Erythrocyte Disorders
Hemolytic and Hypoproliferative Anemias, Erythrocytosis, and Hemoglobin Variants
Anemia with an increased reticulocyte response points toward shortened red-cell survival once the marrow has had time to react. An inadequate response points toward impaired production or ineffective erythropoiesis. The blood film, hemolysis markers, direct antiglobulin test, other cell lines, and targeted studies then identify the affected membrane, enzyme, marrow process, external injury, or hemoglobin.1
The anemia evaluation topic explains the CBC indices, reticulocyte production index, and earlier microcytic and macrocytic patterns. This topic begins with the hemolytic and hypoproliferative disorders that follow that initial classification.
Hemolysis patterns
No single result establishes hemolysis. The strongest interpretation comes from a concordant pattern and its change over time. The absolute reticulocyte count usually rises after marrow compensation begins. Lactate dehydrogenase (LDH) and indirect bilirubin increase as cells break down. Haptoglobin falls as it binds free hemoglobin. Liver disease, inflammation, kidney disease, specimen hemolysis, recent transfusion, and the timing of collection can alter individual markers.1
| Pattern | Supporting findings | Main implications |
|---|---|---|
| Predominantly extravascular hemolysis | Reticulocytosis, indirect bilirubin and LDH increase, haptoglobin decrease, splenomegaly, spherocytes in selected disorders | Macrophages clear intact or partly phagocytosed cells, often in the spleen or liver |
| Intravascular hemolysis | Plasma free hemoglobin, marked haptoglobin depletion, hemoglobinemia, hemoglobinuria, later urinary hemosiderin, schistocytes in fragmentation disorders | Cells rupture within the circulation; severe episodes can injure the kidneys and require urgent communication |
| Ineffective erythropoiesis | Anemia with an inadequate reticulocyte response, LDH and indirect bilirubin increases, erythroid hyperplasia or dysplasia in selected marrow disorders | Precursors die within marrow before entering circulation |
| Hypoproliferation | Anemia with a low absolute reticulocyte count; other cytopenias or marrow hypocellularity may be present | Marrow contains too few functioning precursors or receives insufficient stimulation |
Increased polychromasia should agree with an increased reticulocyte count. A brisk hemolytic episode can initially have a low reticulocyte count, especially when marrow disease, nutrient deficiency, infection, kidney disease, or antibody activity against erythroid precursors limits production. A direct antiglobulin test (DAT) helps identify immune sensitization after hemolysis has been established. Spherocytes, bite cells, blister cells, echinocytes, and schistocytes each narrow the differential, but their significance depends on the complete pattern.
Membrane disorders and paroxysmal nocturnal hemoglobinuria
The erythrocyte membrane attaches its lipid bilayer to a spectrin-based skeleton. Hereditary spherocytosis usually weakens vertical attachment between the bilayer and skeleton. Hereditary elliptocytosis and hereditary pyropoikilocytosis usually weaken spectrin self-association or the mechanics of the spectrin-actin junction. Cation-leak disorders change cell hydration and produce stomatocytic or xerocytic patterns.2,3
| Disorder | Main defect | CBC and film pattern | Useful confirmation and limits |
|---|---|---|---|
| Hereditary spherocytosis | Defects involving ankyrin, spectrin, band 3, or protein 4.2 reduce membrane surface area | Spherocytes, reticulocytosis, increased MCHC in many cases, indirect bilirubin increase, DAT usually nonreactive | Eosin-5-maleimide binding, osmotic-fragility or glycerol-lysis studies, osmotic-gradient ektacytometry, and molecular testing can support the diagnosis. Each method misses some cases. |
| Hereditary elliptocytosis | Weakened spectrin self-association or junctional-complex stability | Elliptocytes range from a minor population to most red cells; anemia varies from absent to hemolytic | Family pattern, morphology, ektacytometry, membrane studies, and molecular testing establish difficult cases |
| Hereditary pyropoikilocytosis | Severe spectrin instability | Marked poikilocytosis with elliptocytes, fragments, and microspherocytes; low MCV can reflect very small fragments | Findings can resemble severe thermal or mechanical injury; membrane and molecular studies resolve the cause |
| Southeast Asian ovalocytosis | Band 3 change produces a rigid membrane | Ovalocytes with transverse ridges; anemia is usually mild or absent | Morphology plus ancestry and molecular testing support the diagnosis |
| Overhydrated hereditary stomatocytosis | Cation influx produces cellular overhydration | Stomatocytes, macrocytosis, and reduced MCHC | Ektacytometry, cation studies, and molecular testing help define the channel disorder |
| Dehydrated hereditary stomatocytosis, or hereditary xerocytosis | Cation loss produces cellular dehydration, commonly through PIEZO1 or KCNN4 variants | Target cells, echinocytes, occasional stomatocytes, and increased MCHC; MCV can vary | Ektacytometry and molecular testing are central because stomatocytes can be sparse |
An increased MCHC is a useful hereditary-spherocytosis clue, especially with spherocytes, reticulocytosis, a family pattern, and a nonreactive DAT. Immune hemolysis and thermal injury also produce spherocytes. Eosin-5-maleimide flow cytometry measures reduced binding to band 3 and closely associated membrane proteins. Osmotic-fragility studies measure lysis across decreasing saline concentrations. Results require a method-specific reference curve, controls, and correlation with the film. Molecular testing is most useful when the phenotype is atypical, family counseling requires a genotype, or functional tests disagree.2
Splenectomy is strongly avoided in overhydrated and dehydrated hereditary stomatocytosis because it can be followed by severe arterial or venous thrombosis.3
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal stem-cell disorder. A somatic PIGA mutation disrupts glycosylphosphatidylinositol (GPI) anchor synthesis. Descendant blood cells lose GPI-anchored complement regulators, including CD55 and CD59, and become vulnerable to complement-mediated intravascular hemolysis. PNH can occur as a hemolytic disorder or alongside aplastic anemia, myelodysplastic neoplasia, or another marrow-failure process. Thrombosis, especially at an unusual site, cytopenias, DAT-negative intravascular hemolysis, and hemoglobinuria are important testing indications.4
High-sensitivity flow cytometry demonstrates a GPI-deficient clone in peripheral blood. The study assesses neutrophils and monocytes with fluorescent aerolysin (FLAER) plus lineage-appropriate GPI-linked markers. FLAER binds the GPI anchor directly and is unsuitable for routine RBC analysis. RBC analysis commonly uses CD59 and can separate cells with normal, partial, and complete GPI-linked protein expression. These are type I, type II, and type III RBC phenotypes. They describe red-cell expression, while the clinical category also depends on hemolysis, thrombosis, and marrow status. Recent transfusion and active hemolysis can reduce the measured RBC clone fraction, so the white-cell clone gives the better estimate of clone size. The report should name the cell lineages, markers, clone fractions, and assay sensitivity.4
Older acidified-serum and sucrose-lysis screens lack the sensitivity and specificity of current flow cytometry. A small GPI-deficient clone in aplastic anemia carries a different interpretation from a large clone with active intravascular hemolysis. Flow results therefore require the CBC, reticulocytes, LDH, bilirubin, haptoglobin, urine findings, thrombosis history, and marrow diagnosis.
Red-cell enzyme defects
Mature red cells rely on anaerobic glycolysis for adenosine triphosphate (ATP) and on the pentose phosphate pathway for reduced nicotinamide adenine dinucleotide phosphate (NADPH). ATP maintains membrane pumps and deformability. NADPH keeps glutathione reduced so the cell can remove peroxide and limit oxidant injury.1
Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase (G6PD) generates NADPH in the first step of the pentose phosphate pathway. Deficiency leaves hemoglobin and membrane proteins vulnerable during oxidant stress. Denatured hemoglobin forms Heinz bodies, which require a supravital stain. Splenic removal of Heinz body material creates bite cells and blister cells. Acute episodes can have both intravascular and extravascular components.
G6PD deficiency is X-linked. Hemizygous males and homozygous or compound-heterozygous females can have uniformly deficient red cells. Heterozygous females have a mosaic population after random X inactivation, so whole-blood activity can fall anywhere from deficient to apparently normal. Infection, fava beans, and specific oxidant medicines can trigger hemolysis. Medication risk is drug-specific; dapsone, rasburicase, standard-dose primaquine, tafenoquine, and methylene blue are high-risk examples in current pharmacogenetic guidance.5
During an episode, the laboratory may find a falling hemoglobin, reticulocytosis after marrow response begins, indirect bilirubin and LDH increases, haptoglobin depletion, hemoglobinuria, bite cells, and supravital Heinz bodies. The DAT is usually nonreactive. Neonates can present with hyperbilirubinemia, with variable evidence of hemolysis.
The quantitative enzyme assay is the main phenotypic test. Acute hemolysis removes older deficient cells while leaving younger cells and reticulocytes with higher activity, which can produce an apparently normal result. Recent transfusion can add donor cells with normal activity. A normal result obtained in either setting should be repeated at steady state under the testing laboratory’s timing recommendation. Molecular testing can define a variant, although genotype alone may leave the degree of deficiency uncertain in a heterozygous female.5
Pyruvate kinase deficiency
Pyruvate kinase catalyzes the ATP-generating conversion of phosphoenolpyruvate to pyruvate near the end of glycolysis. Biallelic PKLR variants reduce ATP, impair membrane stability, and cause chronic hereditary nonspherocytic hemolytic anemia. Increased 2,3-bisphosphoglycerate shifts oxygen release toward tissues, so the clinical effect can appear milder than the hemoglobin concentration suggests. The film may show echinocytes, especially after splenectomy, along with polychromasia and other findings of reduced splenic function.6
Diagnosis combines a compatible chronic hemolytic pattern, reduced RBC pyruvate-kinase activity, and PKLR testing. Reticulocytosis, recent transfusion, and leukocyte contamination can raise the measured activity and obscure deficiency. The laboratory should remove leukocytes as required by the assay and interpret activity with transfusion history, reticulocyte count, and molecular findings. Two pathogenic or likely pathogenic PKLR variants in trans support the diagnosis; an uncertain variant requires further correlation.6
Pyrimidine 5′-nucleotidase deficiency impairs degradation of residual erythrocyte RNA and can cause chronic hemolysis with coarse basophilic stippling. Rare defects involving hexokinase, glucose-phosphate isomerase, phosphofructokinase, aldolase, triosephosphate isomerase, or phosphoglycerate kinase can produce similar hereditary nonspherocytic hemolysis. An enzyme panel or molecular panel is useful after membrane, immune, hemoglobin, and common enzyme causes have been assessed.
Extrinsic and immune hemolysis
External injury can fragment, heat-damage, oxidize, infect, or immunologically target structurally normal red cells. The platelet count, coagulation results, exposure history, DAT, and organ findings separate these processes.
Fragmentation and thrombotic microangiopathy
Microangiopathic hemolytic anemia (MAHA) describes fragmentation in small vessels. Thrombotic microangiopathy (TMA) is a clinical syndrome that usually combines MAHA, thrombocytopenia, and organ injury. Schistocytes are fragments with sharp angles, straight borders, helmet forms, or small crescents. The International Council for Standardization in Haematology considers more than 1% schistocytes suspicious for TMA in adults and full-term neonates when fragments are the main RBC abnormality. Counts of 1% or less can occur in healthy adults, mechanical devices, dialysis, renal disease, and other settings. The film result requires the clinical and laboratory pattern.7
| Process | Main laboratory pattern | Immediate laboratory action |
|---|---|---|
| Thrombotic thrombocytopenic purpura (TTP) | MAHA, severe thrombocytopenia, usually minor routine-coagulation changes, organ ischemia; severe ADAMTS13 activity deficiency below 10% supports immune or congenital TTP | Communicate the pattern urgently. Collect citrated plasma for ADAMTS13 activity and inhibitor or anti-ADAMTS13 testing before plasma exchange or plasma-containing products when feasible. |
| Shiga toxin-producing Escherichia coli-associated HUS | MAHA, thrombocytopenia, acute kidney injury, and a compatible diarrheal illness | Perform stool culture and Shiga-toxin or gene detection under the laboratory’s enteric protocol |
| Complement-mediated TMA | MAHA, thrombocytopenia, prominent kidney injury, and exclusion of more common causes; complement results can be normal | Preserve pretreatment specimens when possible and coordinate specialized complement and genetic studies |
| HELLP syndrome | Hemolysis, increased liver enzymes, and low platelets during pregnancy or postpartum | Treat the combination as urgent and report according to the laboratory’s critical-result procedure |
| Disseminated intravascular coagulation | Thrombocytopenia, increased D-dimer or fibrin-related markers, prolonged PT and often aPTT, falling fibrinogen in overt disease, and variable schistocytes | Trend the complete panel because early results can be subtle and change quickly |
An ADAMTS13 result below 10 IU/dL, or below 10% of normal, supports TTP in the appropriate setting. An inhibitor or anti-ADAMTS13 antibody supports immune TTP; inherited ADAMTS13 deficiency causes congenital TTP. Values from 10% to 20% require correlation and consideration of other TMAs. Plasma exchange and plasma-containing products can alter the result, which makes pretreatment collection valuable. Urgent clinical action proceeds from the pretest probability while testing is under way.8
Mechanical valves and other high-shear devices can cause macroangiopathic fragmentation with schistocytes. Extensive burns and overheated blood can produce fragments, microspherocytes, and acute intravascular hemolysis. Oxidant chemicals can produce methemoglobin, Heinz bodies, bite cells, and blister cells even when G6PD activity is normal. Exposure history and equipment investigation can be as important as the morphology.
Immune hemolysis
Warm IgG usually promotes splenic extravascular clearance and spherocyte formation. IgM activates complement efficiently and can produce hepatic clearance or intravascular lysis. A DAT positive for IgG, C3d, or both supports immune sensitization only when interpreted with objective hemolysis and the transfusion, pregnancy, medication, and antibody history.9
The immune hemolytic anemia diagnostic framework owns cold agglutinin disease, cold agglutinin syndrome, paroxysmal cold hemoglobinuria, DAT preanalytics, and thermal-amplitude testing. The warm, mixed, and drug-induced immune hemolytic anemia topic owns warm and mixed patterns, routine-DAT-negative investigation, drug-dependent testing, adsorption, elution, and transfusion support. Alloimmune hemolysis from transfusion or pregnancy also belongs to Blood Banking.
Marrow failure and hypoproliferative anemia
A low absolute reticulocyte count separates hypoproliferation from a compensated peripheral loss. The other cell lines then show whether the process is erythroid-selective or affects the stem-cell compartment or marrow space.
| Disorder | CBC and reticulocytes | Marrow and defining studies | Main distinction |
|---|---|---|---|
| Aplastic anemia | Pancytopenia with reticulocytopenia; macrocytosis can occur | Hypocellular marrow without an abnormal infiltrate or substantial fibrosis; cytogenetic, molecular, PNH-clone, viral, nutritional, medication, and inherited-failure evaluation exclude alternatives | Stem-cell failure reduces multiple lineages |
| Pure red cell aplasia (PRCA) | Severe anemia and marked reticulocytopenia with preserved neutrophils and platelets | Severe erythroid hypoplasia with preserved granulopoiesis and megakaryocytes; evaluate parvovirus B19, thymoma, immune disease, lymphoid neoplasia, and implicated drugs | Selective erythroid failure |
| Diamond-Blackfan anemia, or DBA syndrome | Usually macrocytic anemia beginning in infancy, very low reticulocytes, and variable congenital findings; Hb F and erythrocyte adenosine deaminase can be increased | Erythroid hypoplasia plus a pathogenic variant in a DBA-associated gene when identified | Inherited ribosome-related erythroid failure; supportive markers are imperfect |
| Transient erythroblastopenia of childhood | Usually normocytic anemia and reticulocytopenia in an otherwise well young child | Temporary erythroid hypoplasia; follow-up shows reticulocyte recovery | Acquired, self-limited childhood PRCA pattern |
| Congenital dyserythropoietic anemia (CDA) | Chronic anemia with an inadequate reticulocyte response for the degree of erythroid expansion; indirect bilirubin and iron loading can increase | Hypercellular erythroid marrow with type-specific dyserythropoiesis; molecular testing distinguishes CDAN1/CDIN1, SEC23B, KIF23, RACGAP1, and related disorders | Ineffective erythropoiesis within a populated marrow |
| Myelophthisic anemia | Usually normocytic anemia with a leukoerythroblastic film, teardrop cells, nucleated RBCs, immature granulocytes, and abnormal platelets | Aspirate can be a dry tap; core biopsy demonstrates metastatic tumor, fibrosis, granuloma, or another infiltrating process | Marrow-space replacement releases immature myeloid and erythroid cells |
| Anemia of chronic kidney disease | Usually normocytic anemia with an inadequate reticulocyte response; iron-restricted erythropoiesis can add microcytosis | CBC, reticulocytes, ferritin, transferrin saturation, kidney function, and evaluation for other causes | Reduced erythropoietin response, inflammation, iron restriction, and uremic effects combine |
Aplastic anemia severity
Current automated-count criteria define severe aplastic anemia by marrow cellularity below 25%, or 25% to 50% cellularity with less than 30% residual hematopoietic cells, plus at least two of these findings:
- absolute neutrophil count below 0.5 × 109/L
- platelet count below 20 × 109/L
- automated absolute reticulocyte count below 60 × 109/L
Very severe aplastic anemia meets the same criteria with an absolute neutrophil count below 0.2 × 109/L. Historical criteria used a lower manual reticulocyte threshold, so the report must identify the counting method. Aplastic anemia is a diagnosis of exclusion. A marrow aspirate and core biopsy, careful film review, and tests for inherited marrow failure, hypoplastic myeloid neoplasia, PNH clones, infection, medication or toxic exposure, and nutritional deficiency resolve the major alternatives.10
Fanconi anemia can present with congenital findings, macrocytosis, increased Hb F, progressive cytopenias, or apparently acquired aplastic anemia. Chromosome-breakage testing exposes lymphocytes to diepoxybutane or mitomycin C and measures excess breaks and radial forms. Somatic mosaicism can produce an inconclusive blood result; testing cultured skin fibroblasts can resolve that setting. Molecular testing identifies the responsible inheritance pattern and also helps evaluate related inherited marrow-failure syndromes.11
DBA syndrome commonly involves a ribosomal-protein gene, with RPS19 the most frequent single gene. Elevated erythrocyte adenosine deaminase and Hb F support DBA, while normal values occur in some affected patients. Age at presentation, congenital findings, serial counts, marrow morphology, and molecular results separate DBA from transient childhood erythroblastopenia and acquired PRCA.12
The classic CDA groups combine characteristic marrow morphology with molecular findings. CDA I often shows internuclear chromatin bridges and CDAN1 or CDIN1 variants. CDA II commonly shows binucleated erythroblasts and biallelic SEC23B variants. CDA III includes giant multinucleated erythroblasts and can involve KIF23 or RACGAP1. Morphology should guide the molecular test while the genotype confirms the classification.13
The 2026 Kidney Disease: Improving Global Outcomes guideline uses hemoglobin below 13.0 g/dL in adult men and below 12.0 g/dL in adult women as the usual anemia thresholds in chronic kidney disease (CKD). These are screening definitions. Patient interpretation still uses the applicable laboratory interval and clinical setting. CKD evaluation includes the reticulocyte response and iron status and looks for blood loss, inflammation, nutritional deficiency, hemolysis, and marrow disease before the anemia is assigned to kidney disease.14
Erythrocytosis
Erythrocytosis is an increased hemoglobin or hematocrit above the appropriate interval. A repeat CBC confirms persistence and allows review for analytic interference. Prior results establish whether the change is longstanding or acquired. Relative erythrocytosis reflects plasma-volume contraction, as with dehydration, diuresis, gastrointestinal fluid loss, or burns. Absolute erythrocytosis reflects increased red-cell mass.15
Primary absolute erythrocytosis arises from an erythroid-cell defect. Polycythemia vera is the main acquired cause and commonly carries JAK2 V617F or an exon 12 variant. Secondary erythrocytosis is driven by erythropoietin (EPO). Causes include chronic hypoxemia, high altitude, sleep-disordered breathing, right-to-left cardiac shunts, carbon monoxide exposure, renal hypoxia, EPO-producing tumors, exogenous EPO, testosterone or other androgens, and high-oxygen-affinity hemoglobin.15
Investigation sequence
- Confirm a persistent increase using the laboratory’s age- and sex-appropriate interval. Review plasma-volume status, prior CBCs, smoking or carbon-monoxide exposure, medications, altitude, cardiopulmonary disease, kidney disease, and family history.
- Measure serum EPO. A subnormal result supports a primary process. A normal or increased result supports secondary causes, with overlap in both directions.
- Test JAK2 V617F when polycythemia vera is plausible. A compatible V617F-negative, low-EPO pattern directs JAK2 exon 12 testing and marrow evaluation.
- Evaluate oxygenation and carbon monoxide with the appropriate method. Pulse oximetry can appear reassuring during carbon-monoxide exposure; co-oximetry measures carboxyhemoglobin.
- In a lifelong or familial pattern, use venous P50, hemoglobin analysis, and targeted genes to investigate high-affinity hemoglobin, 2,3-bisphosphoglycerate defects, altered oxygen sensing, or erythropoietin-receptor signaling.
Leukocytosis, thrombocytosis, basophilia, splenomegaly, a low EPO, and a JAK2 variant support polycythemia vera. Marrow panmyelosis and formal myeloid-neoplasm criteria complete that diagnosis. Secondary erythrocytosis often has isolated erythroid expansion. High-affinity hemoglobins can produce tissue hypoxia with a normal arterial oxygen saturation, making a low P50 and hemoglobin studies important in an otherwise unexplained familial case.
Structural hemoglobin variants
Structural variants change a globin-chain amino acid. Their laboratory effects arise from altered solubility, charge, stability, oxygen affinity, or globin production. The CBC and film show the cellular consequence. Hemoglobin analysis shows the protein fractions, and molecular testing resolves ambiguous or clinically important genotypes.
| Variant or genotype | Main effect | Typical laboratory pattern |
|---|---|---|
| Hb S | Deoxygenated Hb S polymerizes and damages the cell | Hb SS has chronic hemolysis with sickle cells, target cells, polychromasia, nucleated RBCs, and Howell-Jolly bodies after functional asplenia develops |
| Hb C | Reduced solubility and cellular dehydration promote crystal formation | Hb CC usually causes mild hemolysis with target cells, occasional hexagonal crystals, and increased MCHC |
| Hb SC | Hb C-related dehydration raises intracellular Hb S concentration | Target cells, folded or gloved-finger cells, occasional sickle cells, and a clinically significant sickling disorder |
| Hb S/β-thalassemia | Hb S is inherited with reduced or absent β-chain production | Sickle cells and target cells with microcytosis; Hb A amount, Hb A2, iron status, transfusion history, and method help separate β+ from β0 and competing causes of microcytosis |
| Hb D-Punjab | Charge is altered; the variant alone lacks the Hb S polymerization mechanism | Usually little hematologic effect alone; coinheritance with Hb S can produce sickling disease |
| Hb E | A β-chain substitution also activates abnormal splicing and reduces β-chain output | Microcytosis and target cells with little anemia in trait or homozygous Hb E; Hb E/β-thalassemia has variable anemia and increased Hb F |
| Unstable hemoglobin | Globin denatures and precipitates | Chronic or episodic hemolysis with Heinz bodies, bite cells, blister cells, and irregularly contracted cells |
Sickle-solubility testing is an Hb S screen. A positive result shows a detectable sickling hemoglobin and requires fractionation to separate trait, Hb SS, Hb SC, Hb S/β-thalassemia, and other compound states. High Hb F in infancy, severe anemia, a small Hb S fraction, or recent transfusion can produce a negative screen in an affected patient. The test supplies no information about Hb C, Hb D, Hb E, unstable hemoglobins, or most other variants.16
High-performance liquid chromatography, capillary electrophoresis, isoelectric focusing, and gel electrophoresis separate fractions by different properties. Each method has coelution or comigration patterns. A presumptive identity should be checked with a second principle or molecular test when the result affects diagnosis, reproductive counseling, or treatment. Age, transfusion history, iron status, and therapy change the measured percentages. Hb A2 can be increased in Hb SS and varies by method, so an increased value supports Hb S/β-thalassemia only within the full pattern.17
Heinz bodies, bite cells, and blister cells also occur in G6PD deficiency and acquired oxidant injury. Heat-stability and isopropanol tests can support an unstable hemoglobin, while molecular testing establishes the variant when protein studies remain unresolved. High-oxygen-affinity variants may appear during an erythrocytosis work-up and can require P50 measurement because routine fractionation misses some charge-neutral variants.
Reference intervals
Clinical interpretation uses the performing laboratory’s verified or established interval for its method and patient population. Age, sex, pregnancy, altitude, specimen conditions, instrument, reagents, and local population affect CBC intervals. Under the Clinical Laboratory Improvement Amendments, a laboratory verifies manufacturer-provided intervals for its population or establishes appropriate intervals when required by the test system or a method modification.18
The ASCP BOC examination reference-ranges topic contains the composite examination values, including hemoglobin 12.0 to 18.0 g/dL, hematocrit 35% to 50%, MCV 76 to 100 fL, WBC count 3.6 to 10.6 × 109/L, and platelet count 150 to 450 × 109/L. ASCP BOC supplies those values for examination preparation. Patient reports require the performing laboratory’s clinical intervals.19
References
- Keohane EM, Preston MM, Mirza KM, Walenga JM, eds. Rodak's Hematology: Clinical Principles and Applications. 7th ed. Elsevier; 2025. Accessed August 29, 2026.
- Wu Y, Liao L, Lin F. The diagnostic protocol for hereditary spherocytosis: 2021 update. J Clin Lab Anal. 2021;35(12):e24034. doi:10.1002/jcla.24034.
- Stewart GW, Gibson JS, Rees DC. The cation-leaky hereditary stomatocytosis syndromes: a tale of six proteins. Br J Haematol. 2023;203(4):509-522. doi:10.1111/bjh.19093.
- Sutherland DR, Illingworth A, Marinov I, et al. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria and related disorders, part 2: reagent selection and assay optimization for high-sensitivity testing. Cytometry B Clin Cytom. 2018;94(1):23-48. doi:10.1002/cyto.b.21610.
- Gammal RS, Pirmohamed M, Somogyi AA, et al. Expanded Clinical Pharmacogenetics Implementation Consortium guideline for medication use in the context of G6PD genotype. Clin Pharmacol Ther. 2023;113(5):973-985. doi:10.1002/cpt.2735.
- Al-Samkari H, Shehata N, Lang-Robertson K, et al. Diagnosis and management of pyruvate kinase deficiency: international expert guidelines. Lancet Haematol. 2024;11(3):e228-e239. doi:10.1016/S2352-3026(23)00377-0.
- Zini G, d'Onofrio G, Erber WN, et al. 2021 update of the 2012 ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes: impact and revisions. Int J Lab Hematol. 2021;43(6):1264-1271. doi:10.1111/ijlh.13682.
- Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2486-2495. doi:10.1111/jth.15006.
- Michel M, Crickx E, Fattizzo B, Barcellini W. Autoimmune haemolytic anaemias. Nat Rev Dis Primers. 2024;10(1):82. doi:10.1038/s41572-024-00566-2.
- American Society of Hematology. American Society of Hematology 2026 guidelines for the diagnosis and management of severe acquired aplastic anemia. Blood Adv. Published online April 1, 2026. doi:10.1182/bloodadvances.2025019051.
- Mehta PA, Ebens CL. Fanconi anemia. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews. University of Washington, Seattle; 2002. Updated January 15, 2026. Accessed August 29, 2026.
- Sieff C. DBA syndrome. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews. University of Washington, Seattle; 2009. Updated July 31, 2025. Accessed August 29, 2026.
- Iolascon A, Andolfo I, Russo R. Congenital dyserythropoietic anemias. Blood. 2020;136(11):1274-1283. doi:10.1182/blood.2019000948.
- Kidney Disease: Improving Global Outcomes Anemia Work Group. KDIGO 2026 clinical practice guideline for the management of anemia in chronic kidney disease. Kidney Int. 2026;109(suppl 1S):S1-S99. Accessed August 29, 2026.
- Noumani I, Harrison CN, McMullin MF. Erythrocytosis: diagnosis and investigation. Int J Lab Hematol. 2024;46(suppl 1):55-62. doi:10.1111/ijlh.14298.
- Bender MA, Carlberg K. Sickle cell disease. In: Adam MP, Bick S, Mirzaa GM, et al, eds. GeneReviews. University of Washington, Seattle; 2003. Revised February 13, 2025. Accessed August 29, 2026.
- Agarwal AM, Rets AV. Advances in hemoglobinopathies and thalassemia evaluation. Clin Lab Med. 2024;44(3):441-453. doi:10.1016/j.cll.2024.04.006.
- Code of Federal Regulations. 42 CFR § 493.1253(b)(1)(ii), (b)(2)(vi). Accessed August 29, 2026.
- American Society for Clinical Pathology Board of Certification. Medical Laboratory Scientist, MLS(ASCP) and MLS(ASCPi) Examination Content Guideline. Revised June 9, 2026. pp 14-17. Accessed August 29, 2026.