Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is a rare type of hemolytic anemia characterized by antibody production against self RBCs, leading to destruction of these cells in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen and other reticuloendothelial tissues. The disease is generally categorized as warm or cold, depending on the thermal reactivity of the autoantibodies. The etiology is diverse and includes infections, autoimmune diseases, lymphoproliferative disorders, and drugs. The diagnosis is based on laboratory evidence of hemolysis (elevated LDH, indirect bilirubin, reduced haptoglobin) in association with a positive direct antiglobulin test (DAT) or Coombs test. Management involves supportive care, removal of the inciting agent, use of steroids and immunosuppressive agents, and splenectomy in refractory cases.

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Overview

Definition

Autoimmune hemolytic anemia (AIHA) is hemolysis or premature destruction of RBCs due to autoantibodies. There are 2 categories of AIHA based on the thermal reactivity of autoantibodies:

  • Warm AIHA
  • Cold AIHA

Epidemiology

  • 1–3 cases per 100,000 population per year
  • Slightly more likely to occur in females than in males
  • Secondary cause present in 20%–80% of reported cases
  • Warm AIHA:
    • 70%–80% of AIHAs
    •  Seen in children 0–4 years old and in adults > 40 years old
  • Cold AIHA: peak incidence in adults > 60 years old

Etiology

Warm AIHA:

  • Idiopathic/primary: no underlying condition or medication 
  • Secondary: associated with an underlying condition (50%–60% of cases)
    • Lymphoproliferative disorders 
    • Autoimmune disorders 
    • Malignancy
    • Immunodeficiency
    • Infections
    • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Drugs 
    • Allogeneic hematopoietic stem cell transplantation (HSCT): usually 2–6 months after engraftment

Cold AIHA:

  • Idiopathic/primary (cold agglutinin disease)
  • Cold agglutinin syndrome:
    • Lymphoproliferative disorders
    • Infections
    • Autoimmune disease
    • Malignancy 
  • Paroxysmal cold hemoglobinuria (PCH) (seen almost exclusively in children):
    • Idiopathic
    • Secondary (can be acute transient or chronic)

Mixed-type AIHA:

  • Idiopathic
  • Secondary (lymphoproliferative disorders, autoimmune disorders)

Specific causes of AIHAs

Table: Specific causes of warm AIHA (antibody type mostly IgG)
Type Specific cause
Primary Idiopathic
Secondary Viral infection HIV
Other disease/condition
  • Malignancy
  • Lymphoproliferative disorders (e.g., CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia)
  • Autoimmune disorders (e.g., systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus)
  • HSCT
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
Drugs
  • Penicillin
  • Ceftriaxone
  • Methyldopa
Table: Specific causes of cold AIHA (antibody type mostly IgM)
Type Specific cause
Primary Primary cold agglutinin disease (CAD)
Secondary Viral infection
  • EBV
  • CMV
  • PCH commonly presents after viral infection in children.
Bacterial infection
  • Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumoniae
  • PCH also associated with Klebsiella Klebsiella Klebsiella are encapsulated gram-negative, lactose-fermenting bacilli. They form pink colonies on MacConkey agar due to lactose fermentation. The main virulence factor is a polysaccharide capsule. Klebsiella pneumoniae is the most important pathogenic species. Klebsiella, Escherichia coli Escherichia coli The gram-negative bacterium Escherichia coli is a key component of the human gut microbiota. Most strains of E. coli are avirulent, but occasionally they escape the GI tract, infecting the urinary tract and other sites. Less common strains of E. coli are able to cause disease within the GI tract, most commonly presenting as abdominal pain and diarrhea. Escherichia coli, and syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis (congenital and tertiary)
Other conditions
  • Lymphoproliferative disorders
  • Malignancy
  • Autoimmune disorders
Drug Lenalidomide (rare)

Pathophysiology

Warm AIHA

  • Warm autoantibodies are responsible for the majority of AIHA cases.
  • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (predominantly IgG) interact with Rhesus factor (Rh) complex antigens or glycoprotein antigens.
  • Warm autoantibodies react more strongly at 37°C.
  • Pathogenesis:
    • In most cases, hemolysis (facilitated by phagocytic cells) occurs extravascularly.
    • RBC destruction occurs where macrophages are abundant, mostly in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen (also in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow):
      • Fc portion (antibody) is recognized by Fc receptor of phagocytes → phagocytosis of heavy chain of IgG and part of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane → spherocyte formed
      • Cytotoxic T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen → cell-mediated cytotoxicity → RBC hemolysis
      • Liver macrophages recognize complement C3 fragments → RBCs with complements are phagocytosed.
  • Over 95% of warm AIHA cases have a positive direct antiglobulin test (DAT) or Coombs test.
Drug-induced hemolytic anemia

Drug-induced autoimmune hemolytic anemia (AIHA):
Drugs can cause AIHA by:
Top: Binding to specific proteins of a drug that remain on the surface of RBCs and are recognized as new antigens by IgG (penicillin)
Middle: Complement activation induced by immune complexes formed by a drug (quinidine)
Bottom: Alteration of the Rhesus factor (Rh) molecule or a cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane component by a drug, thus making it immunogenic for IgG even after the drug is discontinued (methyldopa)

Image by Lecturio.

Cold AIHA

Cold-sensitive autoantibodies react more strongly at 0–4℃.

  • Cold agglutinins:
    • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (predominantly IgM) interact with RBC I antigen or i antigen below normal core temperature:
      • I antigen: present in 99% of the population
      • i antigen: noted in < 1% 
    • After binding RBCs, IgM autoantibodies activate the classic complement cascade (C1 → C3b).
    • RBCs coated with C3b undergo phagocytosis extravascularly (in the reticuloendothelial system, mostly by Kupffer cells in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver)
    • Results in extravascular hemolysis
    • Upon warming, IgM dissociates, but C3b remains and is, thus, detected on DAT.
  • Donath-Landsteiner antibodies: 
    • Recognize RBC antigens (often the P antigen) in cold temperature and fix complement, leading to hemolysis 
    • Intravascular hemolysis → hemoglobinuria and anemia
    • Found in PCH

Clinical Presentation

  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview:
    • Shortness of breath
    • Tachycardia
    • Fatigue
    • Pallor
    • Palpitations
  • Extravascular hemolysis:
    • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice 
    • Gallstones
    • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Hepatomegaly
    • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy 
  • Intravascular hemolysis:
    • Dark urine (hemoglobinuria)
    • Transient renal failure

Cold AIHA:

  • Acrocyanosis:
    • Dark gray or purple discoloration of toes, fingers, ears, or nose Nose The nose is the human body's primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Anatomy of the Nose on exposure to cold 
    • Can result in gangrene in severe cases
  • Raynaud phenomenon
  • Livedo reticularis: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin with bluish or violaceous reticulated pattern that blanches
Gangrenous change and acrocynosis

Acrocyanosis of the hands:
Acrocyanosis with gangrene (A) and resolution of acrocyanosis (B)

Image: “Gangrenous change and acrocynosis” by Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan. License: CC BY 4.0

Diagnosis

Initial laboratory evaluation

Diagnosis is with evidence of hemolysis and positive DAT.

  • CBC: 
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • MCV varies with reticulocyte count
    • Usually normal leukocyte and platelet counts
  • Reticulocyte count: usually increased
  • Peripheral blood smear:
    • Polychromasia (due to high reticulocyte counts)
    • Spherocytes
    • Schistocytes
    • Nucleated RBCs
    • RBC clumps
  • DAT:
    • Establishes the diagnosis
    • Identifies the presence of antibodies and/or complement bound on RBCs
    • Strength of positive test correlates with severity of hemolysis.
    • Warm AIHA:
      • Positive at  37°C for anti-IgG 
      • Anti-C3 may or may not be positive. 
    • Cold AIHA: positive for anti-C3 and negative for anti-IgG
  • Serum markers of hemolysis:
    • ↑ Indirect bilirubin
    • ↑ LDH 
    • ↑ AST and ALT  
    • Low serum haptoglobin 
  • C3 and C4 levels reduced in cold AIHA 
  • Cold agglutinin titer: high titer in cold AIHA

Additional evaluation

  • Urinalysis, both dipstick and microscopic:
    • Hemoglobinuria → dipstick positive for blood but absence of RBCs
    • Urinalysis normal in extravascular hemolysis
  • BUN/creatinine: renal impairment in intravascular hemolysis
  • Review possible secondary causes:
    • Underlying conditions 
    • Recent infections (i.e., serologic testing positive for Mycoplasma Mycoplasma Mycoplasma is a species of pleomorphic bacteria that lack a cell wall, which makes them difficult to target with conventional antibiotics and causes them to not gram stain well. Mycoplasma bacteria commonly target the respiratory and urogenital epithelium. Mycoplasma pneumoniae (M. pneumoniae), the causative agent of atypical or "walking" pneumonia. Mycoplasma pneumoniae)
    • Medications
    • Transfusion 
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow aspiration on relevant indications (i.e., to exclude CLL CLL Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia)

Management

Principles of management

  • Stabilization of the patient:
    • Assess severity of anemia and associated symptoms (i.e., dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea or those associated with cardiac ischemia).
    • Hemodynamic and ventilatory support as needed
    • Determine need for transfusion (transfuse when necessary).
    • Discontinue suspected offending drug.
  • Treatment of underlying condition, if present, is recommended.
  • Hemolysis will continue for up to 3 weeks (equivalent to the half-life of autoantibodies).

Warm AIHA

  • Folic acid supplementation: Folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 deficiency can develop with chronic hemolysis.
  • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids +/– rituximab:
    • May start with both as initial treatment, OR
    • Initiate rituximab if no response with glucocorticoids after 2–3 weeks
  • Intravenous immunoglobulin (IVIG)
  • Refractory disease:
    • Immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants: mycophenolate, cyclophosphamide, or azathioprine
    • Splenectomy

Cold AIHA

  • Avoid cold.
  • Folic acid supplementation
  • Immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants: rituximab-containing regimens (i.e., rituximab with bendamustine)
  • Plasmapheresis in cases of severe hemolysis

Complications and prognosis

Warm AIHA:

  •  ↑ Risk of venous thromboembolism:
    • Rule out deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis if D-dimer positive.
    • Rule out pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism if dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea is disproportionate to anemia.
  • Evans syndrome: 
    • 2 or more immune cytopenias occur concurrently.
    • AIHA can present with immune-mediated thrombocytopenic purpura ( ITP ITP Immune thrombocytopenic purpura (ITP), formerly known as idiopathic thrombocytopenic purpura, is a condition that develops secondary to immune-mediated destruction of platelets, resulting in thrombocytopenia (platelet count < 100,000/mm³). Immune thrombocytopenic purpura can be either primary or secondary due to drugs or underlying disease. Immune Thrombocytopenic Purpura).
    • Associated with higher mortality rate
  • Majority of cases respond to therapy in 2–3 weeks.
  • Relapse is possible, and patients should be educated to seek medical care if symptoms recur.

Cold AIHA:

  • Survival similar to that of age-matched populations
  • In viral-associated PCH affecting children, recovery is seen within 2 weeks.
  • Recurrent episodes are more often seen in adults.

Differential Diagnosis

  • Hemolytic anemia: group of anemias that are due to destruction or premature clearance of RBCs. Hemolysis can be either intravascular or extravascular (in the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen). The etiology of premature erythrocyte destruction is diverse and can be due to conditions such as RBC membrane defects, erythrocyte enzymatic defects, immune destruction of erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes, mechanical injury, and hypersplenism. In non-autoimmune causes of hemolytic anemia, the DAT is characteristically negative.
  • System lupus erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus): chronic, autoimmune, inflammatory condition that causes immune complex deposition in organs, resulting in systemic manifestations. This disease overwhelmingly affects women, particularly those of African American descent. Notable clinical features include a malar rash, nondestructive arthritis, lupus nephritis, serositis, cytopenias, thromboembolic disease, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. The diagnosis is made by meeting clinical criteria, which includes antinuclear antibodies, SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus-specific antibodies, and specific clinical findings.
  • Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia: most common leukemia in adults. Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia is a monoclonal B-cell proliferation that infiltrates the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow or lymph nodes. The B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells arrest before maturation, and thus these patients have agammaglobulinemia, resulting in recurrent infections. Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia is mainly found incidentally on blood work showing lymphocytosis Lymphocytosis WBCs develop from stem cells in the bone marrow and are called leukocytes when circulating in the bloodstream. Lymphocytes are 1 of the 5 subclasses of WBCs. Lymphocytosis is an increase in the number or proportion of the lymphocyte subclass of WBCs, often as a result of an immune response to infection (known as reactive lymphocytosis). Lymphocytosis. Peripheral smears show smudge cells. Chronic lymphocytic leukemia Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by excess production of monoclonal B lymphocytes in the peripheral blood. When the involvement is primarily nodal, the condition is called small lymphocytic lymphoma (SLL). The disease usually presents in older adults, with a median age of 70 years. Chronic Lymphocytic Leukemia is a leading secondary cause of both warm and cold AIHA and should be considered in cases of AIHA associated with massive splenomegaly or lymphadenopathy.
  • Cryoglobulinemia: disorder due to immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (cryoglobulins) that precipitate in cold temperatures (below 37℃). Cryoglobulinemia is associated with arthralgias, glomerulonephritis, purpura, or peripheral neuropathy. Patients can also exhibit cold-induced Raynaud phenomenon. History of infection (usually hepatitis C virus Hepatitis C Virus Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus) is associated with cryoglobulinemia. Patients will not have cold agglutinin on laboratory testing, and most do not have AIHA.

References

  1. Brugnara, C., Barcellini,W. (2021). Paroxysmal cold hemoglobinuria. UpToDate. Retrieved April 19, 2021, from https://www.uptodate.com/contents/paroxysmal-cold-hemoglobinuria
  2. Brugnara, C., Brodsky, R.A. (2021). Warm autoimmune hemolytic anemia (AIHA) in adults. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/warm-autoimmune-hemolytic-anemia-aiha-in-adults
  3. Luzzatto, L. (2018). Hemolytic anemias. Jameson, J., Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., Loscalzo J. (Eds.),  Harrison’s Principles of Internal Medicine, 20th ed. New York: McGraw-Hill.
  4. Ware, R.E., Despotovic, J.M. (2021). Autoimmune hemolytic anemia in children: classification, clinical features, and diagnosis. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/autoimmune-hemolytic-anemia-in-children-classification-clinical-features-and-diagnosis
  5. Ware, R.E., Despotovic, J.M. (2021). Autoimmune hemolytic anemia in children: Treatment and outcome. UpToDate. Retrieved April 14, 2021, from https://www.uptodate.com/contents/autoimmune-hemolytic-anemia-in-children-treatment-and-outcome
  6. Schick, P.  (2019). Hemolytic anemia. Medscape. Retrieved April 14, 2021, from https://reference.medscape.com/article/201066-overview

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