Autoimmune hemolytic anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Autoimmune hemolytic anemia is a type of hemolytic anemia where the body’s immune system attacks its own red blood cells, leading to their destruction (hemolysis). Antibodies and associated complement system components become fixed onto the red blood cell surface. These antibodies can be detected with the Coombs test or direct Coombs test. Autoimmune hemolytic anemia can also be induced by infections such as Mycoplasma pneumoniae, drugs such as methyldopa and fludarabine, or malignancies such as chronic lymphocytic leukemia or non-Hodgkin lymphoma. Autoimmune hemolytic anemia is classified into 3 broad categories. These include warm-antibody type, cold-antibody type, and mixed-antibody type. Each category is characterized by a different autoantibody (IgG or IgM) and different optimal binding temperatures (37 degrees Celsius or 4-18 degrees Celsius). A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The risk factors for autoimmune hemolytic anemia include systemic lupus erythematosus and immunotherapeutic medications. The natural history of autoimmune hemolytic anemia begins with the hemolytic event. A diagnostic workup is typically initiated soon after the hemolytic event, and the hemolysis subsides after the start of corticosteroids. Most patients will generally achieve remission with no long-term complications. Complications of autoimmune hemolytic anemia usually include infection, thrombosis, iron overload, and end-organ damage from impaired oxygen delivery. Patients with autoimmune hemolytic anemia have a gradual onset of fatigue and can develop shortness of breath and decreased exercise tolerance. The symptoms of autoimmune hemolytic anemia depend on the severity of the disease. Laboratory findings in patients with autoimmune hemolytic anemia include anemia, positive Coombs test, positive indirect antiglobulin test, hemoglobinuria, low haptoglobin, increased spherocytes, and elevated lactate dehydrogenase (LDH). Not all patients will have all of these findings. The severity of hemolysis will determine the degree of laboratory abnormalities. The mainstay of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to the destruction of red blood cells. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades. Medications include corticosteroids, azathioprine, rituximab, mycophenolate mofetil, cyclosporine A, and cyclophosphamide. Splenectomy is the only surgical management option for patients with autoimmune hemolytic anemia. The response rate is moderately high. Assessment for candidacy for splenectomy involves evaluation of the surgical risk and the risk of sepsis from encapsulated organisms. Proper vaccinations must thus be given prior to splenectomy. The primary prevention strategies for autoimmune hemolytic anemia include avoidance of exposure to precipitants.

The history of studies on autoimmune hemolytic anemia begins in the early 20th century with the description of clinical syndromes involving low hemoglobin in the setting of a circulating antibody. Various groups reported on the production of antibodies that could bind to red blood cells at either warm or cold temperatures. Over the years, diagnostic tests were developed and optimized to determine the exact type of antibody involved in hemolysis. Treatment modalities were developed, beginning with corticosteroids. Other immunosuppressive medications, such as rituximab, were soon found to be effective in patients with hemolytic anemia.

Autoimmune hemolytic anemia is classified into 3 broad categories. These include warm-antibody type, cold-antibody type, and mixed-antibody type. Each category is characterized by a different autoantibody (IgG or IgM) and different optimal binding temperatures (37 degrees Celsius or 4-18 degrees Celsius). Each condition is associated with different triggers, including infections, medications, and malignancies. The warm-antibody type is the most common, and the mixed-antibody type is rare and not well characterized.

The pathophysiology of autoimmune hemolytic anemia is different for warm-antibody type and cold-antibody type anemia. The pathophysiology of warm-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgG, followed by extravascular hemolysis by splenic macrophages. The pathophysiology of cold-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgM, followed by intravascular hemolysis. The complement system has a significant role in autoimmune hemolytic anemia and involves the binding of classical complement proteins on the red blood cell surface, followed by cell lysis by the membrane attack complex. In summary, a variety of cell-mediated immunologic mechanisms underlie the pathophysiology of autoimmune hemolytic anemia.

Autoimmune hemolytic anemia is caused by primary and secondary conditions. Secondary conditions that cause autoimmune hemolytic anemia include malignancies, autoimmunity, and medications. Malignancies that cause autoimmune hemolytic anemia include chronic lymphocytic leukemia and non-Hodgkin lymphoma. Autoimmune conditions that cause autoimmune hemolytic anemia include systemic lupus erythematosus, primary biliary cirrhosis, and others. Medications that cause autoimmune hemolytic anemia include methyldopa and fludarabine.

A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The diagnosis of autoimmune hemolytic anemia can sometimes be made by first ruling out these other causes. It is important to distinguish amongst these conditions since the prognosis and treatment of each condition is different.

Overall, the incidence and prevalence of autoimmune hemolytic anemia are low. This condition affects a very small proportion of the population. Autoimmune hemolytic anemia affects men and women equally. There is no racial predilection for autoimmune hemolytic anemia.

The risk factors for autoimmune hemolytic anemia include systemic lupus erythematosus and immunotherapeutic medications. Systemic lupus erythematosus is thought to be a strong risk factor for autoimmune hemolytic anemia. However, immunotherapeutic medications may become a more prevalent risk factor in the coming years as these agents are becoming used increasingly for a variety of cancers. These medications include anti-PD-1 antibodies and anti-CTLA-4 antibodies.

Screening for autoimmune hemolytic anemia is not currently done routinely.

The natural history of autoimmune hemolytic anemia begins with the hemolytic event. A diagnostic workup is typically initiated soon after the hemolytic event, and the hemolysis subsides after the start of corticosteroids. Most patients will generally achieve remission with no long-term complications.

For patients who develop complications, these complications include infection, thrombosis, iron overload, and end-organ damage from impaired oxygen delivery. 

The prognosis of autoimmune hemolytic anemia depends on the severity of the immune activation. The prognosis is overall favorable for most patients.

Patients with autoimmune hemolytic anemia have a gradual onset of fatigue and can develop shortness of breath and decreased exercise tolerance. The symptoms of autoimmune hemolytic anemia depend on the severity of the disease.

Physical exam findings in patients with autoimmune hemolytic anemia vary depending on the severity of the disease. Examination findings include pallor, clubbing, jaundice, scleral icterus, splenomegaly, and abdominal tenderness.

Laboratory findings in patients with autoimmune hemolytic anemia include anemia, positive Coombs test, positive indirect antiglobulin test, hemoglobinuria, low haptoglobin, increased spherocytes, and elevated lactate dehydrogenase (LDH). Not all patients will have all of these findings. The severity of hemolysis will determine the degree of laboratory abnormalities.

There is no primary role for chest X-ray in diagnosis or evaluation of autoimmune hemolytic anemia, but chest X-ray can be useful to help diagnose other conditions associated with autoimmune hemolytic anemia, such as volume overload states from frequent transfusions.

CT scan is useful as an adjunct in the workup of autoimmune hemolytic anemia but is not used in the primary evaluation.

There is no primary role for MRI in the evaluation of autoimmune hemolytic anemia, but MRI can be helpful in assessing for spleen size or iron overload.

Ultrasound of the abdomen is useful in patients with autoimmune hemolytic anemia to assess for spleen size and mesenteric thrombosis.

An echocardiogram can be done in patients with autoimmune hemolytic anemia to assess for high-output cardiac failure and to assess for iron overload.

There are no other diagnostic studies used in the primary evaluation of autoimmune hemolytic anemia.

The mainstay of therapy for autoimmune hemolytic anemia is immunosuppression, since the pathophysiology of autoimmune hemolytic anemia involves immunological activation which leads to the destruction of red blood cells. Suppression of the immunological activation via medications has been the cornerstone of therapy for many decades. Medications include corticosteroids, azathioprine, rituximab, mycophenolate mofetil, cyclosporine A, and cyclophosphamide.

Splenectomy is the only surgical management option for patients with autoimmune hemolytic anemia. The response rate is moderately high. Assessment for candidacy for splenectomy involves evaluation of the surgical risk and the risk of sepsis from encapsulated organisms. Proper vaccinations must thus be given prior to splenectomy.

The primary prevention strategies for autoimmune hemolytic anemia include avoidance of exposure to precipitants. There is no significant role for secondary prevention of autoimmune hemolytic anemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

The history of studies on autoimmune hemolytic anemia begins in the early 20th century with the description of clinical syndromes involving low hemoglobin in the setting of a circulating antibody. Various groups reported on the production of antibodies that could bind to red blood cells at either warm or cold temperatures. Over the years, diagnostic tests were developed and optimized to determine the exact type of antibody involved in hemolysis. Treatment modalities were developed, beginning with corticosteroids. Other immunosuppressive medications, such as rituximab, were soon found to be effective in patients with hemolytic anemia.

• In 1904, Donath and Landsteiner described the syndrome of paroxsymal cold hemoglobinuria (PCH), which is due to an IgG autoantibody that can trigger intravascular hemolysis.^[1] Donath and Landsteiner described a biphasic hemolysin (IgG) that binds red blood cells and low temperatures and triggers complement-mediated intravascular hemolysis at warm temperatures. This is now known as the Donath-Landsteiner antibody.

• In 1945, Coombs described the anti-globin test, which is now known as the Coombs’ test or direct anti-globulin test.^[2] Coombs was able to detect antibodies coating red blood cells, but the limit of detection was poor, with the requirement that a red blood cell needed to be coated with 100-500 molecules of IgG. This threshold was later improved using the super Coombs’ test, which could detect presence of autoimmune hemolytic anemia even when fewer molecules of IgG were present on the red blood cell.

• In 1958, Leslie Zieve conducted a retrospective study on patients with alcoholic liver disease who had hemolytic anemia.^[3]

• In 1968, Balcerzak confirmed the phenomenon of hemolytic anemia in conjunction with cholestatic jaundice and hypercholesterolemia.^[3] This condition was known as Zieve syndrome, named after Leslie Zieve.

• In 1970, Zuelzer and colleagues from Wayne State School of Medicine in Detroit described the nature and proposed etiologies of autoimmune hemolytic anemia.^[4] They noted that autoantibodies could be produced by transient viral infections, such as CMV infection.^[4] It was noted that there was a close correlation between the onset of infection and presence of hemolysis. Zuelzer and colleagues proposed in their manuscript that the etiology for autoimmune hemolytic anemia was an immunologic handicap predisposing to occult viral infections.

• In 1973, Playfair and Marshall-Clarke developed a murine model of autoimmune hemolytic anemia. In this murine model, the mice developed autoantibodies against their own red blood cells upon injection of rat red blood cells. The rat red blood cells triggered antibody production, since the rat antigens were foreign, but the antibodies also reacted against self antigens (murine antigens).^[5] Clinically, the mice developed anemia, elevated reticulocyte count, and positive direct antiglobulin test (Coomb’s test). The mice had decreased survival.^[5]

• In 1985, P.D. Issit described the molecular events leading to the development of autoimmune hemolytic anemia.^[2] He proposed that an autoantibody was first made due to failure of self-recognition and failure of T cell regulation. The production of the autoantibody was less likely related to changes in the red blood cell itself. Other factors that Issit proposed as contributing factors for autoantibody production were drugs, systemic inflammation, infections, and genetic factors. Next, he proposed that this autoantibody could eliminate red blood cells. He proposed that anemia was a result of excess red blood cell destruction by the autoantibody, and this could not be compensated by increased marrow production of red blood cells.

• In 2001, Ikeda and colleagues noted an association between autoimmune hemolytic anemia and multiple other autoimmune conditions.^[6] He reports on Evan’s syndrome (the combination of immune thrombocytopenia purpura and autoimmune hemolytic anemia in a patient with Grave’s disease (an autoimmune condition of the thyroid gland characterized by the presence of thyroid-stimulating antibodies).

• In 2001, M. Zecca and colleagues reported on the use of rituximab and intravenous immunoglobulin (IVIg) in the treatment of autoimmune hemolytic anemia and pure red cell aplasia. Among 15 children with warm autoimmune hemolytic anemia treated with rituximab, 13 patients showed a favorable response.^[7]

• In 2003, S. Paydas and colleagues showed the association between marginal zone lymphoma and autoimmune hemolytic anemia. This followed multiple reports over the years demonstrating the association between a variety of lymphomas and either warm or cold autoimmune hemolytic anemia.

• In 2007, G. D’Arena and colleagues showed that rituximab at a dose of 375 mg/m2 IV weekly was effective in cohort of 11 patients with steroid-refractory autoimmune hemolytic anemia.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Autoimmune hemolytic anemia is classified into 3 broad categories. These include warm-antibody type, cold-antibody type, and mixed-antibody type. Each category is characterized by a different autoantibody (IgG or IgM) and different optimal binding temperatures (37 degrees Celsius or 4-18 degrees Celsius). Each condition is associated with different triggers, including infections, medications, and malignancies. The warm-antibody type is the most common, and the mixed-antibody type is rare and not well characterized.

Category	Features	Subtypes
Warm-antibody type	Accounts for ~75% of cases of autoimmune hemolytic anemia Due to IgG autoantibody[1] Binding occurs optimally at 37 degrees Celsius Extravascular hemolysis (reticuloendothelial system)	Idiopathic Systemic lupus erythematosus Evans’ syndrome[2] Chronic lymphocytic leukemia Non-Hodgkin lymphoma Drugs (methyldopa)
Cold-antibody type	Accounts for ~25% of cases of autoimmune hemolytic anemia Due to IgM autoantibody Binding occurs optimally at 4-18 degrees Celsius Intravascular hemolysis Recognition by the reticuloendothelial system Destruction by macrophages	Cold agglutinin disease[3] Paroxysmal cold hemoglobinuria[4] Mycoplasma infection[5] Malignancy
Mixed warm-antibody and cold-antibody type	Due to IgM subtype Mixed features	Systemic lupus erythematosus Various clinical entities Generally rare

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

The pathophysiology of autoimmune hemolytic anemia is different for warm-antibody type and cold-antibody type anemia. The pathophysiology of warm-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgG, followed by extravascular hemolysis by splenic macrophages. The pathophysiology of cold-antibody type autoimmune hemolytic anemia involves the coating of red blood cells with IgM, followed by intravascular hemolysis. The complement system has a significant role in autoimmune hemolytic anemia and involves the binding of classical complement proteins on the red blood cell surface, followed by cell lysis by the membrane attack complex. In summary, a variety of cell-mediated immunologic mechanisms underlie the pathophysiology of autoimmune hemolytic anemia.

The pathophysiology of warm autoimmune hemolytic anemia involves immunoglobulin G (IgG) antibodies binding to red blood cells at a temperature of 37 degrees Celsius. ^[1] The designation of warm is based on the fact the optimal binding temperature is 37 degrees Celsius, or normal body temperature. The IgG antibodies are typically polyclonal, meaning that they recognize a variety of antigens.^[2] Macrophages bind to the antibody-coated red blood cells via the Fc receptors and result in extravascular destruction. The Fc receptors include Fc-gammaRI (CD64), Fc-gammaRII (CD32), and Fc-gammaRIII (CD16). In 15-20% of cases, the autoantibody involved is IgA.^[2] It has been shown that induction of autoimmune hemolytic anemia is controlled by an immunosuppressive population of T lymphocytes known as regulatory T cells.^[1]

The pathophysiology of cold autoimmune hemolytic anemia, or cold agglutinin disease, involves immunoglobulin M (IgM) antibodies binding to Ii carbohydrate antigens of red blood cells at a temperature of 3-5 degrees Celcius. Agglutination typically occurs in the distal aspects of the extremities, such as the fingers and toes, because these areas have the lowest temperature.^[3] Clinical manifestations of this pathophysiology includes Raynaud’s phenomenon and acrocyanosis.^[3] The IgM molecules will trigger activation of the complement system, which results in red blood cell lysis.^[3] When IgM-bound red blood cells circulate towards warmer areas of the body, such as the trunk, IgM will dissociate from the red blood cells and complement C3b will remain bound.

The complement system is partially involved in the pathophysiology of warm autoimmune hemolytic anemia. There is a stronger role for the complement system in certain types of autoimmune hemolytic anemia, such as paroxysmal cold hemoglobinuria, cold agglutinin disease, and cold agglutinin syndrome.^[3] The complement system plays a role in both extravascular hemolysis and intravascular hemolysis in autoimmune hemolytic anemia.

• Complement activation by immunoglobulin subclasses: The immunoglobulin type that is most potent in activating complement is immunoglobulin M (IgM). However, IgM is not typically detected in the Coombs’ test, so IgM-mediated hemolysis will likely manifest as a Coombs’-negative hemolytic anemia. Immunoglobulin G (IgG) can activate complement, and the different IgG subclasses have differentially ability to activate complement. IgG3, for example, is a more potent activator of complement than IgG1. IgG4 and immunoglobulin A (IgA) are unable to activate complement.^[3]

• Extravascular hemolysis: The pathophysiology of extravascular hemolysis in autoimmune hemolytic anemia involves destruction of red blood cells outside the blood vessels and inside the liver and spleen. This is largely due to complement protein C3b-mediated phagocytosis of red blood cells. This process begins with the C3 convertase, which leads to production of complement protein C3b. This protein normally functions to opsonize bacteria and prevent infection, as part of the innate immune system. However, in pathological conditions such as autoimmunity, C3b binds to the surface of red blood cells. Opsonization by C3b triggers the macrophages of the reticuloendothelial system to phagocytose these opsonized cells via complement receptors on the surface of macrophages. This phagocytosis occurs extravascularly, typically in the liver or spleen. In some cases, ectoenzymes that are located on the surface of macrophages can perforate red blood cell membranes and create spherocytes.^[3] When the amount of red blood cell membrane removed exceeds the intracellular volume removed, the biconcave disc shape becomes a spherocytic shape. This is the pathophysiologic basis for spherocytes in autoimmune hemolytic anemia.^[3] Upon passage through the splenic vasculature, spherocytes can destroyed.

• Intravascular hemolysis: The pathophysiology of intravascular hemolysis in autoimmune hemolytic anemia involves destruction of red blood cells inside the blood vessels. This is largely due to activation of the terminal complement system.^[2] This complement cascade begins with complement protein C5, which is activated to C5a and C5b by the C5 convertase. C5a is a potent anaphylactic molecule, C5b is a membrane-bound protein that binds to downstream complement molcules, such as C6 though C9. The union of C5b and C6 though C9 forms the membrane attack complex. This complex can exert direct cytotoxic activity via the creation of pores in red blood cell membranes, resulting in cell lysis intravascularly.^[2]

• In some cases, the complement system can become activated very strongly, resulting in excess immune activation and red blood cell destruction, which can be lethal. This is due in part to a feedforward loop or positive feedback system, in which activation of the initial components of the complement cascade triggers activation of additional complement components.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Autoimmune hemolytic anemia is caused by primary and secondary conditions. Secondary conditions that cause autoimmune hemolytic anemia include malignancies, autoimmunity, and medications. Malignancies that cause autoimmune hemolytic anemia include chronic lymphocytic leukemia and non-Hodgkin lymphoma. Autoimmune conditions that cause autoimmune hemolytic anemia include systemic lupus erythematosus, primary biliary cirrhosis, and others. Medications that cause autoimmune hemolytic anemia include methyldopa and fludarabine.

• In most cases, autoimmune hemolytic anemia is due to a secondary cause, since there must be autoantibody production in response to a stimulus. Primary autoimmune hemolytic anemia can sometimes be caused by infections such as Mycoplasma pneumoniae or Epstein-Barr virus (mononucleosis).

Secondary autoimmune hemolytic anemia is due to an underlying condition, such as malignancy or autoimmune disorders.

• Malignancy: Blood-related cancers accounts for 50% of cases of secondary autoimmune hemolytic anemia. A variety of malignancies can cause secondary warm autoimmune hemolytic anemia including chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma.^[1] Lymphoproliferative disorders are more commonly associated with secondary autoimmune hemolytic anemia compared to myeloproliferative disorders. The premise behind lymphoproliferative disorders causing secondary autoimmune hemolytic anemia is that these conditions cause abnormal immune activation which results in plasma cells producing antibodies, which can then attack normal red blood cells.
  • Chronic lymphocytic leukemia (CLL): Approximately 10-25% of patients with CLL will develop autoimmune hemolytic anemia ^[1] The presence of autoimmune hemolytic anemia in patients with CLL is an indication for treatment of CLL and suggests a worse prognosis compared to the absence of autoimmune hemolytic anemia. In CLL, the malignant B lymphocytes are not the cells that produce anti-red blood cell antibodies.^[2] The mechanism by which CLL triggers autoimmune hemolytic anemia is thought to be related to antigen presentation by CLL cells and/or impaired self-tolerance upon release of cytokines by CLL cells.^[3]
  • Non-Hodgkin’s lymphoma (NHL): This condition is less commonly associated with autoimmune hemolytic anemia compared to CLL. The frequency of autoimmune hemolytic anemia in non-Hodgkin lymphoma is approximately 2-3%. A variety of NHLs can result in autoimmune hemolytic anemia.
  • Nodular lymphocyte-predominant Hodgkin lymphoma: In rare cares, autoimmune hemolytic anemia can be secondary to Hodgkin lymphoma.^[3]
• Autoimmune disorders^[4] : Systemic autoimmune conditions can also cause secondary autoimmune hemolytic anemia. The premise behind autoimmune conditions causing secondary autoimmune hemolytic anemia is failure of self-recognition by the immune system, resulting in aberrant immune activation and production of autoantibodies that attack normal cells, including red blood cells.^[4] These conditions include:
  • Systemic lupus erythematosus (SLE): One of the 11 diagnostic criteria for SLE is hematologic abnormalities such as cytopenias.
  • Hypothyroidism
  • Sjogren’s syndrome
  • Primary biliary cirrhosis
  • Primary hypogammaglobulinemia
  • Inflammatory bowel disease
• Medications: There are multiple medications associated with autoimmune hemolytic anemia.
  • Methyldopa: This medication is used for the treatment of hypertension.
  • Fludarabine: This medication is a chemotherapy agent that is approved for the treatment of chronic lymphocytic leukemia.
  • Immunotherapeutic agents: This class of medications includes PD-1 inhibitory antibodies, which are used for treatment of cancer.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

A variety of conditions comprise the differential diagnosis of autoimmune hemolytic anemia. These include microangiopathic hemolytic anemia, paroxysmal cold hemoglobinuria, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis, pernicious anemia, and chronic lymphocytic leukemia. The diagnosis of autoimmune hemolytic anemia can sometimes be made by first ruling out these other causes. It is important to distinguish amongst these conditions since the prognosis and treatment of each condition is different.

Type of anemia	MCV	Hemolysis	Intrinsic/Extrinsic	Hb concentration	RDW	Reticulocytosis	Haptoglobin levels	Specific Symptoms	Specific History	Physical examination	Genetics		Iron studies					Specific finding on blood smear
												Hepcidin	Serum iron	Serum Tfr level	Transferrin or TIBC	Ferritin	% Transferrin saturation
Autoimmune hemolytic anemia	Normocytic	+ (Intravascular)	Extrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Painful blue fingers and toes on exposure to cold temperature. Chest pain Chills Dizziness Tachycardia Headache Fatigue	Associated with: SLE CLL Mycoplasia pneumoniae infection	Painful, blue fingers and toes with cold weather	—	Normal	↓(Decreased)	Normal	—	—	—	RBC agglutination
Iron deficiency anemia	Microcytic	—	—	Hypochromic	↑(Increased)	Normal or ↓(Decreased)	Normal	Koilonychia Pica	Menorrhagia GI loss GI surgery Pregnancy	Glossitis Cheilosis Dysphagia	—	Normal	↓(Decreased)	↑(Increased)	↑(Increased)	↓(Decreased)	↓↓↓(Decreased)	Central pallor
Lead poisoning	Microcytic	—	—	Hypochromic	Normal	Normal or ↓(Decreased)	Normal	Burtonian lines Basophilic stippling Wrist drop Foot drop	House painted with chipped paint	Wrist drop Foot drop Burtonian lines	—	Normal	Normal or ↓(Decreased)	Normal	Normal	Normal or ↓(Decreased)	—	RBCs retain aggregates of rRNA (basophilic stippling)
Sideroblastic anemia	Microcytic	—	—	Hypochromic	Normal	Normal or ↓(Decreased)	Normal	Seborrheic dermatitis Glossy Tongue Tingling	Alcohol abuse most common cause Isoniazid use Chloramphenicol use Idiopathic (eg, refractory anemia with ringed sideroblasts [RARS], a myelodysplastic syndrome)	Patient present with symptoms of Vitamin B6, copper deficiency symptoms	Defect in ALA synthase gene Autosomal dominant Autosomal recessive X-linked	Normal	↑(Increased)	Normal	Normal or ↓(Decreased)	↑(Increased)	—	Ringed sideroblasts
Anemia of chronic disease	Microcytic	—	—	Hypochromic	Normal	Normal or ↓(Decreased)	Normal	Headache Shortness of breath	Rheumatoid arthritis SLE Neoplasm Chronic kidney disease	—	—	↑(Increased)	↓(Decreased)	Normal	↓(Decreased)	↑(Increased)	—	—
Thalassemia	Microcytic	—	—	Hypochromic	Normal	Thalassemia trait Normal or ↓(Decreased) Thalassemia Syndromes ↑(Increased)	Normal	α-thalassemia Hydrops fetalis β-thalassemia Skeletal deformities Chipmunk facies	Associated with parvovirus B19	Hepatomegaly Splenomegaly	α-thalassemia α– globin gene deletions Cis deletions Trans deletions β-thalassemia Point mutation in splice sites and promoter sequences	Normal	Normal to ↑(Increased)	Normal	Normal	↑(Increased)	Normal to increased	Target cells Anisopoikilocytosis
G6pd deficiency	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased) but usually causes resolution within 4-7 days	↓(Decreased)	Back pain Hemoglobinuria	History of using Sulfa drugs Antimalarials infections, Fava Beans	Back pain	Defect in G6PD enzyme X-Linked recessive	↓(Decreased)	Normal to ↑(Increased)	Normal	↑(Increased)	↑(Increased)	↑(Increased)	RBC with Heinz bodies Bite cells Blister cells
Pyruvate Kinase deficiency	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Hydrops fetalis Neonatal hyperbilirubinemia Iron overload Perinatal complications	Gallstones	Skin ulcers Splenomegaly of varying degree	Mutation in the PKLR and PKM gene mutations Autosomal recessive	Normal	↑(Increased)	Normal	Normal	↑(Increased)	—	Prickle cells Polychromatophilic erythrocytes
Sickle cell anemia	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Painful crisis Dactylitis Priapism Acute chest syndrome Avascular Necrosis Stroke Autosplenectomy Salmonella osteomyelitis	High altitude Low Oxygen Acidosis African-American race Parvovirus B19 infection	Dactylitis Priapism	Hbs point mutation causes a single amino acid replacement in β chain	Normal or moderately elevated	Normal	Normal	Normal or moderately elevated	↓(Decreased)	Normal	Increased erythropoiesis Howell-Jolly bodies Anisocytosis
HbC disease	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Splenomegaly Cholelithiasis Avascular necrosis of the femoral head Joint pains Increased risk of infections	Gallstones	Enlarged spleen	Glutamic acid–to-lysine mutation in β-globin	Normal	Normal	Normal	Normal	↓(Decreased)	—	Hemoglobin Crystals inside RBCs Target cells
Paroxysmal nocturnal hemoglobinuria(PNH)[1][2]	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Chronic hemolysis Fatigue Chest pain Dyspnea on exertion Headache	Associated with aplastic anemia Thrombosis	Hepatomegaly Ascites Papilledema Skin nodules	PIGA gene mutations Impaired synthesis of GPI anchor for decay-accelerating factor [DAF/CD55] and membrane inhibitor of reactive lysis [MIRL/CD59]	Normal	↓(Decreased)	Normal	↑(Increased)	↓(Decreased)	—	—
Hereditary spherocytosis	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Splenomegaly Aplastic crisis	Associated with parvovirus B19 Cholelithiasis Megaloblastic crisis	Splenomegaly	Mutations in Ankyrin,Band 3, Protein 4.2 and spectrin	Normal	↓(Decreased)	Normal	↑(Increased)	Normal	—	Small, round RBCs with less surface area and no central pallor ( MCHC)
Microangiopathic hemolytic anemia[3]	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Purpura Confusion Aphasia Diplopia	Associated with DIC TTP HUS SLE HELLP syndrome Hypertensive emergency	Numbness of an arm or hand Jaundice Pale conjunctiva	—	Normal	↓(Decreased)	Normal	—	↑(Increased)	—	Helmet cells
Macroangiopathic hemolytic anemia	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Pallor Fatigue	Associated with Prosthetic heart valves Aortic stenosis	Signs of anemia Complications of hemolysis Decreased vascular volume	Autoimmune	Normal	↓(Decreased)	Normal	—	—	—	Spherocytes or schistocytes
Infections	Normocytic	+ (Intravascular)	Intrinsic	Normochromic	↑(Increased)	↑(Increased)	↓(Decreased)	Fever	Associated with Malaria Babesia	Fever Signs of shock Headache	—	Normal	Normal	Normal	—	—	—	Trophozoite Maltese crosses
Iron deficiency anemia(Early)	Normocytic	—	—	Normochromic	↑(Increased)	↓(Decreased)	Normal	Fatigue Headache	Pica Glossitis Cheilosis	Koilonychia Conjuctival pallor Dry skin	—	Normal	↓(Decreased)	↑(Increased)	↑(Increased)	↓(Decreased)	↓(Decreased)	Microcytosis Pencil cells Ellyptocytosis Hypochromasia
Anemia of chronic disease	Normocytic	—	—	Normochromic	Normal	Normal or ↓(Decreased)	Normal	Fatigue Headache	History of: Rheumatoid arthritis SLE Neoplastic disorders Chronic kidney disease	—	—	↑(Increased)	↓(Decreased)	↑(Increased)	↓(Decreased)	↑(Increased)	↓(Decreased)	Normocytic cells but may become microcytic
Aplastic anemia	Normocytic	—	—	Normochromic	↑(Increased)	↓(Decreased)	Normal	Symptoms based on underlying condition	Exposure to Radiation Drugs like Benzene,chloramphenicol,alkylating agents Viral infections like EBV,HIV,Hepatitis Fanconi anemia Idiopathic like Immune mediated, primary stem cell defect	Short stature Cafe-au-lait spots Thumb defects Radial defects	Constitutive expression of Tbet Mutations in the perforin gene Mutations in SAP gene	Normal	↓(Decreased)	↓(Decreased)	Normal	↑(Increased)	↓(Decreased)	Pancytopenia Fatty infiltration
Chronic kidney disease	Normocytic	—	—	Normochromic	↑(Increased)	Normal /↑(Increased)	Normal	Polyuria Hematuria Edema	Pericarditis Encephalopathy Rectal incontinence Decreased libido Restless leg syndrome	Hypertension Mostly normal	—	↑(Increased)	↓(Decreased)	—	↓(Decreased)	↑(Increased)	↓(Decreased)	Normal
Folate deficiency	Macrocytic	—	—	Anisochromic	↑(Increased)	↓(Decreased)	Normal	No neurological symptoms vs B12 deficiency Odynophagia Angular stomatitis	Alcoholics History of using drugs like methotrexate, trimethoprim and phenytoin Low socioeconomic groups with poor nutrition Older people Pregnant and lactating women	Glossitis Signs of heart failure Anencephaly and spina bifida	Impaired DNA synthesis	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	RBC macrocytosis Hypersegmented neutrophils Pancytopenia in severe cases
Vitamin B12 deficiency	Macrocytic	—	—	Anisochromic	↑(Increased)	↓(Decreased)	Normal	Psychosis Insomnia Depression Cognitive slowing Restless leg syndrome	Pernicious anemia Crohn’s disease Gastrectomy Veganism Diphyllobothrium latum infection	Neurological deficit Myelopathy Memory loss with reduced attention span Nystagmus Positive romberg sign Positive Lhermitte’s sign	Impaired DNA synthesis	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	Senile neutrophil Anisocytosis Ovalocytes
Orotic aciduria	Macrocytic	—	—	Anisochromic	↑(Increased)	↓(Decreased)	Normal	Coma Gastro-intestinal manifestation	Episodic vomiting Rhabdomyolysis	Neurological manifestation	Autosomal recessive Deficiency of enzyme UMPS	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	—
Fanconi anemia	Macrocytic	—	—	Anisochromic	↑(Increased)	↓(Decreased)	Normal	Hypopigmentation Cafe-au-lait patches Radial ray abnormality	History of anemia at age 16	Significant for B\L short thumbs	Autosomal recessive X-linked recessive	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	Normal appearing WBC, RBC and Platelets But the number is greatly reduced
Diamond-Blackfan anemia	Macrocytic	—	—	Anisochromic	—	↓(Decreased)	Normal	Pale skin Sleepiness Heart murmurs	Associated with myelodysplastic syndrome Increased risk of AML	Triphalangeal thumbs Short stature Microcephaly Hypertelorism Ptosis Micrognathia	Mutations in: RPL5 RPL11 RPL35A RPS7 RPS10 RPS17 RPS19 RPS24 RPS26	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	—
Liver disease	Macrocytic	—	—	Anisochromic	↑(Increased)	↑(Increased)	Normal	Jaundice Abdominal pain Itchy skin	Hepatitis Binge drinking Gall bladder disease	Ascites Right upper quadrant pain Hepatomegaly Swelling in the legs Ankle swelling	—	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	Round macrocytes Target macrocytes
Alcoholism	Macrocytic	—	—	Anisochromic	↑(Increased)	↑(Increased)	Normal	Memory impairment Nausea Sweating	Increased history of alcohol intake Folic acid deficiency	Truncal obesity Asterixis Encephalopathy Spider angiomas Hematemesis Gynecomastia	—	Normal	↑(Increased)	↑(Increased)	↓(Decreased)	↑(Increased)	↑(Increased)	Oval macrocytes Hypersegmented neutrophils

Characteristic	Causes	Pathophysiology	Laboratory abnormalities	Physical examination	Therapy	Other associations
Autoimmune hemolytic anemia	Abnormal immune activation[4] Failure of self vs. non-self recognition[4] Infections Chronic lymphocytic leukemia Non-Hodgkin’s lymphoma Rheumatologic disease	Polyclonal antibody production that binds to and targets red blood cells for destruction intravascurly or extravascularly[4]	Positive Coombs’ test for IgG Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Pallor Jaundice Shortness of breath Tachypnea	Removal of offending agent Corticosteroids Cyclophosphamide Cyclosporine A Azathioprine Rituximab Splenectomy	Hemolysis can occur at warm or cold temperatures
Microangiopathic hemolytic anemia	Thrombotic thrombocytopenia purpura Hemolytic uremic syndrome Disseminated intravascular coagulation	Formation of small vessel microthombi	Schistocytes on peripheral blood smear Low hemoglobin Thrombocytopenia Elevated creatinine	Bleeding Thrombosis Pyrexia Altered mental status Neurologic deficits Impaired urine output	Treatment of the underlying cause Plasmapheresis if thrombotic thrombocytopenia purpura is the underlying cause	Can be life-threatening pending the underlying cause TTP required immediate treatment
Paroxysmal cold hemoglobinuria	Production of Donath-Landsteiner antibody, triggered by viral or bacterial infection[5]	Biphasic hemolysin (IgG) that binds red blood cells and low temperatures and triggers complement-mediated intravascular hemolysis at warm temperatures[5]	Positive Donath-Landsteiner antibody Microscopic hematuria Negative Coombs’ test for IgG or C3d Negative cold agglutinin titer Indirect hyperbilirubinemia Reticulocytosis Low haptoglobin Elevated LDH	Hematuria in the presence of cold weather Jaundice	Removal of offending agent Steroids Alternative immunosuppression	Associated with syphilis[5] Maternal IgG can cross the placenta and affect the fetus[5]
Paroxysmal nocturnal hemoglobinuria	Genetic defect in anchoring proteins for complement factors on red blood cells	Hemolysis due to loss of complement inhibition on the red blood cell surface, which in turn is due to defect in CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) or other glycophosphatidylinositol-anchored proteins on the red blood cell membrane	Absence of CD55 and CD59 by flow cytometry	Splenomegaly Abdominal tenderness Pallor	Eculizumab Immunosuppressive therapy	Associated with myelodysplastic syndrome Associated with mesenteric and portal venous thrombosis Risk for progression to acute myeloid leukemia
Hereditary spherocytosis[6]	Mutation in ankyrin[6] Mutation in alpha- or beta-spectrin[6] Mutation in band 3[6] Mutation in protein 4.2[6]	Diminished membrane integrity[6] Increased red blood cell fragility Splenic destruction of deformed red blood cells	Positive eosin-5-maleimide binding to red blood cells[6] Positive osmotic fragility testing[6] Spherocytes on peripheral blood smear	Pallor Jaundice Splenomegaly	Removal of offending medication High-dose vitamin B6 (up to 200mg daily) Avoidance of splenectomy Symptomatic transfusion support with iron chelation as needed	Can be autosomal dominant or recessive
Pernicious anemia[7]	Autoimmune gastritis[7] Production of anti-intrinsic factor antibodies[7] Production of anti-parietal cell antibodies[7]	Impaired vitamin B12 absorption due to absence of intrinsic factor	Low vitamin B12 level Presence of anti-intrinsic factor antibodies Presence of anti-parietal cell antibodies	Gastrointestinal discomfort Weakness Tingling Paresthesias	Lifelong vitamin B12 therapy (1000mcg daily)[7]	Associated with diabetes, thyroid disease, vitiligo and other autoimmune conditions
Chronic lymphocytic leukemia[8]	Mutations in hematopoietic stem cells and B lymphocytes	Clonal proliferation of malignant B lymphocytes	Elevated absolute lymphocyte count Anemia (Rai stage III) and thrombocytopenia (Rai stage IV)	Lymph node enlargement Splenomegaly in Rai stage II Hepatomegaly in Rai stage II Pallor Bleeding	Chemotherapy with rituximab Ibrutinib Venetoclax	Secondary autoimmune hemolytic anemia occurs in 10-25% of patients with CLL Treatment with corticosteroids or anti-leukemic therapy will correct the underlying anemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

Overall, the incidence and prevalence of autoimmune hemolytic anemia are low. This condition affects a very small proportion of the population. Autoimmune hemolytic anemia affects men and women equally. There is no racial predilection for autoimmune hemolytic anemia.

• The incidence of autoimmune hemolytic anemia overall is estimated to be between 0.8 in 100,000 and 3 in 100,000 per year.^[1][2][3]
• The incidence of warm autoimmune hemolytic anemia is estimated to be between 1.25 in 100,000 and 1.33 in 100,000.^[4]
• The incidence of drug-induced hemolytic anemia is 1 in 1,000,000.^[4]

• The prevalence of autoimmune hemolytic anemia is 17 in 100,000.^[3]

• The incidence of autoimmune hemolytic anemia in children is 0.2 in 100,000.^[3]
• The incidence of autoimmune hemolytic anemia is higher in adults that in children.^[2]

• Autoimmune hemolytic anemia affects all racial backgrounds equally.

• Autoimmune hemolytic anemia affects men and women equally.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Shyam Patel [2], Irfan Dotani

The risk factors for autoimmune hemolytic anemia include systemic lupus erythematosus and immunotherapeutic medications. Systemic lupus erythematosus is thought to be a strong risk factor for autoimmune hemolytic anemia. However, immunotherapeutic medications may become a more prevalent risk factor in the coming years as these agents are becoming used increasingly for a variety of cancers. These medications include anti-PD-1 antibodies and anti-CTLA-4 antibodies.

In the majority of cases of autoimmune hemolytic anemia, the etiology is not found, and patients have no predisposing risk factors. However, there are certain conditions that can predispose a person to develop autoimmune hemolytic anemia. These conditions have an immunologic or autoimmune basis, with aberrant immune activation that results in the generation of autoantibodies against oneself.

• Systemic lupus erythematosus:
  • The best autoimmune-related known risk factor is systemic lupus erythematosus.^[1]
  • SLE is a multisystem rheumatologic disease that is characterized by production of anti-double stranded DNA and anti-nuclear antibodies, with resultant autoimmune-mediated damage to a variety of organs including the kidneys, brain, skin, and peripheral blood.^[1]

• Immunotherapy:
  • Another risk factor for autoimmune hemolytic anemia is the use of immunotherapeutic agents to treat underlying cancer.
  • Treatment of immunotherapy-related autoimmune hemolytic anemia involves corticosteroids and rituximab.^[2]
    • Pembrolizumab^[3]: This is a humanized monoclonal antibody against PD-1. It is FDA-approved for metastatic or unresectable melanoma. It is approved for metastatic non-small cell lung cancer. It is approved for metastatic head and neck squamous cell carcinoma. It is approved for Hodgkin lymphoma in patients who experienced progression after 3 or more lines of therapy. It is indicated for metastatic urothelial cancer who are ineligible for platinum-based therapy. It is indicated for patients with metastatic gastric or gastroesophageal cancer expressing PD-L1. It is indicated for microsatellite instability-high (MSI-H) tumors after progression on chemotherapy.
    • Nivolumab^[4]: This is a monoclonal antibody against PD-1. This medication is FDA-approved for metastatic melanoma or for adjuvant treatment of melanoma involving regional lymph nodes. It is also approved for metastatic non-small cell lung cancer after progression on platinum-based chemotherapy. It is approved for renal cell carcinoma in patients who have received prior anti-angiogenic therapy. It is approved for patients with Hodgkin disease who have relapsed after autologous stem cell transplant and post-transplant brentuximab. It is approved for recurrent or metastatic head and neck squamous cell carcinoma after relapse with platinum-based chemotherapy. It is approved for metastatic urothelial cancer after progression on platinum-based chemotherapy. It is indicated for microsatellite instability-high (MSI-H) metastatic colon cancer after progression on standard chemotherapy. It is approved for hepatocellular carcinoma after treatment on sorafenib.
    • Ipilimumab^[5]: This is a humanized monoclonal IgG1 antibody against CTLA-4, which is an inhibitory receptor on T lymphocytes. It is FDA-approved for metastatic or unresectable malignant melanoma or for adjuvant treatment for non-metastatic melanoma that involves regional lymph nodes greater than 1mm.
    • Atezolizumab: This is a humanized monoclonal antibody against PD-L1 on tumor cells. This medication is FDA-approved for patients with advanced or metastatic urothelial cancer who are ineligible for cisplatin-based therapy or have disease progression within 12 months of neoadjuvant or adjuvant chemotherapy. It is also approved for patients with metastatic non-small cell lung cancer who have had disease progression on platinum-based chemotherapy.
    • Avelumab: This is a humanized monoclonal IgG1 antibody against PD-L1 on tumor cells. This medication is FDA-approved for patients above the age of 12 with metastatic Merkel cell carcinoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2], Irfan Dotani [3]

Screening for autoimmune hemolytic anemia is not currently done routinely.

• Screening for autoimmune hemolytic anemia is not currently done routinely.
• The incidence of autoimmune hemolytic anemia is low enough such that screening measures are not indicated.
• However, screening is done for other conditions associated with hemolytic anemia, such as sickle cell disease.^[1]
• One important manifestation of sickle cell disease is hyperhemolytic crisis, in which there is massive hemolysis.
• The United States and the United Kingdom have formal screening processes in place for sickle cell disease for newborns.
• Screening for sickle cell disease can prevent early childhood morbidity and mortality.
• Less developed countries, such as countries in Africa, do not have formal screening measures for sickle cell disease in place.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Assosciate Editor(s)-In-Chief: Prashanth Saddala M.B.B.S; Shyam Patel [2], Irfan Dotani [3]

The natural history of autoimmune hemolytic anemia begins with the hemolytic event. A diagnostic workup is typically initiated soon after the hemolytic event, and the hemolysis subsides after the start of corticosteroids. Most patients will generally achieve remission with no long-term complications. For patients who develop complications, these complications include infection, thrombosis, iron overload, and end-organ damage from impaired oxygen delivery. The prognosis of autoimmune hemolytic anemia depends on the severity of the immune activation. The prognosis is overall favorable for most patients.

• The natural history of autoimmune hemolytic anemia begins with the hemolytic event.
• Patients usually present for evaluation after they experience symptoms of fatigue, shortness of breath, or decreased exercise tolerance, as the anemia becomes worse.
• At hemoglobin levels of less than 8 g/dl, symptoms will usually be apparent.
• After presenting with these symptoms and a diagnosis of autoimmune hemolytic anemia is made, patients are started on corticosteroids.
• A response will usually occur within 1-2 weeks, after which symptoms will likely abate.
• Hemoglobin will return towards normal range, and this can be maintained via a steroid taper over the next few weeks to months.
• The natural history of autoimmune hemolytic anemia is self-limited in children if treated with corticosteroids.
• Most children respond very well to steroids and can lead normal lives without frequent relapses or recurrences.^[1]
• After recovery from the initial hemolytic episodes, it is unlikely that children will relapse.
• In older children, autoimmune hemolytic anemia can be chronic.^[1]

• Infection:^[2]
  • This is a serious concern in patients on long-term immunosuppressant therapy, especially in very young children (less than two years).
  • Infections occur due to impaired cell-mediated and humoral immunity.
  • Different immunosuppressive agents have different infectious complication profiles. For example, patients on rituximab can experience the rare but highly lethal infection with JC virus, which causes progressive multifocal leukoencephalopathy. Severe infections can result in death.
• Thrombosis:^[1]
  • Patients with autoimmune hemolytic anemia are at higher risk for thrombosis.
  • Thrombosis is more likely to occur in the active phase of hemolysis, such as during a severe hemolytic episode.
  • Anti-phospholipid antibodies are associated with the occurrence of thrombosis, as these antibodies bind to platelet membranes and induce thrombosis.
  • Patients with autoimmune hemolytic anemia who have a known history of thrombosis or are at high risk for thrombosis from other etiologies should begin anticoagulation.
• Iron overload:
  • Autoimmune hemolytic anemia is frequently complicated by iron overload due to frequent red blood cell transfusions.
  • In patients for whom steroids do not work, red blood cell transfusions can be an important temporizing measure to maintain the hemoglobin concentration with a safe range. For example, a typical hemoglobin threshold of 7g/dl is used when considering transfusion requirements.
  • However, a major adverse effect of frequent transfusions is iron overload, as iron can deposit in a variety of organs and result in impaired organ function. For these reasons, it is best to address the underlying cause (immune activation) of autoimmune hemolytic anemia, rather than provide transfusional support in the long-term.
    • Hepatic iron overload:
      • Iron deposition in the liver can be detected via T2 STAR magnetic resonance imaging (MRI) or by liver biopsy showing Prussian blue staining of hepatocytes.
      • Iron deposition in the liver can result in symptoms of abdominal distension, bleeding, jaundice, edema, and portal hypertension.
      • Treatment involves iron chelators such as deferoxamine, deferasirox, or deferiprone.
    • Cardiac iron overload:
      • Iron deposition in the heart can be detected via echocardiogram showing diastolic dysfunction, electrocardiogram (EKG) showing low voltage complexes, T2 STAR magnetic resonance imaging MRI, or cardiac biopsy showing Prussian blue staining of cardiomyocytes.
      • Iron deposition in the heart can result in symptoms of fatigue, shortness of breath, chest pain, edema, orthopnea, and paroxysmal nocturnal dyspnea.
      • Treatment involves iron chelators such as deferoxamine, deferasirox, or deferiprone.
• End-organ damage from impaired oxygen delivery: The effects of severe anemia affect a variety of organs and tissues that rely heavily on oxygen for energy metabolism. If hemoglobin decreases significantly, typically to values lower than 7g/dl, patients can experience impaired oxygen delivery and end-organ hypoxia. If hemoglobin decreases significantly, typically to values lower than 7g/dl, patients can experience impaired oxygen delivery and end-organ hypoxia.
  • Hypoxic brain injury:
    • This is a rare but important complication of severe anemia.
    • Low oxygen delivery to the brain as a result of autoimmune hemolytic anemia can result in ischemic injury to neurons and supporting tissue.
    • This is functionally similar to cerebrovascular accident, or stroke, which is due to atherosclerotic or embolic blockage of the cerebral circulation.
    • Patients can experience severe symptoms such as numbness, weakness, paralysis, and dysarthria, or slurred speech.
    • Patients can have a significant neurological impairment (including deficits in motor, sensory, cortical, and cerebellar function).
    • Overall, the likelihood of hypoxic brain injury due to autoimmune hemolytic anemia is very low.
  • Myocardial injury:
    • Autoimmune hemolytic anemia can result in impaired oxygen delivery to the cardiac tissue.
    • Myocardial infarction can result from poor oxygen content in the coronary circulation, which is functionally similar to having ischemia due to blockage by an atherosclerotic plaque.
    • Patients can experience severe symptoms such as shortness of breath, fatigue, and decreased exercise tolerance.
    • Anemia is associated with poor outcomes.^[3]
    • Patients can have long-term complications such as congestive heart failure.
  • High-output cardiac failure:
    • Hemolytic anemia can also be associated with high-output cardiac failure, in which the ejection fraction and cardiac output are higher than normal.
    • This is a manifestation of impaired oxygen delivery at the tissue level, for which the body compensated by increasing the circulatory output in an attempt to deliver more oxygen to tissues.
    • High-output cardiac failure can lead to congestive heart failure.

• The prognosis of autoimmune hemolytic anemia is variable and depends on the severity of the immune activation.^[1]
• In the early 2000s, studies reported a 10-year survival of 73%.^[1]
• In the current era, the survival is likely better.^[1]
• The mortality rate is 10-30%.^[1]
• Patients with concurrent immune thrombocytopenia purpura have a higher mortality rate. This condition is known as Evan’s syndrome.^[1]

The prognosis for secondary autoimmune hemolytic anemia depends on the underlying cause.

• Chronic lymphocytic leukemia :
  • In patients with chronic lymphocytic leukemia (CLL), for example, the hemolysis can continue for months to years if the underlying disease is high-risk. On the contrary, patients with CLL with favorable risk features may have limited hemolysis and excellent prognosis.
• Rheumatologic conditions:
  • In patients with systemic lupus erythematosus (SLE) or other rheumatologic conditions, the severity of the hemolytic anemia corresponds with the degree of aberrant immune activation. The severity of the hemolysis parallels other autoimmune components of these diseases. The prognosis in patients with severe SLE may be dismal.

The prognosis of other types of hemolytic anemias is variable and depends on the subtype of hemolytic anemia.

• Paroxysmal cold hemoglobinuria: In contrast to autoimmune hemolytic anemia, patients with paroxysmal cold hemoglobinuria have an excellent prognosis in the absence of cold weather.^[1] Patients can survive for years.
• Drug-induced hemolytic anemia: The prognosis for drug-related hemolysis is excellent with removal of the offending agent. Hemolysis usually resolves once the culprit drug is discontinued. After a period of weeks, the drug-dependent antibody will be eliminated, and the direct antiglobulin test will be negative. However, if the drug is not removed, hemolysis will likely continue and can contribute to severe ongoing anemia.^[1]
• Post-infectious cold hemoglobinuria: The prognosis of post-infectious cold hemoglobinuria is excellent upon clearance of the infectious agent, which is usually a virus. Hemolysis will cease after a period of weeks. The Donath-Landsteiner antibody, which is a biphasic hemolysin, will usually abate once the infection clears.^[1]

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