood.
Splenomegaly Autoimmune haemolytic anaemia causes extravascular haemolysis causing splenomegaly. [4]
Dyspnea Patients can develop progressive dyspnea. This can even ends up with fatal respiratory arrests. [2]
References
  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. 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
  3. 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
  4. 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

Differential Diagnoses

Fact Explanation
Glucose 6 phosphate dehydrogenase deficiency This is a X-linked condition [3] where the attacks are precipitated by the reduced glutathione production in oxidative stresses as in ingestion of fava beans, drugs like as primaquine, sulfonamide and aspirin or illness. Blister cells and bite cells are seen on blood film with reduction of enzyme level after 8 weeks of attack.
Autoimmune haemolytic anaemia There are 2 types of autoimmune haemolytic anaemia: warm and cold. Warm type is IgG mediated at temperature less than 4 centigrades and cold type is IgM mediated at temperature 37 centigrades. [8] This causes extra vascular haemolysis. Direct and indirect coomb’s test are positive [4] and there will be spherocytes in the blood film. [5]
Hereditory spherocytosis This is an autosomal dominant red blood cell membrane defect [6] with spherical red blood cells undergo extravascular haemolysis. There will be spherocytes in the blood film and increased osmatic fragility apart from the other findings in haemolytic anaemia. Red cell survival is decreased which can be investigated with the 51Cr red cell survival technique. [7]
Paroxysmal nocturnal haemoglobonuria This arises due to the acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene. Chronic intravascular hemolysis, occur with resulting in hemolytic anemia and hemosiderinuria. Bone marrow failure and thromboembolia are the other comlications of PNH. There is mild to severe anemia with moderate reticulocytosis and mild jaundice, with negative Coombs test. Dark urine and urinary hemosiderin, are suggestive of intravascular hemolysis. [1]
Infection Malaria can cause haemolysis and haemoglobinuria. They usually present with every third or fourth day fever with other complications such as anaemia, jaundice, splenomegally, hepatomegaly, pulmonary and intestinal complications and cerebral malaria. [2] Thick and thin blood films are done to check the malaria parasites.
References
  1. 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
  2. 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
  3. 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
  4. 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
  5. NANDENNAVAR M, CYRIAC S, KRISHNAKUMAR, SAGAR T. Immune Hemolytic Anemia in a Patient with Tuberculous Lymphadenitis J Glob Infect Dis [online] 2011, 3(1):89-91 [viewed 22 September 2014] Available from: doi:10.4103/0974-777X.77303
  6. FARRé EM, TIESSEN A, ROESSNER U, GEIGENBERGER P, TRETHEWEY RN, WILLMITZER L. Analysis of the Compartmentation of Glycolytic Intermediates, Nucleotides, Sugars, Organic Acids, Amino Acids, and Sugar Alcohols in Potato Tubers Using a Nonaqueous Fractionation Method Plant Physiol [online] 2001 Oct, 127(2):685-700 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC125103
  7. WILEY JS. Red cell survival studies in hereditary spherocytosis J Clin Invest [online] 1970 Apr, 49(4):666-672 [viewed 22 September 2014] Available from: doi:10.1172/JCI106278
  8. 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

Investigations - for Diagnosis

Fact Explanation
Full blood count Anaemia causes lowering of haemoglobin level, [2] 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. [3]
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. [2]
Reticulocyte count Reticulocyte count is increased. [4] Haemolysis causes ineffective erythropoiesis.
Unconjugated bilirubin Haemolysis of red blood cells releases bilirubin in to the blood causing elevation of unconjugated bilirubin. [4]
Direct coomb’s test Positive in autoimmune haemolytic anaemia and negative in other drug induced haemolytic anaemias. [3]
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. [1]
Free IgG antipenicillin antibody This is found in most patients who developed haemolysis following penicillin therapy. [3]
References
  1. 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
  2. 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
  3. 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
  4. 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

Investigations - Fitness for Management

Fact Explanation
Full blood count Sometimes, haemolysis is triggered by the infections such as parvovirus B19, mycoplasma and Epstein bar virus and other. [1] They will have elevated lymphocytes in viral infections.
References
  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

Investigations - Followup

Fact Explanation
Full blood count Haemoglobin level is monitored [3] with the time to see the clinical improvement after avoiding the offending agent. [2]
Direct coomb's test Will become less strongly positive with the avoidance of the precipitating cause/drug.[1]
References
  1. 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
  2. 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
  3. 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

Investigations - Screening/Staging

Fact Explanation
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. [1] 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. [2]
References
  1. 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
  2. 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

Management - General Measures

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. [3]
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. [2]
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. [1]
References
  1. 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
  2. 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
  3. 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

Management - Specific Treatments

Fact Explanation
Steroids/immunosuppressants [1] These drugs can be used to treat warm autoimmune haemolytic anaemia. [3] Methylprednisolone 1 mg kg–1 [8] can be used to treat the autoimmune haemolytic anaemia.
Chlorambucil Used for the treatment of cold autoimmune haemolytic anaemia. This is an alkylating agent [5] used for the autoimmune conditions.
Plasmapheresis and IV immunoglobulin Can be used in autoimmune hemolytic anaemia. [1,6]
Anti B cell therapy [2] Rituximab [2,3], 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. [4]
References
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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