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Inherited Hemolytic Anemias

Overview

Inherited hemolytic anemias constitute a diverse group of genetic disorders characterized by premature red blood cell destruction due to intrinsic erythrocyte defects. These conditions result from mutations affecting the red cell membrane, hemoglobin structure, or erythrocyte enzymes, leading to reduced RBC lifespan and consequent anemia. Understanding these disorders requires comprehensive knowledge of erythrocyte physiology, genetic inheritance patterns, and the pathophysiology of hemolysis. These conditions present unique diagnostic challenges and management complexities, ranging from mild compensated hemolysis to severe transfusion-dependent anemia.

Classification and Pathophysiology

Membrane Disorders

Red cell membrane defects account for the most common inherited hemolytic anemias in Northern European populations:

Hereditary Spherocytosis (HS): - Genetics: Autosomal dominant (75%) or recessive - Defects: Spectrin, ankyrin, band 3, or protein 4.2 - Pathophysiology: Loss of membrane surface area creates spherical RBCs - Consequence: Splenic destruction of rigid spherocytes

Hereditary Elliptocytosis (HE): - Genetics: Autosomal dominant - Defects: Alpha-spectrin, beta-spectrin, or protein 4.1 - Variants: Common HE, hereditary pyropoikilocytosis, spherocytic HE - Clinical: Usually mild, severe in homozygous states

Hereditary Stomatocytosis: - Types: Dehydrated (xerocytosis) and overhydrated variants - Defects: PIEZO1 or KCNN4 gene mutations - Feature: Abnormal cation permeability - Important: Splenectomy contraindicated due to thrombosis risk

Hemoglobinopathies

Structural hemoglobin defects represent the most common genetic disorders worldwide:

Sickle Cell Disease (SCD): - Mutation: Beta globin gene (Glu6Val) - Pathophysiology: HbS polymerization under deoxygenation - Complications: Vaso-occlusive crises, acute chest syndrome, 03 Spaces/Medical Hub/📘 Med terms dictionary/Glossary/Stroke - Variants: SS, SC, S-beta thalassemia

Thalassemia Syndromes: - Alpha-thalassemia: Deletion of alpha-globin genes - Silent carrier (1 gene) - Alpha-thalassemia trait (2 genes) - HbH disease (3 genes) - Hydrops fetalis (4 genes) - Beta-thalassemia: Reduced beta-globin synthesis - Minor (heterozygous) - Intermedia - Major (Cooley's anemia)

Unstable Hemoglobins: - Over 140 variants identified - Heinz body formation - Examples: Hb Köln, Hb Zurich - Drug or infection-induced hemolysis

Enzymopathies

Erythrocyte enzyme defects impair cellular metabolism:

G6PD Deficiency: - Most common: Affects 400 million worldwide - Inheritance: X-linked recessive - Pathophysiology: Impaired pentose phosphate pathway - Triggers: Oxidative stress, drugs, fava beans - Variants: Mediterranean (severe), African (mild)

Pyruvate Kinase Deficiency: - Second most common enzymopathy - Inheritance: Autosomal recessive - Effect: Impaired glycolysis, ATP depletion - Feature: Paradoxical reticulocytosis improvement post-splenectomy

Other Enzyme Defects: - Glucose phosphate isomerase deficiency - Phosphoglycerate kinase deficiency - Pyrimidine 5'-nucleotidase deficiency

Clinical Manifestations

Acute Hemolytic Episodes

Triggered hemolysis in susceptible individuals: - Acute intravascular hemolysis: Dark urine, back pain - Hemoglobinuria: Cola-colored urine - Jaundice: Unconjugated hyperbilirubinemia - Constitutional symptoms: Fever, fatigue, weakness

Chronic Hemolytic State

Ongoing red cell destruction manifests as: - Chronic anemia: Pallor, fatigue, exercise intolerance - Splenomegaly: From increased RBC destruction - Gallstones: Pigmented stones from chronic hemolysis - Leg Ulcers: Poor perfusion in severe cases - Aplastic crises: Parvovirus B19 infection

Disease-Specific Features

Sickle Cell Disease: - Pain crises: Bone, abdomen, chest - Organ damage: Kidney, spleen, liver - 04 Vault/Amboss Library/Clinical knowledge/Urology/Andrology/Priapism: Medical emergency - Retinopathy: Proliferative changes

Thalassemia Major: - Growth retardation - Bone deformities: Frontal bossing, maxillary hyperplasia - Hepatosplenomegaly - Iron overload: From transfusions

G6PD Deficiency: - Favism: Severe hemolysis from fava beans - 03 Spaces/Medical Hub/📝 Exam Prep/Medicine Notebook/Neonatal Jaundice: Risk of kernicterus - Drug-induced hemolysis: Antimalarials, sulfonamides

Diagnostic Approach

Initial Laboratory Evaluation

Essential tests for suspected hemolytic anemia: - Complete blood count: Anemia, reticulocytosis - Blood smear examination: RBC morphology crucial - Hemolytic markers: - Elevated indirect bilirubin - Increased LDH - Decreased haptoglobin - Elevated reticulocyte count

Specific Diagnostic Tests

Membrane Disorders: - Osmotic fragility test: Increased in spherocytosis - Eosin-5'-maleimide (EMA) binding: Flow cytometry for HS - SDS-PAGE: Protein analysis - Ektacytometry: Deformability assessment

Hemoglobinopathies: - Hemoglobin electrophoresis: Identifies variants - High-performance liquid chromatography (HPLC): Quantifies Hb types - Sickle solubility test: Screening for HbS - Molecular genetic testing: Definitive diagnosis

Enzymopathies: - G6PD enzyme assay: May be falsely normal during hemolysis - Pyruvate kinase activity: Specific assay - Enzyme panel: For rare defects - DNA analysis: Confirms mutations

Advanced Investigations

Management Strategies

General Supportive Care

Applicable to all inherited hemolytic anemias: - Folic acid supplementation: 1-5 mg daily - Iron chelation: For transfusion-dependent patients - Vaccination: Pneumococcal, meningococcal, Hib, hepatitis B - Genetic counseling: Family planning

Disease-Specific Management

Hereditary Spherocytosis: - Splenectomy: Curative for hemolysis - Indications: Severe anemia, gallstones, growth failure - Timing: Defer until age >6 years if possible - Partial splenectomy: Option in young children

Sickle Cell Disease: - Hydroxyurea: Increases HbF, reduces crises - Chronic transfusions: Stroke prevention - Pain management: Multimodal approach - Stem cell transplantation: Curative option - New therapies: Voxelotor, Crizanlizumab, Gene therapy

Thalassemia Major: - Regular transfusions: Maintain Hb >9-10 g/dL - Iron chelation: Deferasirox, deferoxamine - Endocrine monitoring: For complications - Bone marrow transplantation: Curative - Gene therapy trials: Emerging option

G6PD Deficiency: - Avoidance: Triggering drugs and foods - Acute management: Supportive care, transfusion if severe - Education: Patient awareness crucial - Neonatal screening: In endemic areas

Transfusion Management

Complications and Monitoring

Acute Complications

Chronic Complications

Iron Overload: - Organs affected: Liver, heart, endocrine glands - Monitoring: Ferritin, T2* MRI - Prevention: Adequate chelation

Organ Dysfunction: - Pulmonary Hypertension: Screen with echo - Renal disease: Monitor creatinine, proteinuria - Endocrinopathies: Growth, thyroid, glucose - 03 Spaces/Medical Hub/📝 Exam Prep/Medicine Notebook/Osteoporosis: DEXA scanning

Thrombotic Complications: - Increased in splenectomized patients - 04 Vault/Amboss Library/Clinical knowledge/Surgery/Vascular surgery/Pulmonary embolism risk - Consider anticoagulation prophylaxis

Reproductive Issues

Special Populations

Neonatal Period

Pediatric Considerations

Pregnancy Management

Emerging Therapies

Gene Therapy

Revolutionary approaches in development: - Lentiviral vectors: For beta-thalassemia and SCD - CRISPR-Cas9: Gene editing trials - Base editing: Precise corrections - Early results: Promising efficacy

Novel Pharmacologic Agents

Fetal Hemoglobin Induction

Prognosis and Outcomes

Factors Affecting Prognosis

  • Severity of mutation: Determines phenotype
  • Access to care: Critical for outcomes
  • Compliance: With chelation and monitoring
  • Complications: Early detection improves survival

Life Expectancy

  • Hereditary spherocytosis: Normal with treatment
  • Sickle cell disease: Improving, now 40-60 years
  • Thalassemia major: Near-normal with optimal care
  • G6PD deficiency: Normal with precautions

Quality of Life

  • Chronic disease burden: Psychological support needed
  • Educational achievement: May be impacted
  • Employment: Consider physical limitations
  • Family planning: Important considerations

Clinical Pearls

  • Osmotic fragility is increased 24 hours after incubation in spherocytosis
  • Bite cells and blister cells suggest G6PD deficiency
  • Post-splenectomy Howell-Jolly bodies confirm splenic absence
  • Basophilic stippling suggests lead poisoning or pyrimidine 5'-nucleotidase deficiency
  • Normal G6PD levels during hemolysis don't exclude deficiency - retest in 3 months
  • Hydrops fetalis from alpha-thalassemia is incompatible with life
  • Methemoglobinemia can occur with certain unstable hemoglobins
  • Consider PNH in patients with hemolysis and thrombosis
  • Heinz bodies require special staining (crystal violet) to visualize
  • Splenectomy in hereditary stomatocytosis increases thrombosis risk significantly

References