What are the most common causes of hemolysis in individuals of African or Mediterranean descent?

Most Common Causes of Hemolysis in Individuals of African or Mediterranean Descent

In individuals of African or Mediterranean descent presenting with hemolysis, glucose-6-phosphate dehydrogenase (G6PD) deficiency and sickle cell disease (including sickle cell trait and other hemoglobinopathies) are the most common hereditary causes and should be screened first-line with G6PD enzyme activity testing and hemoglobin electrophoresis/HPLC. 1

Primary Hereditary Causes

G6PD Deficiency

• G6PD deficiency is the most common hereditary cause of hemolysis globally, with particularly high prevalence in African, Mediterranean, and Asiatic populations due to selective pressure from malaria. 2
• The disorder causes hemolysis triggered by oxidative stress from infections, certain medications (dapsone, methylene blue, primaquine, antimalarials, NSAIDs), or fava beans. 1, 3
• The Mediterranean variant (Gdmed) typically causes more severe, potentially life-threatening hemolysis, while the African variant (GdA-) causes milder, self-limited episodes. 4, 3
• Classic presentation includes acute hemolysis occurring 24-72 hours after oxidative trigger exposure, with pallor, dark red/brown urine (hemoglobinuria), and jaundice. 3
• Peripheral smear shows blister cells, bite cells, and Heinz bodies (with supravital staining). 1

Sickle Cell Disease and Hemoglobinopathies

• Sickle cell disease (HbSS) and sickle β-thalassemia cause chronic hemolysis and are highly prevalent in individuals of African descent, with the HbS mutation maintained at high frequency due to heterozygote protection against malaria. 2
• Hemoglobin SC disease also causes hemolysis, though typically milder than HbSS. 2
• Peripheral smear shows sickle-shaped cells and target cells. 1
• In patients with known sickle cell disease presenting with acute hemolysis beyond baseline, consider delayed hemolytic transfusion reaction (DHTR) with hyperhemolysis, especially if recently transfused. 1, 5

Alpha Thalassemia

• Alpha thalassemia is common in Southeast Asian populations and accounts for 28-55% of nonimmune hydrops fetalis in these regions, though it represents about 10% in most other series. 2
• The disorder causes chronic hemolysis with severe intrauterine hypoxia in homozygous alpha thalassemia (Bart's hemoglobin). 2
• Parents can be screened by mean cell volume <80 fL. 2

Pyruvate Kinase Deficiency

• Pyruvate kinase (PK) deficiency is the most common enzyme abnormality of the glycolytic pathway and causes hereditary nonspherocytic hemolytic anemia with variable severity. 2, 1
• The disorder has worldwide distribution but is less common than G6PD deficiency. 2
• Peripheral smear typically shows anisocytosis, poikilocytosis, and 3-30% echinocytes, especially post-splenectomy. 1

Diagnostic Algorithm for African or Mediterranean Descent Patients

First-Line Screening

• Perform G6PD enzyme activity testing and hemoglobin electrophoresis/HPLC as first-line screening in all patients of African or Mediterranean descent presenting with hemolysis. 1
• Confirm hemolysis with elevated reticulocyte count, elevated LDH, reduced/absent haptoglobin, elevated unconjugated bilirubin, and examine peripheral smear for diagnostic morphologic features. 1, 6

Second-Line Testing (if first-line negative)

• Proceed with direct antiglobulin test (DAT/Coombs) to identify autoimmune hemolytic anemia or drug-induced immune hemolysis. 1
• Measure pyruvate kinase enzyme activity using the ICSH standardized method. 1
• Consider targeted next-generation sequencing panels including globin genes (HBA1, HBA2, HBB), CYB5R3, PKLR, and membrane protein genes. 1

Special Considerations

• Avoid G6PD testing during acute hemolytic crisis, as levels can be falsely elevated; repeat testing after 3 months may be necessary for accurate diagnosis. 3
• In sickle cell disease patients with acute hemolysis beyond baseline, DHTR with hyperhemolysis can occur with negative DAT and no identifiable antibody. 1

Acquired Causes to Consider

Drug-Induced Hemolysis

• Antibiotics (cephalosporins, penicillins, piperacillin), antimalarials (primaquine, quinine/quinidine), and NSAIDs can cause drug-induced hemolytic anemia, particularly in G6PD-deficient patients. 1, 4
• Dapsone and methylene blue are absolutely contraindicated in G6PD deficiency and can cause severe hemolysis with methemoglobinemia. 4, 7, 8

Autoimmune Hemolytic Anemia

• Autoimmune hemolytic anemia can be secondary to malignancies, autoimmune disorders, drugs, and transfusion reactions. 6
• Diagnosed by positive direct antiglobulin test (DAT). 1

Infection-Related Hemolysis

• Viral and bacterial infections, including mycoplasma, malaria, and babesiosis, can trigger hemolysis. 1, 6
• Malaria remains a major cause of mortality in sub-Saharan Africa and can cause severe hemolysis. 2

Critical Pitfalls to Avoid

• Do not test G6PD levels during acute hemolysis, as reticulocytes and young RBCs have higher G6PD activity, leading to falsely normal results. 3
• In sickle cell disease patients with DHTR/hyperhemolysis, avoid additional transfusions if possible; if life-threatening, use extended matched red cells (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s). 1
• Screen for G6PD deficiency before starting oxidant drugs (dapsone, primaquine, methylene blue) in patients with predisposing racial or ethnic backgrounds. 4, 7
• Recognize that G6PD deficiency may not clinically impact patients with sickle cell disease due to relatively increased G6PD activity in young RBC populations, but testing remains important to avoid hemolysis-inducing medications. 9