Question

    Autoimmune Hemolytic Anemia

    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.

    The disorder originates from the following process: auto-immune.

    Presentation

    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.

    Liver, Gall & Pancreas
    Hepatomegaly
    • Further examination by a veterinarian may reveal an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), a heart murmur and/or enlarged lymph nodes.[petwave.com]
    • 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]
    Hepatosplenomegaly
    • Signs and Symptoms Pallor Jaundice Lethargy Abdominal pain Low-grade fever Dark urine (sever hemolysis) Hepatosplenomegaly Diagnostic tests CBC with smear Normocytic, normochromic anemia Reticulocytosis (or rare reticulocytopenia) Spherocytes, schistocytes[pedclerk.bsd.uchicago.edu]
    • Lymphadenopathy or hepatosplenomegaly suggest an underlying lymphoproliferative disorder or malignancy; alternatively, an enlarged spleen may reflect hypersplenism causing hemolysis.[aafp.org]
    Jaundice
    • The hemolysis (destruction) of red blood cells results in the release of hemoglobin , which can lead to jaundice , and further on to anemia when the body cannot produce enough new red blood cells to replace the ones being destroyed.[petmd.com]
    • Jaundice (above) refers to the yellow color that is seen in tissues when the liver is overwhelmed with bilirubin, which is a yellow byproduct of the breakdown of red blood cells.[petwave.com]
    • His maternal grandmother also had anemia and jaundice, although the patient was not aware of the cause.[casesjournal.biomedcentral.com]
    • The dog’s, skin, ears and eyes may become yellow, called jaundice.[petwave.com]
    • Severe disease may cause jaundice or abdominal discomfort and fullness.[merckmanuals.com]
    Scleral Icterus
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  • Entire body system
    Anemia
    • The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms.[en.wikipedia.org]
    • Cold antibody hemolytic anemia is common among the elderly, while warm antibody hemolytic anemia affects all age groups.[symptoma.com]
    • anemia Approximate Synonyms Anemia, autoimmune hemolytic Autoimmune hemolytic anemia Chronic cold agglutinin disease Cold agglutinin disease, chronic Cold antibody hemolytic anemia Cold autoimmune hemolytic anemia Drug induced autoimmune hemolytic anemia[icd10data.com]
    Chills
    • 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]
    • The majority of these side-effects were grade I and II in severity and included nausea (2 pts), fever (1 pt), chills (2 pts), mild headache (2 pts), itching (1 pt) and rash (1 pt).[nature.com]
    • Within minutes, the patient may develop fever, chills, dyspnea, hypotension, and shock.[aafp.org]
    • Streptomycin, Acetaminophen, Cephaosporin, Dipyrone, Isoniazid, Tolmetin Autoantibody Mechanism a-Methyldopa, L-Dopa, Ibuprofen, Procainamide, Thioridazine Diagnosis Many symptoms of AIHA resemble those of other anemias and include nosebleeds, bleeding gums, chills[bio.davidson.edu]
    Fatigue
    • Mild degrees of anemia often cause only slight and vague symptoms, perhaps nothing more than easy fatigue or a lack of energy.[medical-dictionary.thefreedictionary.com]
    • The symptoms of autoimmune hemolytic anemia are similar to those of other types of anemia: fatigue, shortness of breath, heart palpitations, and pallor (unusually pale skin).[empowher.com]
    • We ask about general symptoms (anxious mood, depressed mood, insomnia, fatigue, and pain) regardless of condition.[patientslikeme.com]
    • 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.[orpha.net]
    Fever
    • If the disease is severe, fever, chest pain, syncope or heart failure may occur.[orpha.net]
    • These can include one or more of the following: Pale mucous membranes (pallor of the gums and nasal tissues) Weakness Lethargy Depression Disinterest in normal activities Fever Lack of appetite Vomiting Diarrhea Bloody stool (hematochezia; melena) Discolored[petwave.com]
    • Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, inability to do physical activity, and heart murmur.[hopkinsmedicine.org]
    • The following are some underlying causes of extrinsic hemolytic anemia: enlarged spleen hepatitis Epstein-Barr virus typhoid fever Escherichia coli streptococcus leukemia lymphoma tumors lupus Wiskott-Aldrich syndrome, an autoimmune disorder HELLP syndrome[healthline.com]
    • Symptoms of fever and swollen, painful lymph nodes may accompany CAIHA.[symptoma.com]
    Hodgkin's Disease
    • Immunohemolytic anemia and Hodgkin disease.[scielo.br]
    • Cancer : AIHA can be seen in children with Hodgkin’s disease, acute leukemia, myelodysplasia or post allogenic bone marrow transplant.[pedclerk.bsd.uchicago.edu]
    • Lymphoproliferative disorders such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma and Waldenstorm's macroglobulinemia are the leading causes of secondary cases. [15] , [17] Cold agglutinin syndrome (CAS) Cold-reactive autoantibodies[dx.doi.org]
    Pallor
    • Symptoms, if any, are fatigue, weakness and pallor.[symptoma.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]
    • Signs include pallor, lethargy, splenomegaly, and sometimes icterus, bilirubinuria and hemoglobinuria.[medical-dictionary.thefreedictionary.com]
    • The symptoms of autoimmune hemolytic anemia are similar to those of other types of anemia: fatigue, shortness of breath, heart palpitations, and pallor (unusually pale skin).[empowher.com]
    • These can include one or more of the following: Pale mucous membranes (pallor of the gums and nasal tissues) Weakness Lethargy Depression Disinterest in normal activities Fever Lack of appetite Vomiting Diarrhea Bloody stool (hematochezia; melena) Discolored[petwave.com]
    Rigor
    • URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability.[nytimes.com]
    • A 60-year-old man with fever, rigors, and sweats.[aafp.org]
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  • neurologic
    Dizziness
    • You also might experience shortness of breath and dizziness, and your skin may become pale or jaundiced.[everydayhealth.com]
    • Symptoms may include: Abnormal paleness or lack of color of the skin Yellowish skin, eyes, and mouth (jaundice) Dark-colored urine Fever Weakness Dizziness Confusion Can’t handle physical activity Enlarged spleen and liver Increased heart rate (tachycardia[hopkinsmedicine.org]
    • The signs of anemia are paleness, tiredness, headache, shortness of breath, dizziness, or heart palpitations.[ihtc.org]
    • These common symptoms include: paleness of the skin fatigue fever confusion lightheadedness dizziness weakness or inability to do physical activity Other less common signs and symptoms that are seen in those with hemolytic anemia include: dark urine yellowing[healthline.com]
    • When you have anemia, your body lacks oxygen, so you may experience one or more of the following symptoms: Weakness Shortness of breath Dizziness Fast or irregular heartbeat Pounding or "whooshing" in your ears Headache Cold hands or feet Pale or yellow[hematology.org]
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  • Immune System
    Splenomegaly
    • Medical Definition of autoimmune hemolytic anemia : 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[merriam-webster.com]
    • Hemolysis occurs mainly in the spleen, so mild splenomegaly is relatively common.[orpha.net]
    • Further examination by a veterinarian may reveal an enlarged spleen (splenomegaly), an enlarged liver (hepatomegaly), a heart murmur and/or enlarged lymph nodes.[petwave.com]
    • Signs include pallor, lethargy, splenomegaly, and sometimes icterus, bilirubinuria and hemoglobinuria.[medical-dictionary.thefreedictionary.com]
    • […] hemolytic anemia cold agglutinin disease acrocyanosis (different from Raynaud) painful and blue toes/fingers in the cold “colder” parts of the body symptoms resolve upon warming that part of the body acute hemolytic anemia with the cold Physical exam splenomegaly[medbullets.com]
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  • Skin
    Night Sweats
    • 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]
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  • respiratoric
    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.[orpha.net]
    • […] melena) Discolored urine (dark brownish or orange-ish urine due to abnormal presence of blood, hemoglobin and/or bilirubin) Excessive thirst (polydypsia) Excessive urination (polyuria) Difficulty breathing (rapid, shallow breathing; respiratory distress; dyspnea[petwave.com]
    • Dyspnea and the passage of red urine occur several hours after a large drink.[medical-dictionary.thefreedictionary.com]
    • The patient may complain of dyspnea or fatigue (caused by anemia).[aafp.org]
    • […] presentation A 40-year-old Caucasian American man with reactive arthritis, Graves' disease, type 2 diabetes mellitus, mitral valve prolapse, and Gilbert's disease was admitted with one month of progressive jaundice, fatigue, lightheadedness, and exertional dyspnea[casesjournal.biomedcentral.com]
    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.[orpha.net]
    Respiratory Distress
    • distress; dyspnea; shortness of breath) Exercise intolerance Elevated heart rate (tachycardia) Bounding pulses Icterus/Jaundice Jaundice (above) refers to the yellow color that is seen in tissues when the liver is overwhelmed with bilirubin, which is[petwave.com]
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  • cardiovascular
    Tachycardia
    • […] presence of blood, hemoglobin and/or bilirubin) Excessive thirst (polydypsia) Excessive urination (polyuria) Difficulty breathing (rapid, shallow breathing; respiratory distress; dyspnea; shortness of breath) Exercise intolerance Elevated heart rate (tachycardia[petwave.com]
    • Tachycardia, tachypnoea and hypotension if severe.[patient.info]
    • Symptoms may include: Abnormal paleness or lack of color of the skin Yellowish skin, eyes, and mouth (jaundice) Dark-colored urine Fever Weakness Dizziness Confusion Can’t handle physical activity Enlarged spleen and liver Increased heart rate (tachycardia[hopkinsmedicine.org]
    • Clinically it is manifested by weakness, exercise intolerance, hyperpnea which is only moderate, pallor of mucosae, tachycardia and a large increase in the intensity of the heart sounds.[medical-dictionary.thefreedictionary.com]
    • A resting tachycardia with a flow murmur may be present if the anemia is pronounced.[aafp.org]
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  • urogenital
    Dark Urine
    • 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.[orpha.net]
    • 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]
    • Those affected will often pass dark urine due to the hemoglobin released by destroyed RBCs being cleared from the body by the kidneys.[labtestsonline.org]
    • Other things to look for are yellow tint in the skin, gums, or whites of the eyes, and dark urine (the color of tea or coke).[ihtc.org]
    • Haemoglobinuria can occur in patients with intravascular haemolysis and it produces dark urine.[patient.info]
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  • hematological
    Cooley's Anemia
    • This "beta major" form (also called Cooley's anemia) may result in growth problems, jaundice , and severe anemia.[labtestsonline.org]
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  • Workup

    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.

    Pathology

    Biopsy
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  • Laboratory

    Serum
    Normocytic Normochromic Anemia
    • Signs and Symptoms Pallor Jaundice Lethargy Abdominal pain Low-grade fever Dark urine (sever hemolysis) Hepatosplenomegaly Diagnostic tests CBC with smear Normocytic, normochromic anemia Reticulocytosis (or rare reticulocytopenia) Spherocytes, schistocytes[pedclerk.bsd.uchicago.edu]
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  • Treatment

    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.

    Prognosis

    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.

    Complications

    Acute Anemia
    • Loss of Blood (Hemorrhagic Anemia): If there is massive bleeding from a wound or other lesion, the body may lose enough blood to cause severe and acute anemia, which is often accompanied by shock.[medical-dictionary.thefreedictionary.com]
    • He had acute anemia caused by his white blood cells killing his red ones and quite honestly we were making arrangements for his funeral.[shirleys-wellness-cafe.com]
    Acute Hemolytic Anemia
    • hemolytic anemia with the cold Physical exam splenomegaly jaundice Evaluation Two types of Coombs test direct (direct antiglobulin test, DAT) anti-IgG (Coombs reagent) added directly to patient's RBCs if RBCs coated with Ig (like in warm agglutinin disease[medbullets.com]
    • In cases of acute hemolytic anemia, the dog may experience fever, depression, weakness, fatigability , and pallor of the mucus membranes.[labbies.com]
    Autoimmune Disease
    • In autoimmune diseases, as in systemic lupus erythematosus, this discriminatory function is abrogated.[symptoma.com]
    • Overview of Evans syndrome (Coombs’-positive autoimmune hemolytic anemia and thrombocytopenia) AIHA: Results when IgG present which reacts with RBC antigens at room temperature Causes: viral infections, autoimmune disease (e.g.[errolozdalga.com]
    • It has been postulated that autoimmune diseases are a "mosaic" of genetic, immune, hormonal, and environmental factors.[casesjournal.biomedcentral.com]
    • Autoimmune diseases in general are difficult to diagnose, according to the American Autoimmune Related Diseases Association web site.[empowher.com]
    Congenital Hemolytic Anemia
    • About 20 years later, Hayem distinguished between congenital hemolytic anemia and an acquired type of infectious icterus associated with chronic splenomegaly.[en.wikipedia.org]
    • Causes of and Risk Factors for Hemolytic Anemia There are two major types of hemolytic anemia: Congenital hemolytic anemia is a condition in which red blood cells die off early due to an inherited defect within them.[everydayhealth.com]
    • Children were excluded if they had congenital hemolytic anemias, such as hemoglobinopathies, congenital spherocytosis and erythrocyte enzyme deficiencies.[scielo.br]
    Drug-induced Hemolytic Anemia
    • There is also a type of immune hemolytic anemia called drug-induced hemolytic anemia that you might guess is caused by an adverse reaction to certain drugs.[study.com]
    • See also autoimmune hemolytic anemia (above), alloimmune hemolytic anemia of the newborn. deficiency anemia nutritional anemia. drug-induced hemolytic anemia some drugs such as quinine, quinidine, para-aminosalicylic acid, phenacetin, penicillin, insecticides[medical-dictionary.thefreedictionary.com]
    • This is known as drug-induced hemolytic anemia.[healthline.com]
    • The DAT revealed an anti-IgG antibody on the RBC's, consistent with either a warm autoimmune hemolytic anemia (WAIHA) or a drug-induced hemolytic anemia (DIHA).[casesjournal.biomedcentral.com]
    Hemoglobinuria
    • Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection.[en.wikipedia.org]
    • The best treatment for paroxysmal cold hemoglobinuria is avoidance of exposure to cold.[merckmanuals.com]
    • […] por crioaglutininas , hemoglobinuria por aglutininas frías , anemia hemolítica por anticuerpos fríos , anemia hemolítica por crioaglutininas , enfermedad por crioaglutininas , Anemia hemolítica de anticuerpo frío German Kälteagglutininkrankheit , Kaelteagglutinin-Krankheit[fpnotebook.com]
    • Primary AIHA includes warm reactive, cold reactive and paroxysmal cold hemoglobinuria.[pedclerk.bsd.uchicago.edu]
    • (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease" and "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria" .)[uptodate.com]
    Hemolytic Uremic Syndrome
    • uremic syndrome (HUS) Thrombotic thrombocytopenic purpura (TTP) In paroxysmal nocturnal hemoglobinuria, hemolysis is due to intravascular complement-mediated destruction of erythrocytes.[emedicine.medscape.com]
    • uremic syndrome. [ 42 ] There is a general impression that additional studies should be carried out to establish the role and indications for EPO in hemolytic disorders.[emedicine.medscape.com]
    • These patients have concomitant thrombocytopenia and may have renal and abdominal symptoms (as in Hemolytic uremic syndrome from E. coli O157: H7 shiga-like toxin) Anemia: Can be the result of excess losses (hemolysis or direct blood loss) or insufficient[pedclerk.bsd.uchicago.edu]
    • (CBC complete blood count; LDH lactate dehydrogenase; DAT direct antiglobulin test; G6PD glucose-6-phosphate dehydrogenase; PT/PTT prothrombin time/partial thromboplastin time; TTP thrombotic thrombocytopenic purpura; HUS hemolytic uremic syndrome; DIC[aafp.org]
    Hereditary Spherocytosis
    • spherocytosis [39, 40 ] However, the ability of EPO to reduce transfusion requirement has been questioned in newborns with hereditary spherocytosis [41] and in post-diarrheal hemolytic uremic syndrome. [ 42 ] There is a general impression that additional[emedicine.medscape.com]
    • Splenomegaly: occurs with some causes - eg, hereditary spherocytosis.[patient.info]
    • The diagnosis and management of hereditary spherocytosis.[aafp.org]
    • Other less common types of inherited forms of hemolytic anemia include: Hereditary spherocytosis—results in abnormally shaped RBCs (so called spherocytes) that may be seen on a blood smear .[labtestsonline.org]
    • spherocytosis) Urinalysis hemoglobinuria hemosiderinuria Differential Diagnosis Treatment Warm agglutinin from best initial therapy to further steps in treatment ladder glucocorticoids IVIG splenectomy immunosuppressants Cold agglutinin keep extremities[medbullets.com]
    Hypersplenism
    • Glucose-6-phosphate dehydrogenase Sickle Cell Anemia Thalassemias Hereditary Spherocytosis Paroxysmal Nocturnal Hemogloburia b) Extrinsic Causes Autoimmune Hemolytic Anemia Infections – Malaria, Babesiosis Microangiopathic Hemolytic Anemias – DIC, TTP-HUS Hypersplenism[errolozdalga.com]
    • […] which may be viral or bacterial Medicines, such as penicillin, antimalarial medicines, sulfa medicines, or acetaminophen Blood cancers Autoimmune disorders, such as lupus, rheumatoid arthritis, or ulcerative colitis Certain tumors An overactive spleen (hypersplenism[hopkinsmedicine.org]
    • The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as intrinsic membrane defects, abnormal hemoglobins, erythrocyte enzymatic defects, immune destruction of erythrocytes, mechanical injury, and hypersplenism[emedicine.medscape.com]
    • […] sulfasalazine). [ 1 ] Non-immune: trauma (cardiac haemolysis, microangiopathic anaemia (found in patients with disseminated intravascular coagulation or haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura ), infection (malaria, sepsis), hypersplenism[patient.info]
    • Although a DAT was not reported, the author argued that the hemolysis was autoimmune because malaria and hypersplenism were excluded, and the anemia resolved with methotrexate and prednisolone treatment.[casesjournal.biomedcentral.com]
    Malaria
    • […] wrong with the RBC or hemoglobin, that predisposes to hemolysis Glucose-6-phosphate dehydrogenase Sickle Cell Anemia Thalassemias Hereditary Spherocytosis Paroxysmal Nocturnal Hemogloburia b) Extrinsic Causes Autoimmune Hemolytic Anemia Infections – Malaria[errolozdalga.com]
    • Infections, such as malaria and infectious mononucleosis (mono) Mother-baby blood group incompatibility—may result in hemolytic disease of the newborn Medications—certain medications such as penicillin can trigger the body to produce antibodies directed[labtestsonline.org]
    • Morbidity depends on the etiology of the hemolysis and the underlying disorder, such as sickle cell anemia or malaria.[emedicine.medscape.com]
    • EPO has pleiotropic effects and might inhibit macrophages in Salmonella infections. [43] EPO was reported to be helpful in treating cerebral malaria due to itspleiotropic effect and not its hematopoietic action. [ 44 ] Hence, EPO should be used judiciously[emedicine.medscape.com]
    • […] sulfonamides, sulfasalazine). [ 1 ] Non-immune: trauma (cardiac haemolysis, microangiopathic anaemia (found in patients with disseminated intravascular coagulation or haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura ), infection (malaria[patient.info]
    Microangiopathic Anemia
    • The disease is inherited as an autosomal recessive trait. fragmentation anemia see microangiopathic anemia (below).[medical-dictionary.thefreedictionary.com]
    • […] complication caused by other conditions Autoimmune Hemolytic Anemia as a symptom Disease Topics Related To Autoimmune Hemolytic Anemia Research the causes of these diseases that are similar to, or related to, Autoimmune Hemolytic Anemia: Anemia Hemolysis Microangiopathic[rightdiagnosis.com]
    Paroxysmal Cold Hemoglobinuria
    • Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection.[en.wikipedia.org]
    • The best treatment for paroxysmal cold hemoglobinuria is avoidance of exposure to cold.[merckmanuals.com]
    • (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease" and "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria" .)[uptodate.com]
    • Primary AIHA includes warm reactive, cold reactive and paroxysmal cold hemoglobinuria.[pedclerk.bsd.uchicago.edu]
    • It can be idiopathic or secondary, and classified as warm, cold (cold hemagglutinin disease (CAD) and paroxysmal cold hemoglobinuria) or mixed, according to the thermal range of the autoantibody.[haematologica.org]
    Paroxysmal Nocturnal Hemoglobinuria
    • Physical destruction of RBCs by, for example, an artificial heart valve or cardiac bypass machine used during open-heart surgery Paroxysmal Nocturnal Hemoglobinuria (PNH)—a rare condition in which the different types of blood cells including RBCs, white[labtestsonline.org]
    • nocturnal hemoglobinuria, hemolysis is due to intravascular complement-mediated destruction of erythrocytes.[emedicine.medscape.com]
    • nocturnal hemoglobinuria. 96 , 97 However, these observations need to be confirmed in prospective trials.[haematologica.org]
    • Autoimmune hemolytic anemia and paroxysmal nocturnal hemoglobinuria.[dx.doi.org]
    Pyruvate Kinase Deficiency
    Sickle Cell Disease
    • Diagnosis is made by first ruling out other causes of hemolytic anemia, such as G6PD, thalassemia, sickle-cell disease, etc.[en.wikipedia.org]
    • The first step towards establishing a diagnosis is to rule out the causes of hemolytic anemia, such as sickle cell disease, thalassemia, glucose-6-phosphatase deficiency (G6PD), and other conditions.[dovemed.com]
    • Settings in which EPO therapy has reduced transfusion requirements include the following: Children with chronic renal failure [ 35 ] Autoimmune hemolytic anemia associated with reticulocytopenia [36] A patient with sickle cell disease undergoing hemodialysis[emedicine.medscape.com]
    • Types of Autoimmune Hemolytic Anemia Autoimmune Hemolytic Anemia Message Boards Related forums and medical stories: Blood Conditions (151) Anemia - ice chewing small red spots on arms legs back chest Low Platelets, Low white blood count Sc sickle cell[rightdiagnosis.com]
    • cell disease Hemoglobin electrophoresis, genetic studies Folate, transfusions URINARY TESTS In cases of severe intravascular hemolysis, the binding capacity of haptoglobin is exceeded rapidly, and free hemoglobin is filtered by the glomeruli.[aafp.org]
    Toxic Hemolytic Anemia
    • Excessive Destruction of Red Blood Cells (hemolytic anemia): Anemia may also develop related to hemolysis due to trauma, chemical agents or medications (toxic hemolytic anemia), infectious disease, isoimmune hemolytic reactions, autoimmune disorders,[medical-dictionary.thefreedictionary.com]
  • more...
  • Etiology

    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.

    Epidemiology

    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.

    Sex distribution
    Age distribution

    Pathophysiology

    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].

    Prevention

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

    Summary

    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.

    Patient Information

    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.

    Self-assessment

    References

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    9. Barros MM, Blajchman MA, Bordin JO. Warm autoimmune hemolytic anemia: recent progress in understanding the immunobiology and the treatment. Transfus Med Rev. 2010; 24: 195–210. 
    10. Seve P, Philippe P, Dufour JF, Broussolle C, Michel M. Autoimmune hemolytic anemia: classification and therapeutic approaches. Expert Rev Hematol. 2008; 1(2): 189-204.
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