What diagnoses can cause hemolytic anemia?

Causes of Hemolytic Anemia

Hemolytic anemia results from either hereditary disorders affecting red blood cell structure/function or acquired conditions including immune-mediated destruction, infections, and mechanical trauma.

Hereditary Causes

Red Blood Cell Enzyme Deficiencies

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect causing hemolysis, particularly triggered by oxidative stress from infections or certain medications 1, 2
• Pyruvate kinase deficiency is the most frequent glycolytic pathway enzyme abnormality and the most common cause of hereditary nonspherocytic hemolytic anemia, resulting from ATP depletion in red blood cells 3
• Other enzymopathies include pyruvate kinase deficiency and various glycolytic enzyme defects 4, 2

Red Blood Cell Membrane Disorders (Membranopathies)

• Hereditary spherocytosis is characterized by spherocytes on peripheral smear, positive family history, and negative direct antiglobulin test 2
• Dehydrated hereditary stomatocytosis (DHSt) has emerged as the second most frequent type of congenital hemolytic anemia since genetic diagnosis became available 5
• These disorders cause poor red cell deformability leading to splenic sequestration and destruction 6

Hemoglobinopathies

• Sickle cell anemia and thalassemias (particularly alpha-thalassemia in Southeast Asian populations) cause chronic hemolysis 2
• Alpha-thalassemia in its severe form typically leads to hydrops fetalis and fetal demise 4

Acquired Causes

Immune-Mediated Hemolytic Anemia (DAT-Positive)

• Warm autoimmune hemolytic anemia (wAIHA) is caused by IgG autoantibodies, with DAT positive for IgG, C3d, or both 7
• Cold agglutinin disease (CAD) results from monoclonal IgM antibodies specific to the Ii blood group system, with DAT positive only for C3d 7
• Alloimmune hemolysis from blood group incompatibility, including Rh (D, c, C, e, E), anti-Kell (K, k), anti-Duffy (Fya), and anti-Kidd (Jka, Jkb) antibodies 4
• Drug-induced immune hemolytic anemia (DIIHA) appears similar to wAIHA with DAT showing IgG and/or C3d 7
• Mixed AIHA has DAT positive for both IgG and C3d 7
• Paroxysmal cold hemoglobinuria (PCH) is driven by biphasic cold-reactive IgG antibody recruiting complement, with DAT positive only for C3d 7

Infectious Causes

• Parvovirus B19 is the most commonly reported infectious cause of fetal anemia, targeting erythroid progenitor cells and causing aplastic crisis 4
• Malaria and babesiosis directly invade and destroy red blood cells 2
• Other infections including toxoplasmosis, cytomegalovirus (CMV), coxsackie virus, and syphilis have been associated with hemolytic anemia in rare cases 4

Microangiopathic Hemolytic Anemia

• Thrombotic microangiopathy (TMA) occurs when red cell membranes are damaged by microthrombi in circulation, leading to intravascular hemolysis and schistocyte formation 1, 6
• Atypical hemolytic uremic syndrome (aHUS) involves complement-mediated thrombotic microangiopathy requiring urgent ADAMTS13 activity testing 1

Mechanical and Traumatic Causes

• Direct mechanical trauma from prosthetic heart valves or other cardiovascular devices 6
• Fetomaternal hemorrhage occurring as acute or chronic events 4
• Twin anemia-polycythemia sequence in monochorionic twin pregnancies, occurring spontaneously in 3-5% or after laser therapy for twin-twin transfusion syndrome in 13% of cases 4

Other Acquired Causes

• Oxidative stress from medications or toxins, particularly in patients with underlying enzyme deficiencies 6
• Hypersplenism causing sequestration and premature destruction of red blood cells 8
• Systemic diseases including malignancies and autoimmune disorders 2, 7

Diagnostic Approach

Initial Laboratory Evaluation

• Confirm hemolysis with elevated reticulocyte count, increased LDH, decreased haptoglobin, and elevated unconjugated bilirubin 8, 1, 2
• Peripheral blood smear to identify morphologic abnormalities: spherocytes suggest hereditary spherocytosis, schistocytes indicate microangiopathy, and relatively normal morphology with anisocytosis/poikilocytosis suggests enzyme deficiency 8

Distinguishing Immune from Non-Immune Causes

• Direct antiglobulin test (DAT) differentiates immune-mediated (DAT-positive) from non-immune causes (DAT-negative) 6, 7
• For DAT-negative cases with suspected hereditary disorders, proceed with red cell enzyme assays (particularly G6PD and pyruvate kinase) and consider comprehensive gene panel analysis of 68 hemolytic anemia-related genes 8, 5

Important Caveats

• Reticulocyte count may be falsely low in hereditary hemolytic anemias before splenectomy because younger defective cells are preferentially sequestered in the spleen 8
• Blood testing for enzyme activity should be delayed at least 50 days after transfusion to minimize interference from donor red cells 3
• Haptoglobin is the most sensitive indicator of hemolysis, becoming reduced early in the hemolytic process 8