Autoimmune Hemolytic Anemia

8 Interesting Facts of Autoimmune Hemolytic Anemia 

  1. Autoimmune hemolytic anemia is a rare heterogenous disorder in which autoantibodies target RBC antigens, resulting in the premature destruction of RBCs with inadequate compensation
  2. Classified into warm autoimmune hemolytic anemia and cold autoimmune hemolytic anemia based on the optimal autoantibody-RBC reactivity temperatures, both of which may be primary (idiopathic) or secondary to a variety of conditions 
  3. Clinical presentation is variable; may be insidious or sudden and acute, with signs and symptoms related to anemia or hemolysis (eg, jaundice, dark urine)
  4. Diagnosis is based on laboratory findings of anemia, reticulocytosis, and evidence of hemolysis (eg, increased unconjugated bilirubin, increased lactate dehydrogenase, decreased haptoglobin levels) and serologic evidence of autoantibodies to RBCs
  5. Correct serologic diagnosis of autoimmune hemolytic anemia is essential before initiating therapy as the approach to patients with warm hemolytic anemia differs from those with cold agglutinin syndrome; likewise, in patients with secondary autoimmune hemolytic anemia, treatment should be directed toward the underlying disease
  6. There is no well-established evidence-based treatment for autoimmune hemolytic anemia; therapies are selected according to patient and physician preferences
  7. Warm autoimmune hemolytic anemia is generally treated first with oral corticosteroids, with splenectomy, rituximab, or immunosuppressants reserved for those who fail to respond or relapse 
  8. Cold agglutinin syndrome is often mild and may require no treatment aside from protective measures against exposure to cold temperatures; treatment, if required, consists of rituximab (alone or in combination with other agents) 

Pitfalls

  • Direct antiglobulin testing may occasionally yield false-negative results; clinical correlation is required before excluding diagnosis of autoimmune hemolytic anemia on basis of negative direct antiglobulin test result 
  • Autoimmune hemolytic anemia is a rare disorder in which autoantibodies target RBC antigens, resulting in the premature destruction of RBCs with inadequate compensation
  • Estimated incidence of 1 to 3 cases in 100,000 persons per year 

Classification

  • Classified based on the optimal autoantibody-RBC reactivity temperatures and further classified as primary (idiopathic) or secondary in nature 
    • Warm autoimmune hemolytic anemia
      • Warm autoantibodies react most strongly near 37 °C and exhibit decreased affinity at a lower temperature 
      • Constitutes approximately 75% of all cases of autoimmune hemolytic anemia 
        • This is the most commonly occurring type in children aged 2 to 12 years 
      • IgG antibodies directed mainly against epitopes of the Rh blood group system are most common in this class 
        • Interleukin-10 and interleukin-12 production is also thought to play a role in the altered immune response 
      • Direct antiglobulin test results are positive for IgG or IgG and C3d (complement component 3d) 
      • Subclassified as primary (idiopathic) or secondary, based on cause 
        • Primary (idiopathic)
          • No apparent association with an underlying disorder 
        • Secondary
          • Associated with various lymphoproliferative disorders (eg, non-Hodgkin lymphoma, chronic lymphocytic leukemia)
          • Associated with rheumatic disorders (eg, systemic lupus erythematosus)
          • Associated with nonlymphoid malignancies (eg, ovarian cancer)
          • Associated with chronic inflammatory disorders (eg, ulcerative colitis)
          • Drug-induced autoimmune hemolytic anemia
          • Associated with neoplastic diseases, lymphoproliferative diseases, and autoimmune disorders 
    • Cold autoimmune hemolytic anemia
      • Cold autoantibodies react most strongly near 0 °C to 4 °C and typically show little affinity at physiologic temperatures
      • Subtypes
        • Cold agglutinin syndrome
          • Primarily occurs in people who are middle-aged or elderly 
          • Comprises approximately 15% of all autoimmune hemolytic anemia cases 
          • Direct antiglobulin test results positive for C3d 
          • IgM directed against the I/i blood group system 
          • Subclassified as primary (idiopathic) or secondary, based on cause
            • Secondary forms 
              • Postinfectious (eg, mycoplasma, infectious mononucleosis)
              • Associated with B-cell lymphoproliferative disorder
        • Paroxysmal cold hemoglobinuria:
          • Activated primarily by polyclonal IgG antibodies
            • Bithermic IgG directed against the erythrocyte P antigen on RBCs 
          • Positive Donath-Landsteiner antibody test result 
          • Primarily considered a form of secondary disease and develops most often in children within the first week of infection (upper respiratory infections most common) 
            • May also be secondary to syphilis in adults
    • Mixed autoimmune hemolytic anemia
      • Characterized by the presence of both warm IgG autoantibodies and high-titer IgM cold agglutinins 
      • Accounts for less than 5% of total autoimmune hemolytic anemia cases and is even less common in children 
      • Direct antiglobulin test result is positive for IgG and C3d 
      • Subclassified as primary (idiopathic) or secondary, based on cause
        • Secondary forms include those associated with lymphoproliferative disorder or with autoimmune diseases 
  • Drug-induced autoimmune hemolytic anemia
    • Relatively rare and underdiagnosed class of autoimmune hemolytic anemia with variation in the degree of severity of the associated hemolysis, depending on the causative drug 
    • 150 drugs are estimated to be associated with this disorder 
    • Further classified depending on whether or not the drug is required to be present for hemolytic activity to occur 
      • Drug-dependent autoimmune hemolytic anemia (occurs only in presence of offending drug)
        • Hapten type: noncovalent binding of the drug to RBCs and subsequent targeting by autoantibodies in a drug-dependent manner 
        • Drug-autoantibody immune (ternary) complexes that are mediated by a complement-dependent hemolysis that is drug dependent 
      • Drug-independent autoimmune hemolytic anemia (can occur even after cessation of the offending drug) 

Clinical Presentation

History

  • Clinical presentation is highly variable
    • Onset may be insidious or sudden and acute
    • Patients may describe symptoms related to their anemia including fatigue, weakness, dyspnea with exertion, palpitations, and dizziness
    • In very severe cases that are often of rapid onset, patients may present with fever, pallor, jaundice, and dark urine
    • Patients, particularly those with secondary autoimmune hemolytic anemia, may describe additional symptoms including weight loss, joint pain, abdominal pain, chest pain, cough, and fever
    • Patients with cold autoimmune hemolytic anemia may exhibit episodic signs of acute hemolysis with hemoglobinuria (dark urine) induced by cold temperatures; particularly seen in paroxysmal cold hemoglobinuria
      • Patients with paroxysmal cold hemoglobinuria may develop aching pains in legs and back, abdominal cramps, and headache, often followed by chills and fever within minutes to hours of cold exposure 
        • Raynaud phenomenon and cold urticaria sometimes occur during an attack 
        • First passed urine after onset of symptoms usually contains hemoglobin (hemoglobinuria) and may appear dark 
    • Patients may have history of drug exposure temporally related to symptom onset
      • Patient history may include use of the second-generation cephalosporin cefotetan, or the third-generation ceftriaxone
      • Hapten/drug absorption and autoimmune types of drug-induced autoimmune hemolytic anemia result in mild to moderate hemolysis with insidious onset over a period of days to weeks; may be caused by penicillin and methyldopa respectively 
      • Immune (ternary) complex–mediated drug-induced autoimmune hemolytic anemia (may be precipitated by cephalosporins or quinidine) are typically associated with a sudden onset of severe hemolysis and hemoglobinuria

Physical examination

  • Physical findings are variable and may depend upon the presence and nature of an underlying disease
    • In many cases, physical examination findings are normal
    • Splenomegaly present in approximately 20% of patients 
    • In severe cases, fever, tachycardia, skin and nail bed pallor, jaundice, hepatomegaly, hyperpnea, and signs of heart failure may be present 

Causes

  • Autoimmune hemolytic anemia develops when anti-RBC antibodies (eg, IgG and/or IgM) bind to RBC surface antigens and increase the destruction of erythrocytes via direct lysis through the final components of the complement system or via antibody-dependent cell-mediated cytotoxicity 
  • In approximately half of all cases, the cause of autoimmune hemolytic anemia cannot be determined (ie, idiopathic or primary disorder) 
  • Secondary forms account for 40% to 50% of cases of autoimmune hemolytic anemia and may occur in association with the following conditions: 
    • Autoimmune disorders
      • Lupus erythematosus
      • Rheumatoid arthritis
      • Antiphospholipid syndrome
      • Inflammatory bowel disease (Crohn disease and ulcerative colitis)
      • Primary biliary cirrhosis
      • Evan syndrome
      • Autoimmune thyroid disease
    • Immunodeficiency disorders
      • Common variable immunodeficiency
      • Autoimmune lymphoproliferative syndrome
      • IgA deficiency
      • Posttransplant state (solid organ and autologous bone marrow transplant)
    • Lymphoproliferative disorders
      • Chronic lymphocytic leukemia
      • Non-Hodgkin lymphoma
      • Hodgkin lymphoma
      • Angioimmunoblastic lymphadenopathy
      • Waldenström macroglobulinemia
    • Infections
      • Epstein Barr virus
      • Cytomegalovirus
      • HIV
      • Hepatitis C
      • Mycoplasma pneumonia
      • Varicella, rubella, or human parvovirus B19 (rarely)
  • Autoimmune hemolytic anemia can also develop via a variety of mechanisms after the administration of certain drugs 
    • SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection 
    • Most common drug linked to drug-induced autoimmune hemolytic anemia is methyldopa
    • Hapten and drug-absorption mechanisms
      • Drugs such as penicillins, cephalosporins, tetracycline, carbromal, hydrocortisone, oxaliplatin, and tolbutamide
    • Immune/ternary complex mechanisms
      • Drugs such as stibophen, metformin, quinine, quinidine, amphotericin B, rifampicin, antazoline, thiopental, tolmetin, probenecid, nomifensine, cephalosporins, diclofenac, and doxepin
    • Autoantibody mechanism
      • Drugs such as cephalosporins, tolmetin, α-methyldopa, L-DOPA, mefenamic acid, teniposide, pentostatin, cladribine, fludarabine, lenalidomide, procainamide, and diclofenac
    • Unknown methods of causation
      • Drugs such as mephenytoin, phenacetin, insecticides, chlorpromazine, acetaminophen, ibuprofen, thiazides, omeprazole, carboplatin, nalidixic acid, erythromycin, and streptomycin
    • Nonimmunologic protein absorption mechanisms
      • Cephalosporins, carboplatin, cisplatin, and oxaliplatin

Risk factors and/or associations

Age
  • Primarily limited to adults
    • Warm autoimmune hemolytic anemia tends to peak in the fourth and fifth decades of life 
    • Idiopathic, or primary, chronic cold agglutinin syndrome has its peak incidence after age 50 years and most commonly occurs in the seventh decade of life 
  • May occur in children with primary immunodeficiency disease or autoimmune lymphoproliferative syndrome
  • Self-limited form (paroxysmal cold hemoglobinuria) most commonly occurs in children and is usually precipitated by viral illness 
Sex
  • Warm and cold autoimmune hemolytic anemia are more common in women than in men 
Other risk factors/associations
  • Hematopoietic stem cell transplant
    • Severe and fatal autoimmune hemolytic anemia may complicate hematopoietic stem cell transplant 
      • Reported incidence of 3.6%; associated with transplant from unrelated donors 
  • Viral infections (eg, rubeola, mumps, influenza, adenovirus, undefined upper respiratory infections) may precede development of childhood paroxysmal cold hemoglobinuria 

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is based on:
    • Clinical manifestations of hemolysis (ie, jaundice and abnormally dark urine) and anemia
    • Laboratory findings of anemia, reticulocytosis, and evidence of hemolysis (ie, increased unconjugated bilirubin, increased lactate dehydrogenase, and decreased haptoglobin levels)
    • Serologic evidence of autoantibodies to RBCs
  • Diagnostic procedures
    • Obtain CBC, reticulocyte count, and peripheral blood smear 
    • Measure serum haptoglobin levels, lactate dehydrogenase, and bilirubin and urine hemoglobin to determine presence of hemolysis and to differentiate extravascular and intravascular disease 
    • Establish presence of an autoantibody on patient’s RBCs by the direct antiglobulin test (direct Coombs test)
    • Evaluate patients diagnosed with cold agglutinin syndrome for evidence of infection, lymphoma, or autoimmune disorders 

Laboratory

  • CBC
    • Hematocrit level
      • In warm autoimmune hemolytic anemia, hematocrit level may be greater than 10% or compensated with near–reference range hematocrit level 
      • In cold autoimmune hemolytic anemia, hematocrit levels are often as low as 15% to 20% 
      • Paroxysmal cold hemoglobinuria exhibits rapid fall in hematocrit level during paroxysm 
    • Platelet count is low to within reference range 
    • Mild leukocytosis representing predominantly neutrophils, but also neutropenia, may be present 
    • Reticulocyte index is usually greater that 3%; however, 15% to 40% of patients initially present with an index of no more than 2% 
  • Blood smear
    • Spherocytosis is a common finding in peripheral blood smear in warm hemolytic anemia 
      • Findings such as anisocytosis and polychromasia reflect an increased reticulocyte count 
    • Polychromasia and macrocytosis present from the reticulocytosis 
    • Nucleated RBCs may be present 
    • Erythrophagocytosis and microspherocytes may also be present 
  • Lactate dehydrogenase
    • There is an increase in serum lactate dehydrogenase owing to hemolysis 
  • Haptoglobin
    • Serum levels are reduced in the presence of moderate to severe hemolysis 
      • Serum haptoglobin typically decreases to less than 25 mg/dL in 85% of patients 
    • Serum levels may be within reference range or higher if the hemolysis is mild and hepatic function is still adequate 
  • Bilirubin
    • Mild to moderate increase in indirect (unconjugated) bilirubin concentration owing to hemolysis 
  • Direct antiglobulin test (Coombs test) and subsequent serum antibody identification 
    • Demonstrates the presence of antibodies or complement on the surface of RBCs that is the hallmark of autoimmune hemolysis
    • Positive test result is indicated by binding of anti-IgG or anti-C3 antibodies to patient’s antibody- or complement-coated RBCs
    • 3 principal patterns of RBC sensitization may be detected, reflecting the likely type of autoimmune hemolytic anemia: 
      • Anti-IgG–positive direct antiglobulin test result
        • Warm antibody autoimmune hemolytic anemia
        • Drug-immune hemolytic anemia
      • Anti-C3–positive direct antiglobulin test result
        • Cold agglutinin syndrome
        • Paroxysmal cold hemoglobinuria
        • Drug-immune hemolytic anemia
        • Warm antibody autoimmune hemolytic anemia with subthreshold IgG deposition (occasionally)
      • Anti-IgG plus anti-C3–positive direct antiglobulin test result
        • Mixed warm- and cold-antibody autoimmune hemolytic anemia
        • Drug-immune hemolytic anemia
        • Warm-antibody autoimmune hemolytic anemia
    • Subsequently identify the erythrocyte antigens targeted by the autoantibody by eluting the antibody from the RBC and testing against a panel of control erythrocytes
    • May yield false-negative results owing to the presence of IgA, low-affinity autoantibodies, or low numbers of RBC-bound IgG molecules, which are below the threshold of the test 
  • Cold agglutinins
    • High titers of cold agglutinins (IgM antibodies) confirms cold agglutinin syndrome
  • Donath-Landsteiner antibody test
    • Presence of Donath-Landsteiner autoantibody (polyclonal IgG antibodies) confirms paroxysmal cold hemoglobinuria 
  • Urinalysis
    • In severe cases, hemoglobinuria occurs, resulting in red-brown urine
    • Indicated by a positive urine dipstick reaction for heme in the absence of RBCs

Other diagnostic tools 

  • Proposed definitions for diagnosis 
  • Autoimmune hemolytic anemia
    • Evidence for hemolysis
      • Lactate dehydrogenase greater than upper reference limit
      • Haptoglobin less than lower reference limit
    • Positive direct antiglobulin test
    • Alternative causes, such as a delayed hemolytic transfusion reaction, have been excluded
  • Direct antiglobulin test-negative autoimmune hemolytic anemia
    • Clear evidence of hemolysis
    • Alternative causes of both hereditary and acquired hemolysis have been excluded
    • Diagnosis is supported by either a more sensitive test at a reference center or clear response to corticosteroid treatment
  • Warm autoimmune hemolytic anemia
    • Lack of cold-associated symptoms
    • Direct antiglobulin test positive for IgG, IgA (rarely), or C3d ± IgG when a clinically significant cold-reactive antibody has been excluded
  • Cold agglutinin disease autoimmune hemolytic anemia
    • Monospecific direct antiglobulin test strongly positive for C3d (and negative or weakly positive with IgG)
    • Cold agglutinin titer of 64 or greater at 4 °C (occasional cases have cold agglutinin titer lower than 64)
    • May have a B-cell clonal lymphoproliferative disorder detectable in blood or marrow but no clinical or radiological evidence of malignancy
  • Cold agglutinin syndrome autoimmune hemolytic anemia
    • Monospecific direct antiglobulin test strongly positive for C3d (and negative or weakly positive with IgG)
    • CA titer of 64 or greater at 4 °C
    • Patients have an associated condition present such as infection, autoimmune disorder, overt evidence of a B-cell lymphoma, or other malignancy
  • Mixed autoimmune hemolytic anemia
    • Direct antiglobulin test positive for C3d and IgG
    • Cold antibody with a thermal amplitude of 30 °C or more
    • Evidence of a warm IgG antibody by indirect antiglobulin test or indirect antiglobulin test eluate

Differential Diagnosis

Most common

  • Wide variety of disorders result in hemolytic anemia
    • Microangiopathic hemolysis
      • Thrombotic thrombocytopenic purpura
        • Life-threatening thrombotic microangiopathy characterized by thrombocytopenia, microvasculature occlusion, and hemolysis 
        • Like autoimmune hemolytic anemia, it can present with signs and symptoms of anemia and hemolysis, including fatigue, dyspnea, angina, pallor, and jaundice 
        • Differentiating features include cutaneous signs (eg, petechiae, purpura, ecchymoses), as well as symptoms of thrombocytopenia or prolonged bleeding (eg, excessive bruising, bleeding gums, epistaxis, prolonged bleeding from cuts) 
        • Patients with thrombotic thrombocytopenic purpura can also present with neurologic signs, such as focal neurologic deficits, seizures, ataxia, and coma 
        • Thrombotic thrombocytopenic purpura is distinguished from autoimmune hemolytic anemia by fragmentation of RBCs and relative absence of spherocytes on the blood film and the almost uniform presence of thrombocytopenia, which is lacking in most cases of autoimmune hemolytic anemia 
          • Coombs test result is negative in patients with thrombotic thrombocytopenic purpura
          • Assay for ADAMTS13 activity enables definitive diagnosis; a decrease or lack of activity confirms the diagnosis of thrombotic thrombocytopenic purpura 
      • Disseminated intravascular coagulation
        • Condition characterized by widespread presence of microthrombi in various organs with platelet depletion, resulting in thrombocytopenia and multiple organ dysfunction
        • Can present with similar signs and symptoms, including jaundice, acral cyanosis, tachycardia, and dyspnea; however, presentation depends on the underlying disease or triggering event (eg, trauma, sepsis, obstetric complications, transfusion reactions, toxic reactions)
        • Differentiating features include cutaneous signs (eg, petechiae, ecchymosis), as well as signs of subacute bleeding, spontaneous hemorrhage, hematemesis, hematochezia, focal neurologic deficits, and renal dysfunction
        • Diagnosis is based on a disseminated intravascular coagulation score greater than 5 in a patient with underlying conditions that are associated with disseminated intravascular coagulation 
          • Disseminated intravascular coagulation scoring system is based on demonstration of declining platelet count, elevated fibrin markers, prolonged prothrombin time, and decreased fibrinogen level
    • Infections
      • Clostridial sepsis
        • Sepsis with severe intravascular hemolysis resulting as a complication of infection with Clostridium perfringens
        • Presents with signs of hemolytic anemia
        • Differentiated from autoimmune hemolytic anemia based on direct antiglobulin test results
          • Test result is negative in clostridial sepsis and positive in autoimmune hemolytic anemia
    • Hereditary disorders
      • Hereditary spherocytosis
        • Familial hemolytic disorder characterized by the destruction of RBC membrane proteins
        • Hereditary spherocytosis presents with signs of hemolytic anemia, including jaundice and splenomegaly
        • Unlike autoimmune hemolytic anemia, hereditary spherocytosis is associated with a family history of disease
        • Hereditary spherocytosis is differentiated from autoimmune hemolytic anemia based on direct antiglobulin test results
          • Test result is negative in hereditary spherocytosis and positive in autoimmune hemolytic anemia
      • G6PD (Glucose-6-phosphate dehydrogenase) deficiency
        • Inherited condition of inadequate function of the G6PD enzyme, which results in hemolysis when triggered by an oxidative stressor (eg, infection, fava bean consumption, use of certain medications)
        • Like drug-induced autoimmune hemolytic anemia, G6PD deficiency may present with signs of acute hemolytic anemia (eg, jaundice, splenomegaly) following exposure to certain medications
        • Differentiated from autoimmune hemolytic anemia based on direct antiglobulin test results and analysis of G6PD activity
          • Direct antiglobulin test result is negative in G6PD deficiency and positive in autoimmune hemolytic anemia 
    • Immune-mediated hemolysis
      • Brown recluse spider (Loxosceles reclusa) bite 
        • Like autoimmune hemolytic anemia, brown recluse spider bites may cause hemolysis and a direct antiglobulin test positive for IgG or complement; spherocytes and RBC fragmentation are also noted on the blood film
        • Clinical course is often unpredictable and rapidly progressing 
        • Unlike patients with autoimmune hemolytic anemia, these patients have a history of spider exposure/bites or an unknown lesion that may be attributed to a spider bite
        • Loxosceles reclusa bites can be differentiated by measurement of glycophorin A; however, in most cases diagnosis is presumptive based on clinical features since this test is not readily available 
      • Transfusion-related hemolytic anemia
        • Like autoimmune hemolytic anemia, direct antiglobulin test results may be positive; however, patients have a history of recent blood transfusion and test result may demonstrate incompatibility between donor and recipient
        • Acute transfusion reactions are caused by ABO-incompatible RBC results and occur during or immediately after transfusion; patient may develop fever, chills, dyspnea, hypotension, and shock
        • Delayed hemolytic transfusion reactions are usually caused by low-titer antibodies to minor RBC antigens, occur 3 to 10 days after a transfusion, and have a gradual onset and progression like that of autoimmune hemolytic anemia

Treatment Goals

  • Suppress immune-mediated destruction of RBCs
  • Correct anemia

Admission criteria

  • Admission may be required for severe manifestations of anemia, such as decompensated heart failure or angina or for management of underlying conditions

Recommendations for specialist referral

  • Refer to hematologist for diagnosis and treatment
  • Patients requiring splenectomy should be referred to a gastrointestinal surgical specialist

Treatment Options

Correct serologic diagnosis of autoimmune hemolytic anemia is essential before initiating therapy as the approach to warm hemolytic anemia differs from that of cold agglutinin syndrome; likewise, in patients with secondary autoimmune hemolytic anemia, treatment should be directed toward the underlying disease 

There are no well-established evidence-based treatment practices for autoimmune hemolytic anemia; therapies are selected based on severity of hemolysis and anemia, comorbidities, age, and patient and physician preferences 

Warm autoimmune hemolytic anemia 

  • First line therapy consists of oral corticosteroids 
    • Most patients are initially treated with high-dose prednisone until hemoglobin levels stabilize 
    • Two-thirds of patients respond, typically during the second week of administration; if no or minimal improvement is observed by the third week, therapy is deemed ineffective 
    • In responding patients, the drug dose is tapered slowly over several months until it is withdrawn 
      • Some clinicians use lower doses (less than 10 mg/day) of prednisone for 3 to 6 months 
    • Overall treatment should last a minimum of 3 to 4 months
    • 15% to 20% of patients achieve long-term remission upon withdrawal of corticosteroids 
  • Oral corticosteroids plus IV rituximab is an alternative option for first line therapy 
    • Glucocorticoid therapy plus rituximab is more effective than glucocorticoid monotherapy as first line therapy
  • RBC transfusions are indicated occasionally when there is rapid hemolysis and/or the patient has comorbidity-mediated symptoms (ie, cardiac, pulmonary)
  • Second line treatment for patients who do not respond to corticosteroid therapy or relapse is rituximab 
    • Rituximab
      • Administered once each week for 4 weeks 
      • Almost 80% of patients respond to therapy with approximately 40% achieving complete response 
  • Third line options include splenectomy or immunosuppressant agents
    • Splenectomy
      • Historically, considered to be second line therapy; however, owing to risk of infection and thrombosis, rituximab is preferred 
        • Some experts also recommend patients try other relatively nontoxic immunosuppressant agents, azathioprine or intravenous immune globulin prior to considering splenectomy
      • 40% to 80% of patients initially respond and up to 20% achieve long-term remission
      • Laparoscopic splenectomy combined with postsurgical antibiotic and thrombotic prophylaxis has significantly reduced surgery-related morbidity and mortality
      • However, a long-term increased risk of overwhelming sepsis remains even with appropriate immunizations
    • Medical therapy options include conventional immunosuppressant agents, retreatment with glucocorticoids, and targeted therapies 
      • Conventional immunosuppressive drugs including azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil, and sirolimus can be used 
        • Azathioprine, cyclosporine, and mycophenolate are recommended in international consensus guidelines 
      • Treatment with these immunosuppressant agents may be required for at least 8 to 12 weeks, as clinical response may be slow 
      • High-dose immunoglobulin and plasmapheresis have unproven efficacy and should only be used when all other approaches fail
      • Patients with refractory anemia not responding to at least 3 treatment lines (including splenectomy and/or at least 1 immunosuppressant) should be treated at a specialized center, preferably in the setting of a clinical trial 
      • IV immunoglobulins, plasma exchange, hematopoietic stem cell transplantation, and rarely, danazol, bortezomib, or alemtuzumab may be used as last-resort therapies 
      • New agents that are under investigation include B-cell directed therapies (ibrutinib, venetoclax, parsaclisib) and inhibitors of complement (sutimlimab, pegcetacoplan), spleen tyrosine kinases (fostamatinib), and neonatal Fc receptors (orilanolimab, rozanolixizumab, nipocalimab) 

Cold autoimmune hemolytic anemia

  • Postinfectious forms are usually self-limiting, with recovery occurring within weeks
  • Cold agglutinin syndrome is often mild and may not require treatment
    • Protective measures against exposure to cold temperatures and possible transfusion support in winter may be all that is necessary 
    • Treatment is primarily reserved for cases in which the patient exhibits symptomatic anemia, circulatory symptoms (ranging from moderate acrocyanosis to disabling Raynaud phenomenon), or dependence on transfusions 
      • Rituximab is useful for acute symptomatic cases; approximately 60% of patients respond to therapy, with complete response rate of 20% 
        • May be used alone or in combination with bendamustine, fludarabine, or bortezomib 
      • Bruton tyrosine kinase inhibitors, ibrutinib and acalabrutinib, and the monoclonal anti-C5 antibody, eculizumab, are potentially useful 
  • Paroxysmal cold hemoglobinuria may require transfusions and corticosteroid treatment in rare severe cases 
  • Most treatments that have shown efficacy in warm autoimmune hemolytic anemia are of little value in cold autoimmune hemolytic anemia

Mixed autoimmune hemolytic anemia

  • Treatment of mixed autoimmune hemolytic anemia consists of therapies similar to those for warm autoimmune hemolytic anemia 

Drug-induced autoimmune hemolytic anemia

  • Only treatment required is discontinuation of the offending drug; corticosteroids are typically unnecessary and benefits are unclear 

Drug therapy

  • Corticosteroids
    • Prednisone
      • Prednisone Oral tablet; Adults: Initiate at 1 to 1.5 mg/kg/day PO until hemoglobin stabilized, then gradually decrease to maintenance dose (5 to 10 mg/day) or slowly taper off prednisone. 
  • Monoclonal antibodies
    • Rituximab
      • Rituximab (Murine) Solution for injection; Adults: 375 mg/m2 IV weekly x4 weeks produced a response rate of 71%.
  • Immunosuppressants
    • Azathioprine
      • Azathioprine Oral tablet; Adults: 2 to 3 mg/kg PO daily. 
  • Chemotherapeutic agents
    • Cyclophosphamide
      • Oral Cyclophosphamide (low dose)
        • Cyclophosphamide Oral capsule; Adults: 100 mg PO daily. 
      • IV cyclophosphamide (high dose)
        • Cyclophosphamide Solution for injection; Adults: 50 mg/kg/day IV for 4 days. 

Nondrug and supportive care

Patients should limit exposure to and protect themselves from extremes of heat and cold 

RBC transfusion

  • Occasionally indicated when there is rapid hemolysis and/or the patient has comorbidity-related symptoms (ie, cardiac, pulmonary)
  • Absolute threshold for transfusion is individualized according to age of patient, comorbidities, and severity of symptoms
  • Transfusion therapy in autoimmune hemolytic anemia is challenging and should be guided by an experienced hematologist
  • Most compatible RBCs (ie, those with the least cross-reacting antibodies) should be given
  • Considered a temporizing measure in seriously ill patients owing to the typically rapid consumption of transfused RBCs 

Vitamin supplementation 

  • All symptomatic patients should receive folic acid and any other necessary vitamin supplements regardless of disease severity

Venous thromboembolism prophylaxis 

  • Venous thromboembolism is reported in up to 20% to 25% of patients, usually during active hemolysis episodes
  • Prophylaxis with low-molecular-weight heparin is recommended for hospitalized patients with an acute exacerbation of hemolysis and should be considered in ambulatory patients during severe exacerbations (hemoglobin less than 85 g/L)
  • Immunization
    • Vaccinate against Haemophilus influenzae, meningococcus and pneumococcus species before splenectomy 
  • Infection prophylaxis
    • Pneumocystis jirovecii prophylaxis for patients receiving more than 20 mg corticosteroid/day for over 1 month 
Procedures
Splenectomy 

General explanation

  • Surgical removal of spleen; typically performed laparoscopically
  • Decision to remove spleen must be balanced with increased risk of thrombosis and bacterial infection leading to sepsis
  • Before splenectomy, immunize the patient with the pneumococcal polysaccharide vaccine, and vaccines against Haemophilus influenza and Neisseria meningitidis
    • Also give pneumococcal conjugate vaccine series to children
  • Give antibiotic prophylaxis to all patients who have had a splenectomy for at least 3 years postoperatively, continuing in children until age of 18 years

Indication

  • Second line therapy in patients with warm autoimmune hemolytic anemia refractory to medical therapy

Contraindications

  • Uncontrollable coagulopathy

Complications

  • Hemorrhage
  • Surgical site infection
  • Sepsis secondary to bacterial infection

Monitoring

  • Ongoing follow-up varies according to type, severity, and underlying cause of autoimmune hemolytic anemia
  • Generally, laboratory monitoring for anemia and hemolysis is recommended weekly or biweekly for 1 month, followed by monthly tests for 3 months, then every 3 months for a year and every 4 to 6 months thereafter

Complications

  • Venous thromboembolism 
  • Cholelithiasis
  • Perniosis, hemorrhagic blisters, or cutaneous necrosis with cold exposure in cold agglutinin syndrome 
  • Coronary or pulmonary insufficiency
  • Renal failure
  • Transfusion-related complications

Prognosis

  • The overall estimated mortality rate is 11% in adults and 4% in children 
  • Idiopathic warm antibody autoimmune hemolytic anemia has an unpredictable clinical course characterized by relapses and remissions; older study reported survival rate of 73% at 10 years, which has likely improved 
  • Prognosis of secondary warm autoimmune hemolytic anemia depends on course of precipitating disease 
  • Idiopathic cold agglutinin syndrome generally follows a benign course; patients may survive for many years with only occasional paroxysms of hemolysis
  • Prognosis is favorable for postinfectious cold agglutinin syndrome; the disease is generally self-limiting and recovery occurs within a few weeks 
    • Postinfectious forms of paroxysmal cold hemoglobinuria can also spontaneously cease within days to weeks of onset 
  • Prognosis is favorable for drug-induced autoimmune hemolytic anemia, as disease course is generally mild and hemolysis ceases once the drug is discontinued and clears from circulation 

References

Bass GF et al: Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 13(4-5):560-4, 2014

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