History

Fact Explanation
History of exaerbations after exposing to the cold Autoimmune hemolytic anemia is one of the most common form of acquired hemolytic anemia. There are 2 types of hemolytic anaemias: cold and warm. Cold type occurs at <4 centigrades and is IgE mediated, producing agglutinins. [2] Warm type is IgG mediated and occurs at temperature ≥37°C, does not require complement for activity and there is also no agglutination. There can be mixed type of warm and cold autoimmune hemolytic anemia with a chronic course and severe intermittent exacerbations. [1] Exposure to cold can cause worsening of the hemolysis and hemoglobinuria. [1] Underlying conditions like syphilis, Epstein Barr virus, cytomegalovirus, hepatitis A, B, C viruses and mycoplasma pneumonia, tuberculosis and HIV like infections, lymphoproliferative disorders, connective tissue disorders like systemic lupus erythematosus and rheumatoid arthritis can be the etiology for the hemolysis in these people. [2]
Shortness of breath [1] Exertional dyspnoea [1] can occur due to the anaemia especially in people with heart disease. Difficulty in breathing can occur with mediastinal lymphoma as well.
Lethargy and malaise Anaemia causes reduced blood oxygenation, leading to reduced supply of oxygen to the energy production. Therefore they feel lack of energy. [9]
Right hypochondrial pain May be present due to associated gallstones due to high level of bilirubin in the blood. [8]
Dark urine Suggestive of intravascular haemolysis leading to haemoglobinuria. [1] Prolonged exposure to cold may be the reason and is a rare presentation of the disease.
Joint pain Connective tissue disorders like systemic lupus erythematosus and rheumatoid arthritis can precipitate the anaemia. [2]
Fever, cough and rhinorrhoea Infections can trigger the attacks of cold autoimmune hemolytic anemia. Eg: Syphilis, Epstein Barr virus, Cytomegalovirus, Hepatitis A, B, C viruses and Mycoplasma pneumonia, Tuberculosis etc. [2]
Low grade fever with cough for long term duration This may be the presenting features of mycoplasma infection. [6]
Long term history of fever, night sweats, vomiting, loss of appetite and loss of weight, painless swelling of the lymph nodes in the neck, underarm, stomach, or groin. [3] Lymphoproliferative disorders can be the causative factor for the autoimmune hemolytic anaemia. It may be due to a lymphoma or a leukaemia. [3,7]
References
  1. 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 08 August 2014] Available from: doi:10.1186/1752-1947-5-156
  2. SUDHA REDDY VR, SAMAYAM P, RAVICHANDER B, BAI U. Autoimmune Hemolytic Anemia: Mixed Type--A Case Report Indian J Hematol Blood Transfus [online] 2011 Jun, 27(2):107-110 [viewed 08 August 2014] Available from: doi:10.1007/s12288-011-0065-3
  3. MASOOD A, KAIROUZ S, HUDHUD KH, HEGAZI AZ, BANU A, GUPTA NC. Primary non-Hodgkin lymphoma of liver Curr Oncol [online] 2009 Aug, 16(4):74-77 [viewed 09 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722057
  4. ZHANG J, GRUBOR V, LOVE CL, BANERJEE A, RICHARDS KL, MIECZKOWSKI PA, DUNPHY C, CHOI W, AU WY, SRIVASTAVA G, LUGAR PL, RIZZIERI DA, LAGOO AS, BERNAL-MIZRACHI L, MANN KP, FLOWERS C, NARESH K, EVENS A, GORDON LI, CZADER M, GILL JI, HSI ED, LIU Q, FAN A, WALSH K, JIMA D, SMITH LL, JOHNSON AJ, BYRD JC, LUFTIG MA, NI T, ZHU J, CHADBURN A, LEVY S, DUNSON D, DAVE SS. Genetic heterogeneity of diffuse large B-cell lymphoma Proc Natl Acad Sci U S A [online] 2013 Jan 22, 110(4):1398-1403 [viewed 09 August 2014] Available from: doi:10.1073/pnas.1205299110
  5. KRIDEL R, SEHN LH, GASCOYNE RD. Pathogenesis of follicular lymphoma J Clin Invest [online] 2012 Oct 1, 122(10):3424-3431 [viewed 09 August 2014] Available from: doi:10.1172/JCI63186
  6. KASHYAP S, SARKAR M. Mycoplasma pneumonia: Clinical features and management Lung India [online] 2010, 27(2):75-85 [viewed 18 September 2014] Available from: doi:10.4103/0970-2113.63611
  7. SHEIKH-TAHA M, FRENN P. Autoimmune Hemolytic Anemia Induced by Levofloxacin Case Rep Infect Dis [online] 2014:201015 [viewed 18 September 2014] Available from: doi:10.1155/2014/201015
  8. MCSHERRY CK, FERSTENBERG H, CALHOUN WF, LAHMAN E, VIRSHUP M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg [online] 1985 Jul, 202(1):59-63 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1250837
  9. NALESNIK JG, MYSLIWIEC AG, CANBY-HAGINO E. Anemia in Men with Advanced Prostate Cancer: Incidence, Etiology, and Treatment Rev Urol [online] 2004, 6(1):1-4 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472681

Examination

Fact Explanation
Pallor Haemoglobin level reduces during an attack, patient develops anaemia due to red cell destruction. [1]
Jaundice [1] Haemolysis of red blood cells releases bilirubin into the blood causing elevation of unconjugated bilirubin. [2] This accumulated bilirubin causes yellowish discolouration of eyes and mucous membranes.
Right hypochondrial tenderness Associated with gallstones due to high level of bilirubin in the blood. [2]
Splenomegaly [1] Autoimmune haemolytic anaemia causes extravascular hemolysis. [1]
Dyspnea [1] Patients can develop progressive dyspnea. [2] This can even end up with fatal respiratory arrests. May be due to underlying mediastinal masses due to lymphoma.
Lymphadenopathy May be present in patients with lymphoma, leukaemia, infectious mononucleosis, or other underlying infections. [3] May involve the neck, axillae, groin, abdomen etc.
Lung consolidation: reduced chest expansion, dull percussion, increased vocal fremitus, crepitations Mycoplasma pneumoniae can be a cause for the exacerbation of autoimmune hemolytic anaemia.[4]
Hepatomegaly May be present in patients with lymphoproliferative disorders. [3]
Arm swelling Superior vena cava syndrome [5] can occur due to the compression of superior vena cava by mediastinal mass.
Large abdominal mass, testicular mass and skin lesions Abdominal mass usually occurs in Burkitt lymphoma. Skin lesions may be associated with cutaneous T-cell lymphoma (mycosis fungoides), and other types such as anaplastic large-cell lymphoma, and angioimmunoblastic lymphoma. [3]
References
  1. 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 08 August 2014] Available from: doi:10.1186/1752-1947-5-156
  2. MCSHERRY CK, FERSTENBERG H, CALHOUN WF, LAHMAN E, VIRSHUP M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg [online] 1985 Jul, 202(1):59-63 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1250837
  3. KRIDEL R, SEHN LH, GASCOYNE RD. Pathogenesis of follicular lymphoma J Clin Invest [online] 2012 Oct 1, 122(10):3424-3431 [viewed 09 August 2014] Available from: doi:10.1172/JCI63186
  4. KASHYAP S, SARKAR M. Mycoplasma pneumonia: Clinical features and management Lung India [online] 2010, 27(2):75-85 [viewed 18 September 2014] Available from: doi:10.4103/0970-2113.63611
  5. YAMAMOTO K, MORI S, OKAMOTO T, SHIMOTOHNO K, KYOGOKU Y. Identification of transcriptional suppressor proteins that bind to the negative regulatory element of the human immunodeficiency virus type 1. Nucleic Acids Res [online] 1991 Nov 25, 19(22):6107-6112 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC329097

Differential Diagnoses

Fact Explanation
Glucose 6 phosphate dehydrogenase deficiency This is an X-linked condition [3] where 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.
Warm autoimmune haemolytic anaemia [4] Warm type is IgG mediated at temperature less than 4 centigrades that differ from cold type as it is IgM mediated at temperature 37 centigrades. This causes extravascular haemolysis. [4] Direct and indirect Coomb’s tests are positive and there will be spherocytes in the blood film.
Hereditory spherocytosis [5] This is an autosomal dominant red blood cell membrane defect with spherical red blood cells undergo extravascular haemolysis. There will be spherocytes in the blood film and increased osmotic fragility apart from the other findings of haemolytic anaemia. [5]
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 thromboembolisms are the other complications 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]
Infections Malaria can cause haemolysis and haemoglobinuria. They usually present with every third or fourth day fever with other complications such as anaemia, jaundice, splenomegaly, hepatomegaly, pulmonary and intestinal complications and cerebral malaria. [2] Thick and thin blood films are done to check for 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. VON DEM BORNE AE, ENGELFRIET CP, BECKERS D, VAN DER KORT-HENKES G, VAN DER GIESSEN M, VAN LOGHEM JJ. Autoimmune haemolytic anaemias. II. Warm haemolysins--serological and immunochemical investigations and 51Cr studies Clin Exp Immunol [online] 1969 Mar, 4(3):333-343 [viewed 18 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578975
  5. DAS A, BANSAL D, DAS R, TREHAN A, MARWAHA RK. Hereditary spherocytosis in children: profile and post-splenectomy outcome. Indian Pediatr [online] 2014 Feb, 51(2):139-41 [viewed 12 July 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24632695

Investigations - for Diagnosis

Fact Explanation
Full blood count Anaemia causes lowering of haemoglobin level, packed cell volume and red cell count. Mean corpuscular volume and mean corpuscular haemoglobin is normal as it is a normocytic normochromic anaemia. [1]
Blood picture Red cells are normal in size as this causes normocytic normochromic type [1] of a blood picture. Gross agglutinates, anisopoikilocytosis with predominant macrocytes may be present. [3]
Reticulocyte count Reticulocyte count is increased. [1] Haemolysis causes ineffective erythropoiesis.
Unconjugated bilirubin Haemolysis of red blood cells releases bilirubin into the blood causing elevation of unconjugated bilirubin. [3]
Direct coomb’s test Positive in autoimmune haemolytic anaemia. [2]
Cold IgG IgG is positive (1:512) active from 3°C to 20°C. [1,2]
References
  1. 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 08 August 2014] Available from: doi:10.4103/0973-6247.67027
  2. 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 08 August 2014] Available from: doi:10.1186/1752-1947-5-156
  3. SUDHA REDDY VR, SAMAYAM P, RAVICHANDER B, BAI U. Autoimmune Hemolytic Anemia: Mixed Type--A Case Report Indian J Hematol Blood Transfus [online] 2011 Jun, 27(2):107-110 [viewed 08 August 2014] Available from: doi:10.1007/s12288-011-0065-3
  4. SHEIKH-TAHA M, FRENN P. Autoimmune Hemolytic Anemia Induced by Levofloxacin Case Rep Infect Dis [online] 2014:201015 [viewed 18 September 2014] Available from: doi:10.1155/2014/201015

Investigations - Fitness for Management

Fact Explanation
Full blood count Sometimes, haemolysis is triggered by the infections such as parvovirus B19, mycoplasma and Epstein Barr virus and other. [1] They will have elevated lymphocytes in viral infections and acute phases of leukaemia.
Urinalysis [1] Urinalysis may be needed in the cases where they present with dark urine to see any red blood cells present in the urine. [1]
References
  1. SUDHA REDDY VR, SAMAYAM P, RAVICHANDER B, BAI U. Autoimmune Hemolytic Anemia: Mixed Type--A Case Report Indian J Hematol Blood Transfus [online] 2011 Jun, 27(2):107-110 [viewed 08 August 2014] Available from: doi:10.1007/s12288-011-0065-3

Investigations - Followup

Fact Explanation
Full blood count Haemoglobin level [1] is monitored with time to see the clinical improvement after avoiding the offending situation or after treatment.
Direct coomb's test Will become less strongly positive with the avoidance of the precipitating cause/drug. [1]
References
  1. 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 08 August 2014] Available from: doi:10.1186/1752-1947-5-156
  2. SHEIKH-TAHA M, FRENN P. Autoimmune Hemolytic Anemia Induced by Levofloxacin Case Rep Infect Dis [online] 2014:201015 [viewed 18 September 2014] Available from: doi:10.1155/2014/201015

Investigations - Screening/Staging

Fact Explanation
Thick and thin films for malaria There can be haemoglobinuria causing black water fever in malaria. [1]
Bone marrow biopsy Lymphoproliferative disorders can be the causative factor. [3]
Screening for the infections Infections like Human immunodeficiency virus, Syphilis, Epstein Barr virus, Cytomegalovirus, Hepatitis A, B, C viruses and Mycoplasma pneumonia and tuberculosis may be the cause for the exacerbation of the hemolysis. Screening may be needed where relevant and symptoms and signs are suggestive of an infection. [2]
Rheumatoid factors, anti nuclear antibody Connective tissue disorders like systemic lupus erythematosus and rheumatoid arthritis can precipitate the anaemia. [2]
Fine-needle aspiration (FNA) biopsy To evaluate the lymphadenopathy. [4]
References
  1. 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
  2. SUDHA REDDY VR, SAMAYAM P, RAVICHANDER B, BAI U. Autoimmune Hemolytic Anemia: Mixed Type--A Case Report Indian J Hematol Blood Transfus [online] 2011 Jun, 27(2):107-110 [viewed 08 August 2014] Available from: doi:10.1007/s12288-011-0065-3
  3. SHEIKH-TAHA M, FRENN P. Autoimmune Hemolytic Anemia Induced by Levofloxacin Case Rep Infect Dis [online] 2014:201015 [viewed 18 September 2014] Available from: doi:10.1155/2014/201015
  4. GANOTT MA, ZULEY ML, ABRAMS GS, LU AH, KELLY AE, SUMKIN JH, CHIVUKULA M, CARTER G, AUSTIN RM, BANDOS AI. Ultrasound Guided Core Biopsy versus Fine Needle Aspiration for Evaluation of Axillary Lymphadenopathy in Patients with Breast Cancer ISRN Oncol [online] :703160 [viewed 18 September 2014] Available from: doi:10.1155/2014/703160

Management - General Measures

Fact Explanation
Supportive treatment Patient has to be kept in a warm environment in cold autoimmune haemolytic anaemia. Red cell transfusion may be needed in some occasions with severe anaemia. [2]
Avoidance of precipitants Drugs causing hemolysis such as have to be avoided where possible. Penicillin can be replaced by drugs like erythromycin where possible. [3]
Monitoring for complications of the treatment With the long term treatment of cold autoimmune haemolytic anaemia, especially with prednisolone they can develop complications due to the treatment such as hypertension, glaucoma, severe osteoporosis, and osteoarthritis. [1]
References
  1. 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 08 August 2014] Available from: doi:10.4103/0973-6247.67027
  2. SUDHA REDDY VR, SAMAYAM P, RAVICHANDER B, BAI U. Autoimmune Hemolytic Anemia: Mixed Type--A Case Report Indian J Hematol Blood Transfus [online] 2011 Jun, 27(2):107-110 [viewed 08 August 2014] Available from: doi:10.1007/s12288-011-0065-3
  3. SHEIKH-TAHA M, FRENN P. Autoimmune Hemolytic Anemia Induced by Levofloxacin Case Rep Infect Dis [online] 2014:201015 [viewed 18 September 2014] Available from: doi:10.1155/2014/201015

Management - Specific Treatments

Fact Explanation
Anti B cell therapy [1] 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 to obtain sustained remissions. [1] It can be given as a 4-h intravenous infusion at the dose of 375 mg/m2 once weekly for a total of four doses. [1] There are no serious side effects reported. It has shown that conditions that are not responding to steroid therapy, are completely responding to only one cycle of rituximab. [2]
Corticosteroids/immunosuppressive drugs and alkylating cytostatics[1] These are the other options available for the treatment of cold autoimmune hemolytic anemia. Methylprednisolone 1 mg kg–1 can be used to treat the autoimmune haemolytic anaemia. Chlorambucil is an alkylating agent used for the autoimmune conditions.
Cytotoxic agents [2] Drugs such as cyclophosphamide, cyclosporine can be used for the treatment. [2]
Plasmapharesis Plasmapheresis can remove the causative antibodies and slow down the rate and progression of hemolysis. [2]
Splenectomy [1] May be needed in refractory disease, but the response may be variable. [1]
References
  1. 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 08 August 2014] Available from: doi:10.4103/0973-6247.67027
  2. 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 08 August 2014] Available from: doi:10.1186/1752-1947-5-156