The most obvious pathognomonic sign of AIHA is anemia due to hemolysis. Passage of dark-colored urine indicates presence of free hemoglobin. Hemolysis per se leads to elevated levels of bilirubin in bile and urine, with jaundice indicating disease. Patients may complain of lumbar back pain. Affected individuals which test positive for cold agglutinins, develop acrocyanosis in cold weather [12]. Abdominal pain while eating cold food occurs due to ischemia associated with agglutination of RBCs in the viscera.

A slightly enlarged spleen may be palpable. Reticulocytosis or increased number of young red blood cells likewise indicates bone marrow activity to replace the depletion of erythrocytes in peripheral circulation. Severe hemolytic anemia may lead to cardiopulmonary decompensation and angina.

• Splenomegaly

  Examination demonstrated scleral icterus, splenomegaly, and anemia. By peripheral blood smear, the patient was diagnosed with Plasmodium ovale. [ncbi.nlm.nih.gov]

  anemia caused by the excessive destruction of red blood cells by autoantibodies Splenomegaly is present in more than half the cases of autoimmune hemolytic anemia, and this finding suggests that hemolysis has been occurring for weeks or even months. [merriam-webster.com]

  Hyperreactive malarial splenomegaly: Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of recurrent malarial infection. [en.wikipedia.org]

• Generalized Lymphadenopathy

  lymphadenopathy, splenomegaly and mild hepatitis. [ncbi.nlm.nih.gov]

• Anemia

  […] hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.[9] Signs and symptoms[edit] Spherocytes are found in immunologically-mediated hemolytic anemias.[10] Causes[edit] The causes of AIHA are poorly understood. [en.wikipedia.org]

  Autoimmune hemolytic anemia (including Evans syndrome) What every physician needs to know about autoimmune hemolytic anemia: Autoimmune hemolytic anemia (AIHA) is a rare condition with an incidence of 0.8 per 100,000 per year and a prevalence of 17 per [cancertherapyadvisor.com]

  This occurs in warm antibody hemolytic anemia. In contrast, self-generated cold immunoglobulins are active at temperatures below normal, as in cold antibody hemolytic anemia. [symptoma.com]

  Deficiencies in iron or lead poisoning can produce a microcytic anemia, while B12 and folate deficiencies produce a megaloblastic anemia and can be distinguished by peripheral smear. [pedclerk.bsd.uchicago.edu]

• Fatigue

  Subsequently, he was admitted to our hospital owing to fatigue, a high fever, and jaundice. His clinical findings met the diagnostic criteria of hemophagocytic lymphohistiocytosis, and he was rescued with a high dose of glucocorticoids. [ncbi.nlm.nih.gov]

  The most common sign as experienced is fatigue (tiredness) in the patient. In mild nature of sickness no sign will appear. It is the severe case wherein an affected person shows variety of signs. [web.archive.org]

• Fever

  Infectious mononucleosis is one of the main manifestations of Epstein - Barr virus, which is characterized by fever, tonsillar-pharyngitis, lymphadenopathy and atypical lymphocytes. [ncbi.nlm.nih.gov]

• Hodgkin Lymphoma

  The patients with refractory Hodgkin lymphoma have a poor prognosis. [ncbi.nlm.nih.gov]

  Abstract Background: The occurrence of autoimmune hemolytic anemia (AIHA) in patients with non-Hodgkin's lymphoma (NHL) is well known. [academic.oup.com]

  Five patients (42%) had systemic lupus erythematosus, one patient (8%) had a non-Hodgkin's lymphoma, and six patients (50%) had idiopathic AIHA; four patients (33%) had concomitant thrombocytopenia (Evans' syndrome). Nine patients (75%) were female. [jamanetwork.com]

  The well-known link between AIHA and Hodgkin's lymphoma 17,18 can be observed in one patient from the present series. He initially presented with infection by Mycoplasma pneumoniae and, after 4 years, was diagnosed with Hodgkin's lymphoma. [scielo.br]

• Pallor

  Autoimmune hemolytic anemia (AIHA) is a disorder in which red blood cells are destroyed by immune system (IgG and/or IgM autoantibodies) leading to manifestations of pallor and general symptoms. [symptoma.com]

  An otherwise seemingly normal girl, who had developed limping at the age of 11 months old, referred to Namazi Hospital, Shiraz, Iran, due to pallor and latitude at the age of 3 yrs and was diagnosed of AIHA. [ncbi.nlm.nih.gov]

  Reviewing a peripheral blood smear is helpful; AIHA is suggested by the presence of microspherocytes ( Figure 1 ), which are smaller in size than normal RBCs and lack the central pallor. [cancertherapyadvisor.com]

  The pallor/cyanosis in distal body parts is usually not severe enough to cause infarction – but it is annoying, and patients should be kept warm so they don’t have to suffer from those symptoms, on top of everything else they are dealing with. [pathologystudent.com]

• Dyspnea

  In 2013, he complained of dyspnea. Chest computed tomography showed postoperative recurrence of invasive thymoma. Several chemotherapies were administered. Severe anemia and an increase in the total bilirubin level were observed with chemotherapies. [ncbi.nlm.nih.gov]

  The disease is characterized by symptoms due to the anemia including fatigue, exertional dyspnea, and, more rarely, jaundice and dark urine in case of severe hemolysis. If the disease is severe, fever, chest pain, syncope or heart failure may occur. [orpha.net]

• Exertional Dyspnea

  The disease is characterized by symptoms due to the anemia including fatigue, exertional dyspnea, and, more rarely, jaundice and dark urine in case of severe hemolysis. If the disease is severe, fever, chest pain, syncope or heart failure may occur. [orpha.net]

• Respiratory Distress

  All six patients were hospitalized for the initial management of babesiosis, and one required intensive care for the acute respiratory distress syndrome and intracranial hemorrhage. [nejm.org]

• Tachycardia

  Signs of anemia, such as tachycardia, shortness of breath and exercise intolerance should be addressed through other modalities such as absolute bed rest and oxygen therapy, before transfusion is given. [clinlabnavigator.com]

  Paleness due to anemia, jaundice, tachycardia, darkening in urine color, hepatosplenomegaly are frequently seen clinical findings. [go.gale.com]

  AIHA is characterized by hemolytic anemia, which is most often revealed by an unusual weakness and fatigue with tachycardia and exertional dyspnea, and also in some cases by jaundice, dark urine and/or splenomegaly. [orpha.net]

  Severe anaemia, especially of sudden onset, may cause tachycardia, dyspnoea, angina and weakness. Gallstones may cause abdominal pain. Bilirubin stones can develop in patients with persistent haemolysis. [patient.info]

• Acrocyanosis

  CAIHA patients may experience bluish, cold hands and feet (acrocyanosis) and abdominal pain when eating cold food. Symptoms of fever and swollen, painful lymph nodes may accompany CAIHA. [symptoma.com]

  Introduction Extrinsic hemolytic anemia caused by antibodies type II hypersensitivity Epidemiology peak incidence in 50s-80s Presentation Symptoms warm agglutinin disease chronic hemolytic anemia cold agglutinin disease acrocyanosis (different from Raynaud [step1.medbullets.com]

   Acrocyanosis may occur.Acrocyanosis may occur.  CAD is regarded as a form of WM (as low gradeCAD is regarded as a form of WM (as low grade B cell lymphoma)B cell lymphoma)  Treatment :avoid cold exposureTreatment :avoid cold exposure  Steroids [slideshare.net]

  Cold agglutinin mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red, based on vasculature response. [en.wikipedia.org]

• Jaundice

  Secondary AIHA might not be diagnosed appropriately because the obstructive jaundice observed in type 1 AIP/IgG4-SC can obscure the presence of hemolytic jaundice. [ncbi.nlm.nih.gov]

  The macrophages then proceed in destroying the “tagged” RBCs producing the typical hemolytic by-products which cause some of the clinically relevant signs such as dark urine and jaundiced skin. [pedclerk.bsd.uchicago.edu]

  AIHAs can result in the classic set of symptoms associated with anemia (see page) as well as an unconjugated hyperbilirubinemia and in some cases jaundice if hemolysis is severe. [pathwaymedicine.org]

• Hepatosplenomegaly

  Paleness due to anemia, jaundice, tachycardia, darkening in urine color, hepatosplenomegaly are frequently seen clinical findings. [go.gale.com]

  A 7-month-old boy, presented with prolonged fever, erythematous rash, severe pallor and hepatosplenomegaly. Positive Direct Coombs test and coronary artery aneurysm on echocardiography. [ncbi.nlm.nih.gov]

  Computed tomography (CT) of the chest, abdomen and pelvis was remarkable for hepatosplenomegaly. [dx.doi.org]

• Hepatomegaly

  The most common clinical signs are lymphoid expansion with lymphadenopathy, splenomegaly, and hepatomegaly; immune disease with different types of cytopenia, i… Publisher Full Text (DOI) Autoimmune hemolytic anemia in pregnancy: a challenge for maternal [unboundmedicine.com]

  The spleen tip was palpable; however, there was no hepatomegaly or lymphadenopathy. [ijpmonline.org]

  Thirty-six patients had a CT-scan of the chest and abdomen and pelvis: the presence of splenomegaly, adenopathy or hepatomegaly were not different between groups. [journals.plos.org]

  This liver disease can be associated with the acquired immunodeficiency virus, hepatitis B virus, drug usage or cholestatic syndrome and in around 40% of cases its etiology will be defined as autoimmune. 22 One patient from the present sample developed hepatomegaly [scielo.br]

  H1N1 influenza–associated AIHA in children may respond to treatment with oseltamivir and intravenous immunoglobulin. [6] Fetal splenomegaly and associated hepatomegaly could be due to hemolysis, but infections are the most likely cause. [emedicine.medscape.com]

• Scleral Icterus

  Examination demonstrated scleral icterus, splenomegaly, and anemia. By peripheral blood smear, the patient was diagnosed with Plasmodium ovale. [ncbi.nlm.nih.gov]

  His physical examination was remarkable for scleral icterus, shifting dullness, hepatosplenomegaly and bilateral lower-extremity pitting edema. There was no significant peripheral lymphadenopathy, and there was no evidence of hypertension. [dx.doi.org]

  Physical examination revealed a calm, well-nourished man with scleral icterus and generalized jaundice. Blood pressure was 130/76, heart rate 102/min., respiratory rate 16/min, temperature 97.7F. [casesjournal.biomedcentral.com]

• Night Sweats

  Since hematologic malignancies and lupus are the two most commonly associated secondary causes of AIHA (albeit rare), patients may present with symptoms specific to the condition such as weight loss, night sweats, fevers, abdominal fullness, or lymph [clinicaladvisor.com]

  He denied fevers or chills, but gave a long history of night sweats and occasional diarrhea, which he ascribed to his medications. [casesjournal.biomedcentral.com]

• Dark Urine

  Dark urine: AIHA with an intravascular hemolytic component causes hemoglobin to be spilled into the urine (hemoglobinuria) but can easily be mistaken for bilirubin or simple highly concentrated urine. [pedclerk.bsd.uchicago.edu]

  A 41-year-old woman with Crohn's disease presented to our emergency room (ER) with dark urine, dizziness, and shortness of breath. The activity of Crohn's disease had been controlled, with Crohn's disease activity index (CDAI) score below 100 point. [ncbi.nlm.nih.gov]

  The disease is characterized by symptoms due to the anemia including fatigue, exertional dyspnea, and, more rarely, jaundice and dark urine in case of severe hemolysis. If the disease is severe, fever, chest pain, syncope or heart failure may occur. [orpha.net]

  If your child looks pale, has increased jaundice, dark urine, or is more tired than usual, you should call the doctor. [stjude.org]

• Headache

  […] and sun exposure Muskuloskeletal health Heart health Cancer Autoimmune conditions Mental health Developmental disorders Pregnancy and fertility Aging Fitness and exercise Gastrointestinal health Asthma Infections Everyday aliments: fatigue, pain and headaches [vitamindcouncil.org]

  Leukemia Lymphoma—Non-Hodgkin but also occasionally Hodgkin Collagen-vascular (autoimmune) diseases, such as systemic lupus erythematosus Family history of hemolytic disease Symptoms Symptoms may include: Dark brown urine Yellow or pale skin Muscle pains Headache [winchesterhospital.org]

  Symptoms & Diagnosis The most common symptoms of autoimmune hemolytic anemia are: Dark brown urine Jaundice Pale skin Muscle pain Headache Nausea and vomiting Weakness Shortness of breath Rapid heart beat After ruling out other causes, doctors diagnose [danafarberbostonchildrens.org]

  Headaches 0002315 Hemolytic anemia 0001878 Muscle weakness Muscular weakness 0001324 30%-79% of people have these symptoms Immunodeficiency Decreased immune function 0002721 Lymphoma Cancer of lymphatic system 0002665 Pallor 0000980 5%-29% of people [rarediseases.info.nih.gov]

• Dizziness

  A 52-year-old man presented with a 1-month history of general weakness and dizziness. Hemoglobin level was 4.2 g/dL, and direct and indirect Coombs tests both yielded positive results. [ncbi.nlm.nih.gov]

  They include: pale or yellowing skin tiredness dizziness heart palpitations Cold AIHA This is also called cold hemolysis. [medicalnewstoday.com]

  Roumier et al transfused 39/60 (65%) patients with WAIHA because of anemia (Hb<8 g/dL) with symptoms of poor tolerance such as dizziness and/or comorbidities. [dovepress.com]

  Patients with AIHA usually present with acute onset shortness of breath, dyspnea on exertion, palpitations, dizziness, progressive weakness or tiredness. [cancertherapyadvisor.com]

• Asthenia

  Clinical Picture of AIHA The clinical picture of AIHA, especially in elderly patients, include: 1) manifestations related to anemia i.e. pallor, tachycardia, polypnea, asthenia, and excessive fatigability under stress, these latter are difficult to interpret [omicsonline.org]

  Administrative data (age, gender), clinical presentation at diagnosis (asthenia, dyspnea, jaundice, angina), biological data (hemoglobin level (g/L), mean corpuscular volume (MCV, μ3), LDH level (UI/L), bilirubin level (μmol/L), DAT pattern, leukocyte [journals.plos.org]

The key of laboratory diagnosis in AIHA is to demonstrate the occurrence of hemolysis and to determine the presence of autoantibodies and complement. Clinical laboratory techniques include:

• Differential blood count
• Complete blood count
• Reticulocyte counts
• Serum haptoglobin level
• Lactate dehydrogenase (LDH)
• Bilirubin
• Coombs test

Microscopy of stained peripheral blood films will reveal the presence of red and white blood cells and their relative numbers. Damaged red cells release LDH confirming hemolysis, likewise bilirubin from hemoglobin.

Presence of immunoglobulins G and M, and C3d from the surface of RBCs can be demonstrated with the use of homologous monoclonal antibodies. Normally warm antibody AIHA (WAIHA) is readily detectable in RBCs coated with IgG or IgG + complement; if only with C3d, the antibody may be a cold antibody. A cold agglutinin titre of > 1:512 is required for the precise diagnosis of cold antibody AIHA (CAIHA). Inconclusive results e.g., negative antiglobulin test, low titre cold antibodies, or presence of Donath-Landsteiner antibodies should be referred to a specialized laboratory for confirmation.

Diagnosis of secondary AIHA includes evaluation of patient's status, onset of illness, possible predisposing factors such as infections, drug intake, transfusion, vaccination, and other immune diseases. Other causes of hemolytic anemia should be ruled out. Complete abdominal CT scan may be needed to detect malignancies and splenomegaly. Bone marrow aspirate is recommended.

• Reticulocytosis

  Her laboratory reports showed anaemia, reticulocytosis, leucocytosis, elevated Lactate Dehydrogenase (LDH), alkaline phosphatase levels, hyperbillirubinemia and positive direct Coomb's test. [ncbi.nlm.nih.gov]

  However, like all hemolytic anemias AIHAs are characterized by a reticulocytosis and low haptoglobin levels. Spherocytes may be visible on peripheral blood smear in patients with AIHA. [pathwaymedicine.org]

• Neutropenia

  Evans syndrome is a rare condition manifested by combined autoimmune hemolytic anemia (AIHA) and thrombocytopenia or neutropenia. It is often associated with other autoimmune disorders, immunodeficiencies, and non-Hodgkin's lymphoma. [ncbi.nlm.nih.gov]

  [Case Reports] Cureus 2020; 12(2):e6845Patel BP, Jakob JC Evans Syndrome (ES) is a rare autoimmune disorder that presents with simultaneous or sequential development of autoimmune hemolytic anemia (AIHA), thrombocytopenia, and/or neutropenia. [unboundmedicine.com]

  Concurrent or sequential thrombocytopenia and/or neutropenia could represent Evans syndrome Lymphadenopathy could indicate the presence of chronic lymphocytic leukemia or other lymphoproliferative disorder A malar rash and/or arthritis might suggest systemic [cancertherapyadvisor.com]

  Evans syndrome : Evan’s syndrome is seen when AIHA presents along with a second concomitant autoimmune cytopenia, most commonly thrombocytopenia and occasionally neutropenia. Children with Evans syndrome typically have a chronic course. [pedclerk.bsd.uchicago.edu]

• Normocytic Anemia

  Clinically normochrome and normocytic anemia, reticulocytosis, polychromasia in peripheral smear, spherocytes, indirect hyperbilirubinemia and increased lactate dehydrogenase are seen. Direct coombs test is the diagnostic test. [go.gale.com]

  In the former, direct blood loss should be investigated in the case of a normocytic anemia, and testing should include occult blood testing to rule out chronic GI bleeds. [pedclerk.bsd.uchicago.edu]

  The test also shows features of a normochromic, normocytic anemia with anisocytosis. [archivesofpathology.org]

• Hyperuricemia

  Wadsworth, Hyperuricemia and Reticulocytopenia in Association With Autoimmune Hemolytic Anemia in Two Children, American Journal of Clinical Pathology, 10.1309/8DXD-VJT9-UN60-YACT, 122, 6, (849-854), (2004). Deepa H. Trivedi and James B. Bussel, 21. [oadoi.org]

• Haptoglobin Decreased

  Over the course of the next 5 days, the Hb and Hct decreased to 4.1 g/dL and 12%, respectively, direct bili increased to 12.3 mg/day, reticulocytes slightly increased to 0.9%, and haptoglobin decreased to less than 8 mg/dL. [ncbi.nlm.nih.gov]

  Haptoglobin: -Decreased with intravascular hemolysis. Urine analysis: -When hemolysis has been acute and brisk the patient may have hemoglobinuria. [oncologynurseadvisor.com]

• Leukocytosis

  Mild leukocytosis and thrombocytosis may be present. The diagnosis of AIHA depends on the demonstration of a positive direct antiglobulin test (DAT), indicating the presence of immunoglobulin and/or complement on red blood cells. [clinlabnavigator.com]

  There was no fever, leukocytosis, or pertinent travel history to suggest malaria or babesiosis, and there was no evidence of spider or insect bites. [casesjournal.biomedcentral.com]

  Typically, patients with WAIHA exhibit a mild leukocytosis with neutrophilia but, occasionally, patients present with leucopenia, neutropenia, or thrombocytopenia due to associated immune-mediated neutrophil and/or platelet destruction.1 The laboratory [dovepress.com]

  A leukocytosis >10 G/L was observed in 19 patients and attributed to infection (n = 4), lymphoproliferative neoplasm (n = 4) or to bone marrow hyperstimulation secondary to AIHA (n = 11) as no other causes were identified. [journals.plos.org]

  Seo-Jin Jea, Soo-Young Kim, Byung Min Choi, Jung Hwa Lee, Kwang Chul Lee and Chan-Wook Woo, A Pediatric Case of Autoimmune Hemolytic Anemia followed by Excessive Thrombocytosis and Leukocytosis, The Korean Journal of Hematology, 10.5045/kjh.2007.42.3.288 [oadoi.org]

The rationale of treatment of AIHA lies in alleviating symptoms and in averting a hemolytic crisis by sudden decrease of red blood cells. Short-term and long-term effects of intervention may be anticipated. The treatment modality follows whether AIHA is primary or secondary, warm or cold antibody-mediated.

Transfusion may be needed depending upon the patient's condition and the aforementioned considerations. For warm antibody-mediated hemolytic anemia, blood group antigens are involved and RBC can be transfused safely except those obtained from an allogenic donor. Steroids should be administered immediately in WAIHA. For cold antibody-mediated hemolytic anemia, donor's blood is prewarmed with commercial warming coils.

Treatment of primary WAIHA

First-line treatment: Glucocorticoid is the drug of choice administered, per orem (prednisone or PDN), or parenteral methylprednisolone), at a dose of 1mg/kg/day. With this initial dose, hematocrit greater than 30% and hemoglobin level greater than 10g/dL should be expected in three weeks. Otherwise, a second-line treatment should be considered in lieu of steroids [13]. As soon the treatment goal is achieved, PDN is lowered to 20-30 mg/d within a few weeks, then, the dose is tapered slowly to 2.5-5 mg/d per month, or on alternate days to offset the deleterious side effects of prolonged steroid use. Meanwhile, hemoglobin and reticulocyte counts are closely monitored. Steroid therapy may be discontinued after 3-4 months when the patient is in remission at 5 mg PDN/day. Supplementation with calcium, vitamin D, bisphosphonates, and folic acid is recommended. About 80% of patients recover partially or completely after PDN therapy.

Second-line treatment: The following patients qualify under this option:

1. Patients who did not respond well to initial steroid treatment and required more than 15 mg/day PDN maintenance dose.
2. Patients who required between 15 and 0.1 mg/kg/day PDN may be advised to take this option.
3. Patients who respond well to PDN at 0.1 mg/kg/day or less may continue treatment with low-dose PDN.

In any case, benefit versus risk should be weighed for each treatment option. Rituximab and splenectomy are the only second-line alternatives with proven short-term efficacy. Splenectomy is the next best choice, because of high short-term efficacy and minimal surgical risk. Prior to surgery, patients should be vaccinated against pneumococci, meningococci and hemophilus. Pneumococci vaccination should be repeated every 5 years. Patients should be advised on the risk for venous thromboembolism and to consult a doctor for antibiotic therapy in case of fever or infection.

Laparoscopic splenectomy has been successful in almost all cases of primary AIHA, as the spleen is not too large. Postoperative thromboprophylaxis using low-molecular-weight heparin is prescribed for all patients even after discharge from the hospital. Withdrawal of steroids is gradual to avoid hemolytic crises in case of recurrence. About two thirds of patients (ranging from 38-82%) experience short-term partial or complete recovery after splenectomy.

An other option for second line treatment is rituximab, a monoclonal antibody against CD20 which is found on the surface of B cells of the adaptive immune system. The standard IV regimen is 375 mg/m2 on days 1, 8, 15, 22 as 4 doses. Patients on steroid therapy should continue taking steroids until the first signs of response to rituximab become evident.

The short-term benefit-to-risk ratio for rituximab is high and it is recommended for patients who can not undergo splenectomy because of high risk for venous thromboembolism, obesity, and presence of untreated hepatitis B virus infection. Second-line therapy often consists of high-dose immunoglobulin after or concurrent with PDN since the efficacy is considered high and the risk of side effects is reduced.

Treatment in patients with refractory/recurrent disease following splenectomy or rituximab: Patients in this category may undergo retreatment with low doses of PDN and, if both alternatives fail, splenectomy is the only other option.

Treatment in secondary WAIHA

• WAIHA associated with systemic lupus erythematosus: The preferred first-line treatments are steroids, prescribed as in primary AIHA, and with high rate of success. Recurrence rate was low (3-4/100 patient-years) in patients treated with a maintenance dose of 5-20 mg PDN (in some patients, with azathioprine or cyclophosphamide).
• CLL-associated WAIHA: Chronic lymphocytic leukemia (CLL)–associated WAIHA. CLL-associated WAIHA may be either “spontaneous” or drug-induced. The stage and clinical course of illness with CLL will affect treatment. Patients are older than those with primary AIHA, are at a greater risk of infection and with higher comorbidity rates. Steroids are considered appropriate for patients with early nonprogressive CLL although the efficacy of steroid monotherapy has yet to be established by controlled studies. Steroid monotherapy has been successful in the treatment of fludarabine-induced CLL-associated AIHA. In AIHA associated with untreated “active” CLL long-term steroid treatment with chlorambucil has been successful, with 84% CR/PR, and 54% of the patients in CR are relapse-free after 5 years. Toxicity is tolerable. Multidrug therapy has been tried with good results in patients with steroid-refractory AIHA in CLL. The treatment in this kind of patients is a combination of rituximab, dexamethasone and cyclophosphamide or rituximab, cyclophosphamide, vincristine, and PDN or and rituximab and cyclosporine, an effective immunomodulatory agent. Rituximab monotherapy was found to be less active and more toxic in CLL-WAIHA than in primary AIHA [14]. Data on long-term benefits and efficacy of rituximab are lacking.
• WAIHA in non-Hodgkin lymphoma: Intensive antilymphoma chemotherapy with or without rituximab is indicated for B-cell lymphoma, follicular lymphoma, angioimmunoblastic T-cell lymphoma, and other T-cell lymphomas.
• Drug-related WAIHA: AIHA may occur during or after exposure to drugs. Drug related AIHA has been linked to treatment of CLL with fludarabine and other antileukemic drugs. Fludarabine-triggered AIHA may be potentially fatal. This type of disorder responds to steroids although only 50% of patients go on remission without steroids. Interferon treatment likewise presdiposes to WAIHA especially in hepatitis C patients. Recovery from WAIHA follows after withdrawal of interferon.

Treatment of CAIHA

All cases of cold autoantibody hemolytic anemia (CAIHA) are presumably secondary. The underlying disorders in most cases are lymphoproliferative disorders, including IgM–monoclonal gammopathy, and less frequently, autoimmune disorders, infections, and rarely drugs.

• Primary chronic cold agglutinin disease:Anemia is often mild and chronic. Only 50% of patients require treatment with drugs. Patients need to avoid exposure to cold weather. CAIHA does not respond well to steroids and/or removal of spleen. The drug of choice is rituximab given at a standard dose for lymphoma.
• Secondary CAIHA: Chronic cold agglutinin AIHA may occur in indolent and aggressive B- and T-cell lymphoma. Antilymphoma chemotherapy is prescribed.

Except in the elderly and patients with cardiovascular disease, there is spontaneous recovery in AIHA. AIHA is a rare disorder and, in any case, mortality rates are generally low. Prognosis is good in secondary AIHA when co-existing disease conditions are recognized and eliminated clinically.

Autoimmune hemolytic anemia is triggered by the attachment of autoantibodies and C3 complement to erythrocytes. Warm or cold autoantibody types, but rarely mixed types are present [5] [6] [7]. Warm autoantibodies are self-generated immunoglobulins that adhere to the erythrocytes at body temperatures above normal. This occurs in warm antibody hemolytic anemia. In contrast, self-generated cold immunoglobulins are active at temperatures below normal, as in cold antibody hemolytic anemia. Erythrocytes that are coated with autoantibodies and complement rupture easily and are phagocytosed by macrophages in the liver and spleen.

Unable to recognize the RBC as "self", antibodies and complement are part of the immune system's reaction to a foreign body that needs to be eliminated. The presence of antibodies and complement can be demonstrated by direct Coombs test or direct antiglobulin test (DAT).

Secondary AIHA may result from other illnesses, such as neoplasms, lymphoproliferative disorders, infections, and other autoimmune diseases. Sometimes AIHA may develop following an allogeneic hematopoietic stem cell transplant.

The annual incidence was estimated to be 0.8 per 100,000 population [1]. An earlier estimate was 1-3 per 100,000 [8]. The prevalence is 17 cases per 100,000 population [2]. AIHA affects women more than men. Women who are affected, are usually under 50 years of age. Cold antibody hemolytic anemia is common among the elderly, while warm antibody hemolytic anemia affects all age groups.

As it were, the precise etiology of AIHA remains to be elucidated. What is known is that warm IgG antibody hemolytic anemia is associated with the Rh blood group system [9]. IgG-coated erythrocytes are targeted and destroyed in the spleen by macrophages [10]. In cold antibody AIHA, IgM-coated RBCs are bound by complement at the level of C3 resulting in the formation of a complex with other complement proteins, which facilitate opsonization and phagocytosis by hepatic macrophages [11].

Autoimmune hemolytic anemia can not be anticipated but one can be aware of conditions that may trigger the occurrence of the disorder.

The body's immune system is a closely coordinated network of structures and processes designed to provide protection against foreign bodies. In autoimmune diseases, as in systemic lupus erythematosus, this discriminatory function is abrogated. Hemolytic anemia is the process of premature destruction of red blood cells (RBCs). The disorder develops if the bone marrow is unable to counterbalance for the premature loss of RBCs.

The severity of anemia depends on the onset of hemolysis, be it gradual or sudden, and on the level of red cell destruction. Mild forms of hemolysis may be asymptomatic whereas severe hemolytic anemia may be critical, causing cardiopulmonary symptoms as decompensation and angina.

Autoimmune hemolytic anemia (AIHA) is a relatively rare condition. Primary or idiopathic AIHA is less frequently encountered than secondary AIHA. Further more, secondary AIHA requires that other underlying disorders be identified and treated as well. AIHA is diagnosed on the basis of laboratory tests and here substantial amounts of improvements have been made, on the other hand, treatment modalities have not advanced much [3] [4]. Meanwhile, steroids continue to be the mainstay in AIHA therapy. Splenectomy is recommended in refractory cases.

Autoimmune hemolytic anemia (AIHA) is a rare disorder in which the body' s immune system destroys its own red blood cells by releasing proteins that are meant to protect it from "outsiders" or so-called "non-self", such as infectious disease agents. The proteins are antibodies or immunogloblins G and M produced by the bone marrow and thymus gland, and complement, from the liver. Autoantibody and complement-coated red cells rupture or lyze and are eliminated by phagocytic while blood cells (phagocytes) in the liver and spleen. Red blood cells (erythrocytes) are killed prematurely, thus, are unable to attain their normal life span of 120 days, resulting in anemia (loss of hemoglobin) and symptoms like pallor and general debility.

The disorder affects women more than men. The exact cause of AIHA is not known, hence, it is called primary idiopathic AIHA. Secondary AIHA is usually associated with some underlying condition (infection, other autoimmune disease, malignancy, drugs) that need to be diagnosed and treated together with AIHA.

According to the type of immunoglobulin produced, AIHA is of two categories, namely:

• Warm autoantibody hemolytic anemia (WAIHA), in which IgG (immunoglobulin G) adheres to red blood cells at temperatures equal to or above normal body temperature and
• Cold autoantibody hemolytic anemia (CAIHA), in which immunoblobulin M (IgM) attaches to red blood cells at temperatures below normal.

AIHA patients may be asymptomatic if destruction of erythrocytes is not massive and onset is gradual. Symptoms, if any, are fatigue, weakness and pallor. CAIHA patients may experience bluish, cold hands and feet (acrocyanosis) and abdominal pain when eating cold food. Symptoms of fever and swollen, painful lymph nodes may accompany CAIHA.

The presence of young red blood cells (reticulocytes) in peripheral circulation beyond normal range indicate that the bone marrow is compensating for the loss of mature red cells. Antibodies and complement can be detected by appropriate immunological tests in serum or on the surface of erythrocytes. Routine clinical laboratory methods can confirm other hematological abnormalities.

Treatment may be deferred in asymptomatic cases. Otherwise several options are available. Initially, oral or parenteral corticosteroid can be administered in gradually diminishing doses. Second-line treatment include: IV administration of an immunoglobulin against CD20; drug combinations especially for WAIHA and CAIHA; and, finally, if chemotherapeutics fail, for some reason or another, splenectomy.

While there are surgical risks, there are also the side effects of chemotherapy to consider, the patient's status, and personal decision. Follow-up is important even after discharge from the hospital. In the case of secondary AIHA, protection against recurrence of infection and concomitant diseases must be considered.

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