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

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

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

References

↑ Bunyaratvej A, Butthep P (January 1992). “Cytometric analysis of paroxysmal nocturnal hemoglobinuria erythrocytes”. J Med Assoc Thai. 75 Suppl 1: 237–42. PMID 1402472.
↑ 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.
↑ 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.
↑ ^4.0 ^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.
↑ ^5.0 ^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.
↑ ^6.0 ^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.
↑ ^7.0 ^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.
↑ 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.

Template:WikiDoc Sources

[pmid1402472-1] Bunyaratvej A, Butthep P (January 1992). “Cytometric analysis of paroxysmal nocturnal hemoglobinuria erythrocytes”. J Med Assoc Thai. 75 Suppl 1: 237–42. PMID 1402472.

[pmid25553278-2] 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.

[pmid26251142-3] 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.

[pmid25705656-4] 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.

[pmid25699184-5] 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.

[pmid24237975-6] 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.

[pmid27602354-7] 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.

[pmid28102226-8] 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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