Autoimmune hemolytic anemia differential diagnosis

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

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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

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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

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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

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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

## References

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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.CS1 maint: Unrecognized language (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Multiple names: authors list (link)
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.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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