What are the causes of hemolysis in patients with various medical histories, including autoimmune disorders and genetic conditions?

Causes of Hemolysis

Hemolysis results from either intrinsic red blood cell defects (hereditary causes) or extrinsic factors that damage normal red cells (acquired causes), with the most clinically important acquired causes being autoimmune destruction, drug-induced hemolysis, microangiopathic injury, and infections. 1

Acquired Causes of Hemolysis

Autoimmune Hemolytic Anemia

• Autoantibodies against red blood cell surface antigens cause premature destruction through the mononuclear-phagocytic system, presenting with positive direct antiglobulin test 1
• Can be secondary to malignancies, autoimmune disorders (such as systemic lupus erythematosus), drugs, and transfusion reactions 1
• In patients on immune checkpoint inhibitors, autoimmune hemolytic anemia is a recognized immune-related adverse event requiring specific diagnostic workup including autoimmune serology and direct agglutinin testing 2

Drug-Induced Hemolytic Anemia

Common culprit medications include:

• Antibiotics: Cephalosporins (especially cefotetan, ceftriaxone), penicillins, piperacillin (one of the three most common causes currently), ciprofloxacin 2, 3
• Antimalarials: Primaquine, quinine/quinidine 2
• Other medications: Ribavirin, rifampin, dapsone, interferon, NSAIDs (including diclofenac), fludarabine, lorazepam 2, 4, 3
• Methyldopa was historically one of the first drugs identified as causing autoimmune hemolytic anemia 4

Critical caveat: Piperacillin, cefotetan, and ceftriaxone can cause both in vitro and in vivo effects that mimic autoimmune hemolytic anemia, and the only treatment needed is drug discontinuation 3

Microangiopathic Hemolytic Anemia

• Occurs when red cell membranes are physically damaged in circulation, leading to intravascular hemolysis with characteristic schistocytes on peripheral smear 1
• Associated with hemolytic-uremic syndrome, which can be provoked by various drugs including immunomodulators 4

Infectious Causes

• Direct invasion of red blood cells by parasites such as malaria and babesiosis 1
• Viral and bacterial infections (including mycoplasma) can trigger hemolysis and should be evaluated in the diagnostic workup 2

Transfusion-Related Hemolysis

• Incompatible blood transfusion causes severe intravascular hemolysis through complement fixation 5
• Alloantibodies in patients with sickle cell disease can cause acute or delayed hemolytic transfusion reactions, sometimes with hyperhemolysis (hemoglobin dropping below pretransfusion levels) 2

Hereditary Causes of Hemolysis

Enzyme Deficiencies

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary cause, leading to hemolysis in the presence of oxidative stress from infections, fava beans, or specific medications 1, 6

  • The Mediterranean variant typically causes more severe, potentially life-threatening hemolysis compared to the African variant (GdA-), which causes milder, self-limited episodes 6, 7
  • Found in 10-15% of Black men and women (African variant) and predominantly in individuals from Mediterranean regions, India, and Southeast Asia (Mediterranean variant) 6, 8
  • Contraindicated medications include dapsone and methylene blue; primaquine is contraindicated in severe deficiency 6

• Pyruvate kinase (PK) deficiency causes chronic hemolysis with variable severity, from fully compensated hemolysis to severe neonatal anemia requiring transfusion 2

  • Characterized by increased 2,3-DPG levels causing rightward shift in oxygen dissociation curve, allowing better tolerance of anemia 2
  • Splenomegaly occurs in approximately 80% of patients 2

Red Cell Membrane Disorders

• Hereditary spherocytosis is characterized by spherocytes on peripheral smear, positive family history, and negative direct antiglobulin test (distinguishing it from autoimmune hemolytic anemia) 1
• Hereditary stomatocytosis is important to identify before splenectomy, as splenectomy is contraindicated due to thrombophilic risk 2

Hemoglobinopathies

• Sickle cell anemia and thalassemia cause chronic hemolysis as part of their disease pathophysiology 1

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• An acquired clonal disorder causing intravascular hemolysis due to complement-mediated red cell destruction 2
• Should be screened for in the diagnostic workup of unexplained hemolysis 2

Additional Extrinsic Causes

Physical Trauma

• Severe burns cause direct thermal injury to red blood cells leading to intravascular hemolysis 5
• Mechanical trauma from prosthetic heart valves or other cardiovascular devices 1

Envenomation

• Insect, spider, or snake bites can cause hemolysis and should be specifically queried in the history 2

Diagnostic Approach Priority

When evaluating hemolysis, the history must specifically address:

• New medication exposures (especially antibiotics, antimalarials, NSAIDs) 2
• Racial/ethnic background (Mediterranean, African, Indian, Southeast Asian descent) to assess G6PD deficiency risk 6, 7
• Recent infections (viral, bacterial including mycoplasma, parasitic) 2
• Envenomation history (insect, spider, snake bites) 2
• Family history of anemia or hemolysis (suggests hereditary causes) 1
• Autoimmune disorder history or malignancy 1

Laboratory evaluation should include: CBC with peripheral smear (looking for schistocytes, spherocytes, or parasites), reticulocyte count, LDH, haptoglobin, bilirubin (direct and indirect), direct antiglobulin test, G6PD level (if appropriate ethnic background), and DIC panel if severe 2, 1