Hemolytic Anemias

Hemolytic anemias result from premature destruction of red blood cells (RBCs). For information on hemolytic anemias as a result of hemoglobin synthesis abnormalities, refer to the following topics: Hemoglobinopathies, Unstable Hemoglobinopathies, Thalassemias. For information about hemolytic anemias associated with mechanical RBC destruction and thrombocytopenia, refer to Thrombotic Microangiopathies.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Suspicion of hemolysis based on clinical and laboratory presentation
- Increased reticulocytosis, lactate dehydrogenase, and bilirubin
- Decreased haptoglobin
- Anemia with deformed and fragmented erythrocytes on peripheral smear in some disorders

Laboratory Testing

CBC with peripheral smear – initial screening
- Platelet count
  - Decreased – consider disseminated intravascular coagulation (DIC); Hemolysis, Elevated Liver enzyme levels, Low Platelet count (HELLP) syndrome; thrombotic thrombocytopenia purpura (TTP); hemolytic uremic syndrome (HUS); atypical HUS (aHUS)
    - Order D-dimer, ADAMTS13 activity
  - Normal – consider vasculitis, mechanical factors
- Cells noted may help with diagnosis
  - Spherocytes – hereditary spherocytosis or elliptocytosis, immune-mediated hemolytic anemias
    - Examination of peripheral smear
      - Fast, easy screen
    - If considered hereditary – RBC surface protein band 3 testing
      - Highly sensitive and specific for disease
    - If considered acquired – direct Coombs testing
      - IgG+ – autoimmune hemolytic anemia
      - C3+ – cold agglutinins disease, paroxysmal cold hemoglobinuria (PCH)
        Confirm PCH with Donath Landsteiner testing
  - Schistocytes/fragmented cells – suggests microangiopathic RBC destruction
    - Consider DIC, TTP, HELLP, HUS, aHUS, mechanical cardiac valve, vasculitis, malignant hypertension
    - Order D-dimer testing
      - Increased D-dimer – DIC
      - Normal D-dimer and clinical presentation consistent with thrombotic microangiopathy (TMA)
        Pregnant – consider HELLP
        
        Not pregnant – order ADAMTS13 activity or E. coli Shiga-like toxin by EIA (dependent on presentation)
        ADAMTS13 activity <10% – TTP
        
        Normal test results – aHUS
        
        Positive Shiga toxin and history of diarrheal illness – classical HUS
  - Polychromasia
    - Without other reproducible morphologic abnormality
      - Consider one or more of the following tests: pyruvate kinase (PK), hexokinase (HK), glucose phosphate isomerase (GPI)
    - With or without platelet decrease
      - Consider paroxysmal nocturnal hemoglobinuria testing
  - Sickle cells – consider hemoglobin evaluation by high-performance liquid chromatography (HPLC)
    - Abnormal red cells (eg, sickle cells and target cells) – may indicate hemoglobinopathy
    - Do not repeat hemoglobin electrophoresis in patients who have a prior result and who do not require therapeutic intervention or monitoring of hemoglobin variant levels (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
  - Stomatocytes – hereditary stomatocytosis likely
  - Basophilic stippling levels
    - Acquired – serum lead levels testing
    - Nonacquired – 5’ nucleotidase testing
  - Heinz body stain positive – suggests hemoglobinopathies, glucose-6 phosphate dehydrogenase (G6PD) deficiency, chemical and toxin exposure
    - Consider G6PD testing or isopropanol heat stability of the signals
    - If G6PD deficiency has been ruled out – Heinz bodies may implicate presence of toxin or drug
  - Agglutination
    - Consider testing with direct Coombs (+) (anti-thyroglobulin)
      - Cold agglutinin disease (IgG-/C3d+)
      - Warm autoimmune hemolytic anemia (IgG+/C3d-)
  - Unusual red cell inclusions – if infection is suspected, consider evaluation for Babesia, malaria, Bartonella spp
Reticulocyte count – usually elevated; does not give specific diagnosis

Molecular testing – can be performed if confirmation is necessary or other testing does not confirm diagnosis

Genes involved in hereditary membrane disorders

Genes Involved in Hereditary Membrane Disorders
Condition	Genes	Inheritance
Hereditary spherocytosis	ANK1, SLC4A1, SPTB, EPB42	AD/AR
Hereditary elliptocytosis/pyropoikilocytosis	SPTA1, SPTB, EPB41	AD/AR
Hereditary stomatocytosis	PEIZO1	AD
AD, autosomal dominate; AR, autosomal recessive

Genes involved in RBC enzyme deficiency

Genes Involved in Red Blood Cell (RBC) Enzyme Deficiency
Condition	Genes	Inheritance
Glucose 6 phosphate dehydrogenase deficiency	G6PD	XR
Pyruvate kinase deficiency	PKLR	AR
Glucose phosphate isomerase deficiency	GP1	AR
Glutathione reductase deficiency	GSR	AR
Phosphoglycerate kinase deficiency	PGK1	XL
Triosephosphate isomerase deficiency	TPI1	AR
Adenylate kinase 1	AK1	AR
Pyrimidine 5’ nucleotidase	NT5C3	AR
Hexokinase 1	HK1	AR
AR, autosomal recessive; XL, x-linked; XR, x-linked recessive

Differential Diagnosis

See Classification in Background

Background

Epidemiology

Prevalence – varies by etiology of hemolysis
- Common – autoimmune hemolytic anemia, G6PD deficiency, PK deficiency, hereditary spherocytosis (HS)
- Rare – paroxysmal nocturnal hemoglobinuria (PNH)
Sex – M:F, equal
Ethnicity
- Higher prevalence of G6PD deficiency in individuals of African, Kurdish or Sephardic Jewish, Arab, Mediterranean, Southeast Asian, and Asian-Indo/Pakistani descent
- Sickle cell disease most often found in Africans

Classification

Hereditary
- Red cell enzyme defects
  - G6PD deficiency
  - PK deficiency
- RBC membrane defects
  - HS
  - Stomatocytosis
  - Hereditary elliptocytosis
  - Hereditary pyropoikilocytosis
- Hemoglobin synthesis abnormalities
  - Hemoglobinopathies
    - Sickle cell disease and other qualitative hemoglobin disorders
    - Alpha (α) thalassemia, beta (β) thalassemia
Acquired
- Immune
  - Infectious
    - Cytomegalovirus (CMV)
    - Epstein-Barr virus (EBV)
    - Hepatitis C virus (HCV)
    - HIV
    - Leptospira spp
    - Plasmodium spp
    - Mycoplasma pneumoniae
    - Parvovirus
    - Babesia microti
  - Autoimmune (Bass, 2014)
    - Warm antibody disease
      - Primary
      - Secondary associated with
        Lymphoproliferative disorders (eg, non-Hodgkin lymphoma)
        
        Nonlymphoid malignancies (eg, ovarian cancer)
        
        Chronic inflammatory disorders (eg, ulcerative colitis)
        
        Drugs
    - Cold agglutinin syndrome
      - Primary
      - Secondary associated with
        Lymphoproliferative disorders
        
        Infections (eg, mycoplasma)
        
        PNH
    - Mixed antibody disease
      - Primary
      - Secondary often associated with rheumatic disease
    - Drug induced (>150 drugs)
      - Drug dependent
      - Drug independent
  - Microangiopathic red cell destruction
    - TTP
    - HUS
    - aHUS
    - DIC
    - HELLP syndrome
- Nonimmune
  - Environmental factors (physical disruption)
    - Mechanical valves
  - PNH

Clinical Presentation

Clinical presentation of specific hemolytic disorders

Cell membrane disorders (mechanical weakness or fragility of erythrocyte membrane skeleton)
- Hereditary spherocytosis
  Prevalence – 1/1,000-3,000 in Caucasians
  
  Inheritance – variable
  Autosomal dominant variants in ankyrin and α-spectrin – 75% of cases
  
  Autosomal recessive or de novo variants – 25% of cases
  
  Variants may occur in ANK1, EPB42, SLC4A1, SPTB genes
  
  Clinical presentation
  Range of severity from asymptomatic to severe disease
  
  Anemia, splenomegaly, jaundice, gallstones (particularly in pediatric cases)
  
  Reticulocytosis (after prior anemia)
- Hereditary elliptocytosis
  Incidence – 1/2,000-4,000 in Caucasians
  
  Inheritance – autosomal dominant
  Involves gene variants associated with defects in spectrin – SPTA1, SPTB, and EPB41
  
  Clinical presentation
  Usually no significant hemolysis – may be asymptomatic
- Hereditary pyropoikilocytosis
  Incidence – uncommon
  
  Inheritance – autosomal recessive (felt to be a subset of hereditary elliptocytosis)
  Same gene variants as hereditary elliptocytosis, homozygous/compound heterozygotes
  
  Clinical presentation – usually presents in infancy or early childhood
- Dehydrated hereditary stomatocytosis (xerocytosis)
  Incidence – 1/50,000 in Caucasians
  
  Inheritance – autosomal dominant
  Gene variants in PIEZO1
  
  Clinical presentation – asymptomatic to moderately severe disease
RBC enzyme defects
- Overview
  >20 disorders recognized
  
  Deficiencies of enzymes include (Gallagher, 2015)
  G6PD
  
  Phosphofructokinase M (PFK)
  
  HK
  
  GPI
  
  PK
  
  Triosephospate isomerase (TPI)
  
  Phosphoglycerate kinase (PGK)
  
  Pyrimidine 5’-nucleotidase (P5N)
  
  Usually associated with normocytic normochromic hemolytic anemia with no specific abnormalities of RBC morphology – occasional bite cells can be seen
  
  Severity of hemolysis is variable – may be a result of an external stressor (eg, infection, administration of drugs, or ingestion of some foods)
  
  Nonhematological manifestations possible – myopathy, neurological dysfunction, intellectual disability
  
  Diagnosis is based on detection of reduced specific enzyme activity and/or molecular genetic testing to identify causative variant(s)
- G6PD deficiency
  Prevalence
  400-600 million worldwide
  
  Most common enzyme deficiency worldwide
  
  Ethnicity
  African
  
  Kurdish Jewish
  
  Sephardic Jewish
  
  Arab
  
  Mediterranean
  
  Southeast Asian and Asian-Indo/Pakistani
  
  Northern Europeans (0.1%)
  
  Inheritance
  X-linked recessive
  
  >400 G6PD gene variants have been described
  Some are benign
  
  Others result in intermittent or chronic hemolytic anemia
  
  >99% of G6PD deficiency in individuals of African descent are caused by the G6PDA allele
  
  Most affected individuals have moderate G6PD deficiency (~10% normal activity), resulting in acute hemolytic anemia in response to oxidative stress
  
  Rare variants cause severe G6PD deficiency (<10% normal activity), resulting in chronic nonspherocytic hemolytic anemia in absence of oxidative stressors
  
  Female variant carriers may have hemolytic episodes even if G6PD enzyme studies are normal, because deficient as well as nondeficient RBCs coexist in various proportions
  Female presentation also dependent on presence or absence of imbalanced x-activation
  
  Clinical presentation
  Most patients are asymptomatic
  Usually only symptomatic if residual enzyme activity is ≤10%
  
  Patients may present with fatigue, back pain, anemia, and jaundice as an indicator of hemolysis
  
  Hemolysis occurs when patient is exposed to environmental stressors
  Viral and bacterial infections – most common
  
  Many oxidative stressors secondary to drug exposure – most commonly sulfa, nitrofurantoin, antimalarials, toluidine blue, methylene blue

Enzymatic hemolytic anemias

Enzymatic Hemolytic Anemias
Deficiency	Incidence/Ethnicity	Inheritance	Gene	Clinical Presentation
Pyruvate kinase	1/20,000 in Caucasians Mediterranean populations	AR Carriers recognized by erythrocytes – activity ~50% of normal	PKLR >180 different variants	Neonatal anemia Mild to severe hemolysis
Glucose phosphate isomerase	Rare	AR	GPI	Infancy/early childhood Moderate to severe hemolytic anemia Rare – neurologic disease (eg, developmental delay)
Phosphofructokinase (glycogen storage disease VII, Tauri disease)	Rare Ashkenazi Jewish	AR	PFKM	Adolescence/adulthood Exertional myopathy Mild, well-compensated hemolytic anemia
Triosephospate isomerase	Rare 240 cases	AR	TPI1	Infancy Cardiomyopathy Progressive neurologic impairment
Phosphoglycerate kinase	Rare	X-linked	PGK1	CNS disorders Developmental delay Myopathy Some patients lack myopathy or CNS disorder
Hexokinase	Rare	AR	HK1	Neonatal/adulthood Neonatal severe anemia
Pyrimidine 5’-nucleotidase	Rare	AR	NT5C3A	Mild to moderate hemolytic anemia with basophilic stippling Splenomegaly
AR, autosomal recessive; CNS; central nervous system

Acquired hemolytic anemias – immune mediated
- Incidence – 1-3/100,000
- Age – 30s-40s
- Sex – M<F
- Common types
  Warm and cold antibody disease
  IgG – warm antibody disease
  
  IgM – most common for cold antibody disease
- Clinical presentation
  Warm autoimmune hemolytic anemia
  
  Antibody generally directed broadly against Rh antigens
  
  Symptoms usually a result of anemia
  Slow, insidious onset
  
  May have jaundice
  
  Cold agglutinin hemolysis
  Episodic acute hemolysis with hemoglobinuria
  
  Acrocyanosis in response to cold and vasoocclusive phenomena of fingers, toes, ears, and nose present in some patients
  
  90% of patients have monoclonal B-cell lymphoproliferative bone marrow disorders
  
  Drugs – immune mediated
  Severity depends on the drug and varies from mild to severe hemolysis
  
  >150 drugs have been implicated – cephalosporins, nonsteroidal anti-inflammatory drugs (NSAIDs) are most common
Paroxysmal cold hemoglobinuria
- Incidence – rare
- Age – 5 years (median)
- Caused by a biphasic antibody (Donath-Landsteiner antibody) and inherited CD59 deficiency
- Clinical presentation
  Pallor, hemoglobinuria, and mild jaundice
  
  Patients usually have a history of recent viral infection

ARUP Lab Tests

Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

RBC Band 3 Protein Reduction in Hereditary Spherocytosis 2008460
Method: Qualitative Flow Cytometry

Recommended Use

Confirm diagnosis of hereditary spherocytosis when hemolytic anemia and spherocytes are present

Limitations

Not typically used as a screening test, but has been proposed as a screening test by many authorities

Osmotic Fragility, Erythrocyte 2002257
Method: Spectrophotometry

Recommended Use

Functional testing of RBC sensitivity to osmotic stress; do not use to distinguish between spherocytes in hereditary spherocytosis and acquired autoimmune hemolytic anemia

Limitations

For patients with acute hemolysis, a normal test result cannot exclude an abnormality, since osmotically labile cells may be hemolyzed and not present

Testing should be performed during a state of prolonged homeostasis with stable hematocrit

Heinz Body Stain 0049090
Method: Supravital Stain

Recommended Use

Use as a nonspecific screen for hemolysis due to drugs/toxins, enzyme deficiencies, thalassemias, and unstable hemoglobins

Limitations

Results are unreliable in infants <6 months

Glucose-6-Phosphate Dehydrogenase 0080135
Method: Quantitative Enzymatic

Recommended Use

Preferred initial screening test for G6PD deficiency

For genetic testing, refer to G6PD mutations for individuals of African descent or G6PD deficiency sequencing for individuals with other high-risk ethnic backgrounds

Glucose-6-Phosphate Dehydrogenase (G6PD) 2 Mutations 0051684
Method: Polymerase Chain Reaction/ TaqMAN

Recommended Use

Preferred genetic test for individuals of African descent

Detect single most common pathogenic G6PD variant (A- allele) in individuals of African descent

For initial screening for GP6D deficiency, refer to glucose-6-phosphate dehydrogenase

Limitations

Only the G6PD A- allele (A376G and G202A variants together on same chromosome) and the G6PD A+ allele (A376G variant in isolation) are detected

Analytical sensitivity may be affected by rare primer- or probe-site variants

Diagnostic errors can occur due to rare sequence variations

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) Sequencing 2007163
Method: Polymerase Chain Reaction/Sequencing

Recommended Use

Preferred test for individuals of high-risk ethnic backgrounds other than those of African descent; for initial screening for GP6D deficiency, refer to glucose-6-phosphate dehydrogenase

Appropriate test for symptomatic individuals of African descent who do not carry the A- allele

Detect most G6PD deficiency-causing gene variants

Limitations

Sequencing may detect variants of unknown clinical significance

Diagnostic errors can occur due to rare sequence variations

Regulatory region variants, deep intronic variants, and large deletions/duplications will not be detected

Hemoglobin Evaluation Reflexive Cascade 2005792
Method: High Performance Liquid Chromatography/Electrophoresis/RBC Solubility/Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer/Sequencing

Recommended Use

Optimal test for initial and confirmatory diagnosis of any suspected hemoglobinopathy

A faculty hematopathologist personally directs and interprets each stage of testing to completion

A comprehensive report is provided

Do not use for follow-up of an individual with known diagnosis

Genes include HBB (β-globin), HBA1, and HBA2 (α-globins)

Reflex pattern – if an abnormal hemoglobin is detected or if CBC data is suggestive of a hemoglobinopathy, one or more reflexive tests (electrophoresis, solubility testing, mutational analysis, and/or sequencing) may be added

Refer to Additional Technical Information document for further content

Limitations

May not detect all Hb variants

Regulatory region variants and sequence variants in genes other than HBB, HBA1, and HBA2 will not be detected

The phase of identified variants may not be determined

Specific breakpoints of large deletions/duplications will not be determined; it may not be possible to distinguish variants of similar size

Individuals carrying both a deletion and a duplication within the α-globin gene cluster may appear to have a normal number of α-globin gene copies

Sequencing of both HBA1 and HBA2 genes may not be possible in individuals harboring large α-globin deletions on both alleles

Rare syndromic or acquired forms of α thalassemia associated with ATRX gene variants will not be detected

Diagnostic errors can occur due to rare sequence variations

Hemoglobin Evaluation with Reflex to Electrophoresis and/or RBC Solubility 0050610
Method: High Performance Liquid Chromatography/Electrophoresis/RBC Solubility

Recommended Use

Effective test for screening and follow-up of individuals with known hemoglobinopathies

Optimal test for initial diagnosis of a suspected hemoglobinopathy is hemoglobin evaluation reflexive cascade

Quantitation of hemoglobin is recommended for definitive diagnosis in infants ≥1 year

Reflex pattern – if abnormal peaks suggestive of a hemoglobin variant are detected, then RBC solubility and/or capillary electrophoresis will be added to aid in identification and confirmation of the variant

Diagnostic errors can occur due to rare sequence variations

Beta Globin (HBB) HbS, HbC, and HbE Mutations 0051421
Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Recommended Use

Confirm suspected HbS, HbC, or HbE variants

Limitations

Detects only three most common missense variants in β-globin gene

Other β- and α-globin variants are not identified

Diagnostic errors can occur due to rare sequence variations

Pyruvate Kinase 0080290
Method: Quantitative Enzymatic

Recommended Use

Preferred initial test for screening for pyruvate kinase (PK) deficiency

Limitations

Patients who have recently received transfusions have normal donor cells that may mask PK-deficient erythrocytes

Direct Coombs (Anti-Human Globulin) 0013008
Method: Hemagglutination

Recommended Use

Identify antibodies as cause of hemolysis

Cold Agglutinins 0050175
Method: Semi-Quantitative Hemagglutination

Recommended Use

Identify antibodies as cause of hemolysis

Antibody Detection, RBC 0010004
Method: Hemagglutination

Recommended Use

Identify antibodies as cause of hemolysis

Hereditary Hemolytic Anemia Panel Sequencing 2012052
Method: Massively Parallel Sequencing

Recommended Use

Determine etiology, elicit inheritance pattern, and assess recurrence risk in individuals with:

Unexplained hemolytic anemia
Unexplained hyperbilirubinemia
Family history of unexplained hemolytic anemia
Pregnancy with hydrops fetalis of unknown etiology

Refer to Test Fact Sheet for list of genes tested

Limitations

Refer to Test Fact Sheet for limitations

Test Fact Sheet(s)

Hereditary Hemolytic Anemia Panel, Sequencing

Medical Experts

Agarwal, Archana Mishra, MD, Medical Director, Hemoglobin Laboratory in the Special Genetics Division; Associate Medical Director, Molecular Oncology at ARUP Laboratories ; Assistant Professor of Clinical Pathology, University of Utah

Best, Hunter, PhD, Medical Director, Molecular Genetics and Genomics; Co-Scientific Director, NGS and Biocomputing; Director, High Complexity Platforms-NGS, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Blaylock, Robert C., MD, Medical Director, Blood Services, and Phlebotomy and Support Services, Immunohematology Reference, Clinical Laboratory and Transfusion Services at the University of Utah Hospitals and Clinics at ARUP Laboratories ; Associate Professor of Clinical Pathology, University of Utah

Couturier, Marc Roger, PhD, D(ABMM), Medical Director, Microbial Immunology, Parasitology and Fecal Testing, and Infectious Disease Antigen Testing at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Krautscheid, Patti, MS, LCGC, Genetic Counselor, Molecular Genetics and Special Genetics Laboratories at ARUP Laboratories

Lyon, Elaine, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, Medical Director, Pharmacogenomics at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Mao, Rong, MD, FACMG, Laboratory Section Chief, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Associate Professor, Pediatrics, and Co-Director, Clinical Molecular Genetics Fellowship Program, University of Utah

Prchal, Josef T., MD, Medical Director, Special Genetics at ARUP Laboratories; Professor, Division of Hematology and Hematologic Malignancies, Dept. of Internal Medicine; Adjunct Professor in Human Genetics and Pathology; Huntsman Cancer Institute Investigator, University of Utah

Wittwer, Carl T., MD, PhD, Medical Director, Immunologic Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

References

Guidelines

Bolton-Maggs PH, Stevens RF, Dodd NJ, Lamont G, Tittensor P, King M, General Haematology Task Force of the British Committee for Standards in Haematology. Guidelines for the diagnosis and management of hereditary spherocytosis. Br J Haematol. 2004; 126(4): 455-74. PubMed
Bolton-Maggs PH, Langer JC, Iolascon A, Tittensor P, King M, General Haematology Task Force of the British Committee for Standards in Haematology. Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update Br J Haematol. 2012; 156(1): 37-49. PubMed
Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Mar 2019]

General References

Barcellini W. Immune Hemolysis: Diagnosis and Treatment Recommendations. Semin Hematol. 2015; 52(4): 304-12. PubMed

Bass GF, Tuscano ET, Tuscano JM. Diagnosis and classification of autoimmune hemolytic anemia. Autoimmun Rev. 2014; 13(4-5): 560-4. PubMed

Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008; 371(9606): 64-74. PubMed

Gallagher PG. Diagnosis and management of rare congenital nonimmune hemolytic disease. Hematology Am Soc Hematol Educ Program. 2015; 2015: 392-9. PubMed

Grace RF, Zanella A, Neufeld EJ, Morton H, Eber S, Yaish H, Glader B. Erythrocyte pyruvate kinase deficiency: 2015 status report. Am J Hematol. 2015; 90(9): 825-30. PubMed

Höchsmann B, Schrezenmeier H. Congenital CD59 Deficiency. Hematol Oncol Clin North Am. 2015; 29(3): 495-507. PubMed

Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update. Expert Rev Hematol. 2011; 4(6): 607-18. PubMed

Naik R. Warm autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015; 29(3): 445-53. PubMed

Shanbhag S, Spivak J. Paroxysmal cold hemoglobinuria. Hematol Oncol Clin North Am. 2015; 29(3): 473-8. PubMed

Zantek ND, Koepsell SA, Tharp DR, Cohn CS. The direct antiglobulin test: a critical step in the evaluation of hemolysis. Am J Hematol. 2012; 87(7): 707-9. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Agarwal AM, Nussenzveig RH, Reading NS, Patel JL, Sangle N, Salama ME, Prchal JT, Perkins SL, Yaish HM, Christensen RD. Clinical utility of next-generation sequencing in the diagnosis of hereditary haemolytic anaemias. Br J Haematol. 2016; PubMed

Christensen RD, Agarwal AM, Nussenzveig RH, Heikal N, Liew MA, Yaish HM. Evaluating eosin-5-maleimide binding as a diagnostic test for hereditary spherocytosis in newborn infants. J Perinatol. 2015; 35(5): 357-61. PubMed

Christensen RD, Yaish HM, Nussenzveig RH, Agarwal AM. Siblings with severe pyruvate kinase deficiency and a complex genotype. Am J Med Genet A. 2016; 170(9): 2449-52. PubMed

Christensen RD, Yaish HM, Nussenzveig RH, Reading S, Agarwal AM, Eggert LD, Prchal JT. Acute kernicterus in a neonate with O/B blood group incompatibility and a mutation in SLC4A1. Pediatrics. 2013; 132(2): e531-4. PubMed

Reading S, Ruiz-Bonilla JA, Christensen RD, Cáceres-Perkins W, Prchal JT. A patient with both methemoglobinemia and G6PD deficiency: A therapeutic conundrum. Am J Hematol. 2017; 92(5): 474-477. PubMed

Reading S, Sirdah MM, Shubair ME, Nelson BE, Al-Kahlout MS, Al-Tayeb JM, Aboud LN, Shaban MA, Luzzatto L, Prchal JT. Favism, the commonest form of severe hemolytic anemia in Palestinian children, varies in severity with three different variants of G6PD deficiency within the same community. Blood Cells Mol Dis. 2016; 60: 58-64. PubMed

Sirdah M, Reading S, Perkins SL, Shubair M, Aboud L, Prchal JT. Hemolysis and Mediterranean G6PD mutation (c.563 C>T) and c.1311 C>T polymorphism among Palestinians at Gaza Strip. Blood Cells Mol Dis. 2012; 48(4): 203-8. PubMed

Sirdah M, Reading S, Vankayalapati H, Perkins SL, Shubair ME, Aboud L, Roper D, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Gaza Strip Palestinians. Blood Cells Mol Dis. 2012; 49(3-4): 152-8. PubMed

Sirdah MM, Shubair ME, Al-Kahlout MS, Al-Tayeb JM, Prchal JT, Reading S. Possible association of 3' UTR +357 A>G, IVS11-nt 93 T>C, c.1311 C>T polymorphism with G6PD deficiency. Hematology. 2017; 22(6): 370-374. PubMed

Swierczek S, Agarwal AM, Naidoo K, Lorenzo FR, Whisenant J, Nussenzveig RH, Agarwal N, Coetzer TL, Prchal JT. Novel exon 2 α spectrin mutation and intragenic crossover: three morphological phenotypes associated with four distinct α spectrin defects. Haematologica. 2013; 98(12): 1972-9. PubMed

Testing Algorithms

Hemolytic Anemias Testing Algorithm

Read more about Hemolytic Anemias Testing Algorithm

Educational Videos

Last Update: January 2019

Hemolytic Anemias

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Classification

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hemolytic Anemias Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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Hemolytic Anemias

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Classification

Clinical Presentation

ARUP Lab Tests

Test Fact Sheet(s)

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hemolytic Anemias Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult