Hemolytic Anemias¶
Chapter 105 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 105
Key Clinical Points¶
- Reticulocyte count is the definitive parameter for hemolysis; both percentage (>2%) and absolute count (>150,000/μL) are typically increased.
- Hemolytic anemias (HAs) are classified as inherited or acquired, and intracorpuscular (membrane, enzyme, hemoglobin) or extracorpuscular (immune, mechanical, etc.).
- Hereditary spherocytosis (HS) prevalence is 1:2000–5000 in European ancestry; splenectomy is indicated for severe cases (Hb <8 g/dL) at age 4–6 years.
- G6PD deficiency is X-linked; heterozygous females show variable expression due to X-chromosome inactivation mosaicism.
- Pyruvate kinase (PK) deficiency is autosomal recessive; mitapivat (10 mg/kg/day) is an allosteric activator of PK.
- Chronic extravascular hemolysis leads to iron overload (secondary hemochromatosis) and organ damage (liver, heart).
- Osmotic fragility testing is the primary diagnostic for HS; EMA-binding test identifies ankyrin deficiency.
- Splenectomy is strictly contraindicated in stomatocytosis due to severe thromboembolic complications.
- Parvovirus B19 infection can cause aplastic crisis in patients with chronic hemolysis (e.g., PK deficiency).
- Compensated hemolysis may be asymptomatic; decompensation occurs during pregnancy, folate deficiency, or renal failure.
1. DEFINITION & OVERVIEW¶
Hemolytic anemias (HAs) are defined as anemias resulting from increased destruction of red cells.
• Core Features: ◦ Increased peripheral blood red cell consumption with normal or elevated marrow production. ◦ Differentiation from blood loss: Hemolysis occurs within the body; blood loss involves physical removal. ◦ Classification by etiology: Inherited/acquired; intracorpuscular/extracorpuscular. ◦ Clinical presentation varies by severity and hemolysis site (intravascular/extravascular).
Definition (Harrison's 22e): 'Hemolytic anemias (HAs) are anemias resulting from increased destruction of red cells.'
1.1 General Clinical and Laboratory Features¶
Clinical manifestations include:
• Jaundice, splenomegaly, gallstones, and hemoglobinuria (intravascular hemolysis). • Bone marrow overactivity may cause skeletal changes in severe congenital cases.
Laboratory features:
• Elevated unconjugated bilirubin, LDH, and reticulocytes (percentage >2% or absolute >150,000/μL). • Reduced haptoglobin in intravascular hemolysis. • Macrocytic blood smear with polychromasia and nucleated red cells. • Bone marrow aspirate typically shows erythroid hyperplasia unless otherwise indicated.
Table 105-1: Classification of Hemolytic Anemias | Classification | Intracorpuscular Defects | Extracorpuscular Factors | | --- | --- | --- | | Inherited | Hemoglobinopathies, Enzymopathies, Membrane-cytoskeletal defects | Paroxysmal nocturnal hemoglobinuria (PNH), Familial (atypical) hemolytic-uremic syndrome | | Mechanical destruction | | Drugs, Infectious | | Microangiopathic | | | | Autoimmune | | |
Table 105-2: Features Common to Most Patients with a Hemolytic Disorder | Feature | General Examination | Other Physical Findings | Hemoglobin Level | MCV, MCH | Reticulocytes | Bilirubin | LDH | Haptoglobin | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Jaundice, Pallor | Spleen may be enlarged | Bossing of skull in severe congenital cases | From normal to severely reduced | Usually increased | Almost always increased (mostly unconjugated) | Increased (up to 10× normal with intravascular hemolysis) | Reduced to absent if hemolysis is at least in part intravascular |
2. EPIDEMIOLOGY¶
Population-specific prevalence:
• Hereditary spherocytosis (HS): 1:2000–5000 in European ancestry. • Hereditary elliptocytosis (HE): 1:2000–4000 globally. • Pyruvate kinase (PK) deficiency: 1:10,000 in most populations. • G6PD deficiency: High prevalence in malaria-endemic regions (Africa, Mediterranean, Southeast Asia). • Southeast Asia ovalocytosis (SAO): Up to 5–7% in Papua New Guinea and neighboring regions.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Red cell components and hemolysis mechanisms:
• Red cell structure: Hemoglobin, membrane-cytoskeleton complex, and metabolic machinery. • Membrane-cytoskeleton abnormalities: Cause mechanical instability and reduced deformability (HS, HE, stomatocytosis). • Enzyme deficiencies: Disrupt ATP production or oxidative defense (PK, G6PD).
3.1 Inherited Membrane-Cytoskeleton Disorders¶
Genetic defects in membrane-cytoskeleton proteins:
• SPTA1/β-spectrin mutations: HS (dominant or recessive), HE (dominant). • ANK1/ankyrin mutations: HS (dominant; accounts for majority of cases). • SLC4A1/band 3 mutations: HS (dominant), Southeast Asia ovalocytosis (dominant; provides protection against malaria). • PIEZO1/KCNN4 mutations: Dehydrated hereditary stomatocytosis. • RHAG/ABCB6 mutations: Chronic nonspherocytic hemolysis, pseudohyperkalemia.
Table 105-3: Inherited Diseases of the Red Cell Membrane-Cytoskeleton Complex | Gene | Chromosomal Location | Protein Produced | Disease(s) with Certain Mutations (Inheritance) | Comments | | --- | --- | --- | --- | --- | | SPTA1 | 1q22-q23 | α-Spectrin | HS (recessive), HE (dominant) | Mutations account for ~65% of HE; severe forms may involve coexisting mutations. | | ANK1 | 8p11.2 | Ankyrin | HS (dominant) | May account for majority of HS cases. | | SLC4A1 | 17q21 | Band 3 (AE1) | HS (dominant), Southeast Asia ovalocytosis (dominant) | Polymorphic mutation provides malaria resistance in heterozygotes. | | PIEZO1 | 16q23-q24 | Mechanosensitive ion channel | Dehydrated hereditary stomatocytosis (dominant) | Associated with perinatal edema and pseudohyperkalemia. | | KCNN4 | 19q13.31 | KCNN4 (Gardos channel) | Dehydrated hereditary stomatocytosis (dominant) | Clinical presentation similar to that of PIEZO1 mutants. | | ABCB6 | 2q35-q36 | ABCB6 | Familial pseudohyperkalemia (dominant) | | | RHAG | 6p21.1-p11 | Rhesus-associated glycoprotein | Chronic nonspherocytic hemolysis (recessive) | Associated with total loss of all Rh antigens; specific mutations cause overhydrated stomatocytosis. |
3.2 Enzyme Abnormalities¶
Key enzyme defects in red cell metabolism:
• Pyruvate kinase (PK) deficiency: Autosomal recessive, 1:10,000 prevalence. • G6PD deficiency: X-linked; triggers hemolysis via oxidative stress (favism, infections). • Other rare enzymes: Hexokinase (HK), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPD).
Table 105-4: Red Cell Enzyme Abnormalities Causing Hemolysis | Enzyme (Acronym) | Gene Symbol; Chromosomal Location | Prevalence | Clinical Manifestations | Extra-Red Cell | Comments | | --- | --- | --- | --- | --- | | Hexokinase (HK) | HK1; 10q22 | Very rare | | May benefit from splenectomy; BMTc | | G6PI | GPI; 19q31.1 | Rare | NM, CNS | May benefit from splenectomy | | PFK | PFKM; 12q13 | Very rare | Myopathy; myoglobinuria | | | Aldolase | ALDOA; 16q22-24 | Very rare | Myopathy | | | TPI | TPI1; 12p13.31 | Very rare | CNS (severe), NM | | | GAPD | GAPDH; 12p13.31 | Very rare | Myopathy | | | BPGM | BPGM; 7q33 | Very rare | Erythrocytosis rather than hemolysis | | | PGK | PGK1; Xq21.1 | Very rare | CNS, NM | May benefit from splenectomy; BMTc | | PK | PKLR; 1q22 | Rare (2) | | May benefit from splenectomy; BMTc | | G6PD | G6PD; Xq28 | Common (1) | | In almost all cases, only AHA from exogenous trigger | | GSS | 20q11.22 | Very rare | CNS | | | GSR | 8p12 | Very rare | Cataracts | | | GCLC | 6p12.1 | Very rare | CNS | | | CYB5R3 | 22q13.2 | Rare | CNS | | | AK | AK1; 9q34.11 | Very rare | CNS | May benefit from splenectomy | | P5N | NTSC3A; 7p14.3 | Rare (3) | | May benefit from splenectomy |
4. CLINICAL FEATURES¶
Clinical manifestations vary by hemolysis type:
• Compensated hemolysis: Asymptomatic with normal hemoglobin and elevated reticulocytes. • Decompensated hemolysis: Anemia, jaundice, splenomegaly, gallstones, and complications (iron overload, aplastic crisis).
Differential diagnosis considerations:
• Acute vs. chronic presentation. • Intravascular vs. extravascular hemolysis (hemoglobinuria vs. unconjugated bilirubin).
4.1 Compensated Hemolysis versus Hemolytic Anemia¶
Compensated state:
• Normal hemoglobin with elevated reticulocytes (count >2% or absolute >150,000/μL). • No symptoms but may show mild anemia in decompensation triggers (pregnancy, folate deficiency, renal failure).
5. DIFFERENTIAL DIAGNOSIS¶
Key differentials include:
• AIHA vs. HS: Distinguish autoimmune hemolytic anemia from hereditary spherocytosis. • G6PD vs. other enzyme defects. • PNH vs. cold agglutinin disease. • MAHA vs. mechanical destruction.
Table 105-8: Classification of Acquired Immune Hemolytic Anemias | Clinical Setting | Type of Antibody | | --- | --- | | | Cold (mostly IgM, 4°C–30°C) | Primary: CAD; Secondary to infection (Mycoplasma → PCH); Secondary to drugs (drug-dependent or independent) | | Warm (mostly IgG, 37°C) | Primary: AIHA (idiopathic); Secondary to infection (Babesia); Secondary to drugs (e.g., cefotetan, ceftriaxone, piperacillin, methyldopa, fludarabine) |
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic approach:
- Initial screening: CBC, reticulocyte count, bilirubin, LDH, haptoglobin.
- Site determination: Hemoglobinuria (intravascular) vs. unconjugated bilirubin (extravascular).
- Direct testing: Osmotic fragility (HS), EMA-binding test (membrane defects), G6PD activity assay.
- Advanced testing: Flow cytometry for PNH, molecular genetic analysis for inherited disorders.
- Imaging: Ultrasound for splenomegaly, liver iron quantification in chronic hemolysis.
6.1 Diagnostic Algorithms¶
Step-by-step diagnostic pathway:
• Step 1: Confirm hemolysis via reticulocyte count (>2% or >150,000/μL) and LDH/haptoglobin ratio. • Step 2: Differentiate intravascular/extravascular hemolysis (hemoglobinuria vs. unconjugated bilirubin). • Step 3: Screen for inherited causes (osmotic fragility, EMA test, G6PD assay). • Step 4: Confirm genetic mutations in suspected cases via molecular analysis.
7. MANAGEMENT & TREATMENT¶
Treatment strategies:
• Hereditary spherocytosis: Splenectomy for severe cases (Hb <8 g/dL or symptomatic); folic acid supplementation. • Pyruvate kinase deficiency: Mitapivat (10 mg/kg/day), blood transfusions in severe cases (Hb <6 g/dL), folic acid (5 mg/day). • G6PD deficiency: Avoid oxidant triggers (fava beans, specific drugs like primaquine or dapsone). • Iron overload management: Phlebotomy or chelation therapy for secondary hemochromatosis. • Aplastic crisis: Blood transfusion for parvovirus B19-induced crises.
7.1 Treatment of Hereditary Spherocytosis¶
Management guidelines:
• Splenectomy: Indicated for hemoglobin <8 g/dL or symptomatic cases. • Post-splenectomy: Pneumococcal vaccination, lifelong penicillin prophylaxis. • Alternative therapies: hydroxyurea in refractory cases.
7.2 Treatment of Pyruvate Kinase Deficiency¶
Therapeutic options:
• Mitapivat: 10 mg/kg/day (allosteric PK activator). • Blood transfusions: For severe anemia (Hb <6 g/dL). • Folic acid supplementation: 5 mg/day to support erythropoiesis.
7.3 Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)¶
Management pathways based on complement inhibition:
• C5 Blockade (e.g., Eculizumab): ◦ Mechanism: Prevents MAC formation. ◦ Outcome: Reduces intravascular hemolysis; however, some extravascular hemolysis may persist if blockade is incomplete. • C3 Blockade (e.g., Pegcetacoplan): ◦ Mechanism: Prevents C3 cleavage into C3b. ◦ Outcome: Prevents both MAC formation and opsonization by C3b; provides more robust protection against hemolysis.
8. PROGNOSIS & COMPLICATIONS¶
Long-term outcomes:
• Inherited HAs: Variable prognosis based on severity and treatment response. • Complications: ◦ Iron overload (liver cirrhosis, heart failure) from chronic extravascular hemolysis. ◦ Thromboembolism: High risk in stomatocytosis; splenectomy is contraindicated. ◦ Aplastic crisis: Triggered by Parvovirus B19 in patients with chronic hemolysis (e.g., PK deficiency). • Mortality: Rare with modern management but significant in untreated severe cases.
9. SPECIAL CONSIDERATIONS¶
Key considerations:
• Pregnancy: Increased hemolysis risk due to folate deficiency and placental demands. • Infections: Parvovirus B19, malaria, and viral hepatitis as triggers. • Drug interactions: Antimalarials (e.g., primaquine) in G6PD deficiency.
9.1 Pregnancy and Infection¶
Pregnancy-specific management:
• Monitor for decompensation (Hb <8 g/dL, reticulocyte count >5%). • Folic acid supplementation (4 mg/day) to prevent megaloblastic changes. • Avoid splenectomy in early pregnancy due to thromboembolism risk.
10. KEY PEARLS & CLINICAL TRAPS¶
Critical pearls:
• Reticulocyte Count: Retic >2% or absolute >150,000/μL confirms hemolysis. • Osmotic Fragility: Diagnostic for HS but not specific for other membrane defects. • G6PD Safety: Must be ruled out before using oxidant drugs (e.g., primaquine, sulfonamides). • Stomatocytosis Warning: Splenectomy is strictly contraindicated due to high thromboembolic risk. • Intravascular Markers: Hemoglobinuria and low haptoglobin indicate intravascular hemolysis.
Reference Tables¶
TABLE 105-2 Features Common to Most Patients with a Hemolytic Disorder¶
Harrison's 22e, p.791
| 105 | Hemolytic Anemias Lucio Luzzatto, Lucia De Franceschi |
|---|---|
TABLE 105-2 Features Common to Most Patients with a Hemolytic Disorder
| GENERAL EXAMINATION | JAUNDICE, PALLOR |
|---|---|
| Other physical findings | Spleen may be enlarged; bossing of skull in severe congenital cases |
| MCV, MCH | Usually increased |
| Bilirubin | Almost always increased (mostly unconjugated) |
| Haptoglobin | Reduced to absent if hemolysis is at least in part intravascular |
TABLE 105-1 Classification of Hemolytic Anemias a Inherited¶
Harrison's 22e, p.791
| INTRACORPUSCULAR DEFECTS | EXTRACORPUSCULAR FACTORS |
|
|---|---|---|
| Inherited | Hemoglobinopathies Enzymopathies Membrane-cytoskeletal defects |
Familial (atypical) hemolytic- uremic syndrome |
| Paroxysmal nocturnal hemoglobinuria (PNH) |
TABLE 105-3 Inherited Diseases of the Red Cell Membrane-Cytoskeleton Complex¶
Harrison's 22e, p.794
| GENE | CHROMOSOMAL LOCATION |
PROTEIN PRODUCED | DISEASE(S) WITH CERTAIN MUTATIONS (INHERITANCE) |
COMMENTS |
|---|---|---|---|---|
| SPTA1 | 1q22-q23 | α-Spectrin | HS (recessive) | Rare |
| HE (dominant) | Mutations of this gene account for about 65% of HE. More severe forms may be due to coexistence of an otherwise silent mutant allele. |
|||
| 14q23-q24.1 | β-Spectrin | HS (dominant) HE (dominant) |
||
| ANK1 | 8p11.2 | Ankyrin | HS (dominant) | May account for majority of HS. |
| 17q21 | Band 3; also known as AE (anion exchanger) or AE1 |
HS (dominant) Southeast Asia ovalocytosis (dominant) Stomatocytosis (cryohydrocytosis) |
||
| EPB41 | 1p33-p34.2 | Band 4.1 | HE (dominant) | Mutations of this gene account for about 5% of HE, mostly with prominent morphology but little/no hemolysis in heterozygotes; severe hemolysis in homozygotes. |
| 15q15-q21 | Band 4.2 | HS (recessive) | ||
| RHAG | 6p21.1-p11 | Rhesus-associated glycoprotein | Chronic nonspherocytic hemolytic anemia (recessive) |
Very rare; associated with total loss of all Rh antigens. One specific mutation in this gene entails loss of stomatin from the cell membrane, causing overhydrated stomatocytosis. |
| 16q23-q24 | PIEZO1 (mechanosensitive ion channel component 1 channel) |
Dehydrated hereditary stomatocytosis (dominant) |
||
| KCNN4 | 19q13.31 | KCNN4 Intermediate conductance calcium-activated potassium channel protein 4 (Gardos channel) |
Dehydrated hereditary stomatocytosis (dominant) |
Clinical presentation similar to that of PIEZO1 mutants. |
| 2q35-q36 | ATP-binding cassette subfamily B member 6 |
Familial pseudohyperkalemia (dominant) |
||
| SLC2A1 | 1p34.2 | GLUT1 glucose transporter | Overhydrated hereditary stomatocytosis |
Associated with serious neurologic manifestations. |
| ANK1 | ||||
| EPB42 | ||||
| SPTB | SPTA1 | |||
| SLC2A1 | ||||
| RHAG | ||||
| PIEZ01 | ||||
| KCNN4 | ||||
| ABCB6 |
TABLE 105-4 Red Cell Enzyme Abnormalities Causing Hemolysis¶
Harrison's 22e, p.796
| ENZYME (ACRONYM) | GENE SYMBOL; CHROMOSOMAL LOCATION |
PREVALENCE OF ENZYME DEFICIENCY (RANK) |
CLINICAL MANIFESTATIONS EXTRA-RED CELL |
COMMENTS |
|---|---|---|---|---|
| Glycolytic Pathway | ||||
| Hexokinase (HK) | HK1; 10q22 | Very rare | May benefit from splenectomy; BMTc | |
| Glucose-6-phosphate isomerase (G6PI) | GPI; 19q31.1 | Rare (4); at least 60 cases reporteda |
NM, CNS | May benefit from splenectomy |
| Phosphofructokinase (PFK)b | PFKM; 12q13 | Very rare | Myopathy; myoglobinuria |
|
| Aldolase | ALDOA; 16q22-24 | Very rare | Myopathy | |
| Triose phosphate isomerase (TPI) | TPI1; 12p13.31 | Very rare | CNS (severe), NM | |
| Glyceraldehyde 3-phosphate dehydrogenase (GAPD) |
GAPDH; 12p13.31 | Very rare | Myopathy | |
| Bisphosphoglycerate mutase (BPGM) | BPGM; 7q33 | Very rare | Erythrocytosis rather than hemolysis; some of the rare mutations are in the enzyme active site |
|
| Phosphoglycerate kinase (PGK) | PGK1; Xq21.1 | Very rare | CNS, NM | May benefit from splenectomy; BMTc |
| Pyruvate kinase (PK) | PKLR; 1q22 | Rare (2)a | May benefit from splenectomy; BMTc | |
| Redox | ||||
| G6PD; Xq28 GSS; 20q11.22 GSR; 8p12 GCLC; 6p12.1 CYB5R3; 22q13.2 |
Common (1)a Very rare Very rare Very rare Rare |
Very rarely granulocytes CNS Cataracts CNS CNS |
||
| Nucleotide Metabolism | ||||
| Adenylate kinase (AK) | AK1; 9q34.11 | Very rare | CNS | May benefit from splenectomy |
| Pyrimidine 5’ nucleotidase (P5N) | NTSC3A; 7p14.3 | Rare (3)a | May benefit from splenectomy |
TABLE 105-5 Current World Health Organization Classification of Glucose 6-Phosphate Dehydrogenase (G6PD) Variants¶
Harrison's 22e, p.798
| G6PD VARIANT CLASS |
MEDIAN OF G6PD ACTIVITY (% OF NORMAL) |
ASSOCIATED CLINICAL MANIFESTATIONS |
|---|---|---|
| Aa | <20%b | Chronic hemolytic anemia |
| <45% | ||
| Ca | >60% | None reported |
| Any |
TABLE 105-6 Drugs That Carry Risk of Clinical Hemolysis in Persons with Glucose 6-Phosphate Dehydrogenase Deficiency¶
Harrison's 22e, p.799
| DRUG CLASS | ||
|---|---|---|
| HIGH | MEDIUM TO LOW | |
| Antimalarials | Primaquine Tafenoquine |
Chloroquine Hydroxychloroquine Quinine |
| Dapsone | Sulfadimidine Sulfamethoxazole Sulfasalazine |
|
| Antibacterial/ antibiotics |
Chloramphenicol Ciprofloxacin Cotrimoxazole Nalidixic acid Nitrofurantoin Norfloxacin p-Aminosalicylic acid |
|
| Niridazole | ||
| Antipyretic/ analgesics |
Acetylsalicylic acid high dose (>3 g/d) |
Acetaminophen Acetanilide Phenacetin Phenazopyridine |
| Rasburicase Pegloticase Methylene blue Toluidine blue |
Ascorbic acid (>1 g) Doxorubicin Probenecid Vitamin K analogues |
TABLE 105-7 Diseases and Clinical Situations in Which Hemolysis Is Largely Intravascular Mismatched blood transfusion…¶
Harrison's 22e, p.801
| ONSET/TIME COURSE | MAIN MECHANISM | APPROPRIATE DIAGNOSTIC PROCEDURE |
COMMENTS | |
|---|---|---|---|---|
| Mismatched blood transfusion |
Abrupt | Nearly always ABO incompatibility |
Repeat cross-match | |
| Chronic with acute exacerbations |
Complement (C)-mediated destruction of CD59(−) red cells |
Flow cytometry to display a CD59(−) red cell population |
||
| Paroxysmal cold hemoglobinuria (PCH) |
Acute | Immune lysis of normal red cells |
Test for Donath-Landsteiner antibody |
Often triggered by viral infection |
| Very acute | Exotoxins produced by Clostridium perfringens |
Blood cultures | ||
| Microangiopathic | Acute or chronic | Red cell fragmentation | Red cell morphology on blood smear |
Different causes ranging from endothelial damage to hemangioma to leaky prosthetic heart valve |
| Abrupt | Mechanical destruction | Targeted history taking | ||
| Favism | Acute | Destruction of older fraction of G6PD-deficient red cells |
G6PD assay | Triggered by ingestion of large dish of fava beansa |
TABLE 105-8 Classification of Acquired Immune Hemolytic Anemias¶
Harrison's 22e, p.802
| CLINICAL SETTING | TYPE OF ANTIBODY | |
|---|---|---|
| COLD, MOSTLY IgM, OPTIMAL TEMPERATURE 4°C–30°C |
WARM, MOSTLY IgG, OPTIMAL TEMPERATURE 37°C; OR MIXED |
|
| Primary | CAD | AIHA (idiopathic) |
| EBV CMV Other |
||
| Secondary to other infection |
Mycoplasma infection: paroxysmal cold hemoglobinuria |
Babesia |
| CAD in: Waldenström’s disease Lymphoma |
||
| Secondary to drugs: drug- induced immune hemolytic anemia |
Small minority (e.g., with lenalidomide) |
Majority: currently most common culprit drugs are cefotetan, ceftriaxone, piperacillin, methyldopa, fludarabine |
| Drug-dependent: antibody destroys red cells only when drug present (e.g., rarely penicillin) |
||
| Drug-independent: antibody can destroy red cells even when drug no longer present (e.g., methyldopa) |