Autoimmune hemolytic anemia differential diagnosis

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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]

Overview

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.

Differentiating Autoimmune hemolytic anemia from other Diseases

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
  • Extrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
Associated with:
  • SLE
  • CLL
  • Mycoplasia pneumoniae infection
  • Painful, blue fingers and toes with cold weather
--
  • Normal
  • ↓(Decreased)
  • Normal
-- -- --
  • RBC agglutination
Iron deficiency anemia -- --
  • ↑(Increased)
  • Normal or ↓(Decreased)
  • Normal
--
  • Normal
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↓↓↓(Decreased)
Lead poisoning -- --
  • Normal
  • Normal or ↓(Decreased)
  • Normal
  • House painted with chipped paint
--
  • Normal
  • Normal or ↓(Decreased)
  • Normal
  • Normal
  • Normal or ↓(Decreased)
--
  • RBCs retain aggregates of rRNA (basophilic stippling)
Sideroblastic anemia -- --
  • Normal
  • Normal or ↓(Decreased)
  • Normal
  • Normal
  • ↑(Increased)
  • Normal
  • Normal or ↓(Decreased)
  • ↑(Increased)
--
Anemia of chronic disease -- --
  • Normal
  • Normal or ↓(Decreased)
  • Normal
-- --
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • ↓(Decreased)
  • ↑(Increased)
-- --
Thalassemia -- --
  • Normal
  • Thalassemia trait

Normal or ↓(Decreased)

  • Thalassemia Syndromes

↑(Increased)

  • Normal
α-thalassemia

β-thalassemia

α-thalassemia
  • α- globin gene deletions
  • Cis deletions
  • Trans deletions

β-thalassemia

  • Normal
  • Normal to ↑(Increased)
  • Normal
  • Normal
  • ↑(Increased)
Normal to increased
  • Target cells
  • Anisopoikilocytosis
G6pd deficiency
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased) but usually causes resolution within 4-7 days
  • ↓(Decreased)
History of using
  • Sulfa drugs
  • Antimalarials
  • infections,
  • Fava Beans
  • ↓(Decreased)
  • Normal to ↑(Increased)
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↑(Increased)
Pyruvate Kinase deficiency
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • Skin ulcers
  • Splenomegaly of varying degree
  • Normal
  • ↑(Increased)
  • Normal
  • Normal
  • ↑(Increased)
--
  • Prickle cells
  • Polychromatophilic erythrocytes
Sickle cell anemia
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
Normal or moderately elevated
  • Normal
  • Normal
Normal or moderately elevated
  • ↓(Decreased)
  • Normal
HbC disease
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • 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]
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • 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
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • ↓(Decreased)
  • Normal
  • ↑(Increased)
  • Normal
--
  • Small, round RBCs with less surface

area and no central pallor ( MCHC)

Microangiopathic hemolytic anemia[3]
  • Intrinsic
  • ↑(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
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
Associated with
  • Prosthetic heart valves
  • Aortic stenosis
  • Signs of anemia
  • Complications of hemolysis
  • Decreased vascular volume
  • Autoimmune
  • Normal
  • ↓(Decreased)
  • Normal
-- -- --
  • Spherocytes or schistocytes
Infections
  • Intrinsic
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
Associated with
  • Malaria
  • Babesia
  • Fever
  • Signs of shock
  • Headache
--
  • Normal
  • Normal
  • Normal
-- -- --
  • Trophozoite
  • Maltese crosses
Iron deficiency anemia(Early) -- --
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Pica
  • Glossitis
  • Cheilosis
  • Koilonychia
  • Conjuctival pallor
  • Dry skin
--
  • Normal
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↓(Decreased)
  • Microcytosis
  • Pencil cells
  • Ellyptocytosis
  • Hypochromasia
Anemia of chronic disease -- --
  • Normal
Normal or ↓(Decreased)
  • Normal
  • History of:
    • Rheumatoid arthritis
    • SLE
    • Neoplastic disorders
    • Chronic kidney disease
-- --
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↓(Decreased)
  • Normocytic cells but may become microcytic
Aplastic anemia -- --
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Symptoms based on underlying condition
  • Constitutive expression of Tbet
  • Mutations in the perforin gene
  • Mutations in SAP gene
  • Normal
  • ↓(Decreased)
  • ↓(Decreased)
  • Normal
  • ↑(Increased)
  • ↓(Decreased)
Chronic kidney disease -- --
  • ↑(Increased)
Normal /↑(Increased)
  • Normal
--
  • ↑(Increased)
  • ↓(Decreased)
--
  • ↓(Decreased)
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
Folate deficiency -- --
  • Anisochromic
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Alcoholics
  • History of using drugs like methotrexate, trimethoprim and phenytoin
  • Low socioeconomic groups with poor nutrition
  • Older people
  • Pregnant and lactating women
  • Impaired DNA synthesis
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
Vitamin B12 deficiency -- --
  • Anisochromic
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Impaired DNA synthesis
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
Orotic aciduria -- --
  • Anisochromic
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Coma
  • Gastro-intestinal manifestation
  • Neurological manifestation
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
--
Fanconi anemia -- --
  • Anisochromic
  • ↑(Increased)
  • ↓(Decreased)
  • Normal
  • Significant for B\L short thumbs
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
  • Normal appearing WBC, RBC and Platelets
  • But the number is greatly reduced
Diamond-Blackfan anemia -- --
  • Anisochromic
--
  • ↓(Decreased)
  • Normal
Mutations in:
  • RPL5
  • RPL11
  • RPL35A
  • RPS7
  • RPS10
  • RPS17
  • RPS19
  • RPS24
  • RPS26
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
--
Liver disease -- --
  • Anisochromic
  • ↑(Increased)
  • ↑(Increased)
  • Normal
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
--
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
Alcoholism -- --
  • Anisochromic
  • ↑(Increased)
  • ↑(Increased)
  • Normal
--
  • Normal
  • ↑(Increased)
  • ↑(Increased)
  • ↓(Decreased)
  • ↑(Increased)
  • ↑(Increased)
Characteristic Causes Pathophysiology Laboratory abnormalities Physical examination Therapy Other associations
Autoimmune hemolytic anemia
  • Polyclonal antibody production that binds to and targets red blood cells for destruction intravascurly or extravascularly[4]
  • Removal of offending agent
  • Corticosteroids
  • Cyclophosphamide
  • Cyclosporine A
  • Azathioprine
  • Rituximab
  • Splenectomy
  • Hemolysis can occur at warm or cold temperatures
Microangiopathic hemolytic anemia
  • Formation of small vessel microthombi
  • Bleeding
  • Thrombosis
  • Pyrexia
  • Altered mental status
  • Neurologic deficits
  • Impaired urine output
  • Can be life-threatening pending the underlying cause
  • TTP required immediate treatment
Paroxysmal cold hemoglobinuria
  • Biphasic hemolysin (IgG) that binds red blood cells and low temperatures and triggers complement-mediated intravascular hemolysis at warm temperatures[5]
  • 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
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]
  • Positive eosin-5-maleimide binding to red blood cells[6]
  • Positive osmotic fragility testing[6]
  • Spherocytes on peripheral blood smear
  • 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
  • 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)
  • 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

References

  1. Bunyaratvej A, Butthep P (January 1992). "Cytometric analysis of paroxysmal nocturnal hemoglobinuria erythrocytes". J Med Assoc Thai. 75 Suppl 1: 237–42. PMID 1402472.
  2. Kahng J, Kim Y, Kim JO, Koh K, Lee JW, Han K (January 2015). "A novel marker for screening paroxysmal nocturnal hemoglobinuria using routine complete blood count and cell population data". Ann Lab Med. 35 (1): 35–40. doi:10.3343/alm.2015.35.1.35. PMC 4272963. PMID 25553278.
  3. Morishita E (July 2015). "[Diagnosis and treatment of microangiopathic hemolytic anemia]". Rinsho Ketsueki (in Japanese). 56 (7): 795–806. doi:10.11406/rinketsu.56.795. PMID 26251142.
  4. 4.0 4.1 4.2 Berentsen S, Sundic T (2015). "Red blood cell destruction in autoimmune hemolytic anemia: role of complement and potential new targets for therapy". Biomed Res Int. 2015: 363278. doi:10.1155/2015/363278. PMC 4326213. PMID 25705656.
  5. 5.0 5.1 5.2 5.3 Akpoguma AO, Carlisle TL, Lentz SR (2015). "Case report: paroxysmal cold hemoglobinuria presenting during pregnancy". BMC Hematol. 15: 3. doi:10.1186/s12878-015-0023-7. PMC 4334594. PMID 25699184.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Gallagher PG (2013). "Abnormalities of the erythrocyte membrane". Pediatr Clin North Am. 60 (6): 1349–62. doi:10.1016/j.pcl.2013.09.001. PMC 4155395. PMID 24237975.
  7. 7.0 7.1 7.2 7.3 7.4 Chan CQ, Low LL, Lee KH (2016). "Oral Vitamin B12 Replacement for the Treatment of Pernicious Anemia". Front Med (Lausanne). 3: 38. doi:10.3389/fmed.2016.00038. PMC 4993789. PMID 27602354.
  8. Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG; et al. (2017). "Chronic lymphocytic leukaemia". Nat Rev Dis Primers. 3: 16096. doi:10.1038/nrdp.2016.96. PMC 5336551. PMID 28102226.


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