• ABO and Rh incompatibility between infant and mother
• Cardiac lesions with turbulent flow, left-sided more common than right-sided
• Prosthetic heart valve (especially aortic)
• Kasabach-Merritt syndrome
• Hypersplenism

• Congenital infections with syphilis, rubella, cytomegalovirus (CMV), and toxoplasmosis
• Malaria
• Bartonellosis
• Clostridium perfringens (via a toxin)
• Mycoplasma pneumoniae
• HIV
• Hemolytic uremic syndrome (HUS)

• Immune-complex “innocent bystander” mechanism
  • Quinidine
  • Acetaminophen
  • Amoxicillin
  • Cephalosporins
  • Isoniazid
  • Rifampin

• Immune-complex drug-adsorption mechanism
  • Penicillin
  • Cephalosporins
  • Erythromycin
  • Tetracycline
  • Isoniazid

• Drug-induced autoimmune hemolytic anemia
  • a-methyldopa

• Toxic drug-induced hemolysis
  • Ribovirin (generally mild and not clinically significant)

• Snake and spider venoms
• Extensive burns

• Cardiac hemolysis
• Abnormal microcirculation
  • Thrombotic thrombocytopenic purpura (TTP)
  • Disseminated intravascular coagulopathy (DIC)
  • Malignant hypertension
  • Eclampsia
  • Hemangiomas
  • Renal graft rejection

• “March” hemoglobinuria (due to prolonged physical activity)

• Lymphomas
• Thymoma
• Lymphoproliferative disorders

• RBC membrane defects
  • Hereditary spherocytosis (HS)
  • Hereditary elliptocytosis (HE)
  • Pyropoikilocytosis
  • Paroxysmal nocturnal hemoglobinuria

• Enzyme defects
  • Pyruvate kinase deficiency (PK)
  • Glucose-6-phosphate dehydrogenase deficiency (G6PD)

• Thalassemias (b-thalassemia major is the most severe)
• Hemoglobinopathies
  • Sickle cell anemia (Hgb SS and SC variants)
  • Unstable hemoglobins

• Autoimmune Hemolytic Anemia (AIHA)
  • Warm antibody mediated
  • Cold antibody mediated
  • Hemolytic transfusion reaction

Question: Is the patient pale, fatigued, or jaundiced? Is there a history of tea colored urine?
Significance: The presence of hemoglobinuria is a sign of intravascular hemolysis, while pallor, fatigue, and jaundice may occur with either intravascular or extravascular hemolysis.

Question: Is there a history of anemia, splenectomy, or early cholrecystectomy in multiple family members?
Significance: While hereditary membrane defects and enzyme deficiencies are autosomal dominant and X-linked disorders, respectively, a negative familial history does not always rule out these diagnoses. In some cases, the diagnosis of HS has not been identified, yet multiple members of a family have had their gallbladders removed at an early age, which may indicate the presence of this defect. Thalassemia (especially b-thal) and sickle cell anemia may present in early childhood with chronic hemolysis with or without a familial history.

Question: Is there a history of travel?
Significance: Malaria is endemic to Africa, India, and parts of Central America.

Question: What drugs is the patient taking? What is the diet history? Specifically ask about exposure to fava beans, mothballs, and antibiotics.
Significance: Drugs can themselves cause hemolysis or can induce hemolysis if there is an underlying disorder such as G-6-PD deficiency.

Question: How old was the child at the first signs and symptoms of hemolysis (pallor or jaundice)?
Significance: Hereditary causes of hemolysis are most often chronic or recurrent, although the diagnosis may be delayed until the child is older if the process is mild. Acute, acquired hemolytic disorders may also recur (such as AIHA, Evan syndrome, lupus, etc.).

Question: What is the general appearance of the child? Is there any vital sign instability?
Significance: Acute processes such as autoimmune hemolytic anemia (both warm and cold antibody mediated) may present with a child in extremis. Tachycardia is a common finding in nearly all cases of acute hemolysis. Blood pressure instability is a late finding. More chronic processes such as HU, G-6-PD and PK deficiencies, thalassemia or sickle cell disease may be picked up on routine physical or laboratory examination. These children often appear well (except for jaundice) but may become more anemic with an acute illness.

Question: Is there an underlying systemic illness?
Significance: Hemolysis that is a secondary problem (i.e., due to infection, tumors, etc.) may be found incidentally during evaluation of the primary process.

Question: Is there any hepatosplenomegaly or lymphadenopathy?
Significance: Splenomegaly, often impressive, as well as hepatomegaly are common findings in extravascular hemolysis. Hepatomegaly may be more pronounced if the child is in heart failure due to acute, severe anemia. Remember that splenomegaly may be either the cause of, or more frequently, a result of a hemolytic process. If significant lymphadenopathy is present, look for any underlying etiology like lymphoproliferative disorders or other tumors.

Question: What is the skin exam?
Significance: Pallor is nearly a universal finding in acute hemolysis and in exacerbations of chronic hemolysis. Jaundice is more common in intravascular hemolysis. The presence of ecchymoses or petechiae suggest DIC or thrombocytopenia.

Test: CBC with differential and reticulocyte count
Significance: The level of anemia and the reticulocyte count must be interpreted together. Chronic hemolysis due to HS, for example, may have a nearly normal hemoglobin but usually has an increased reticulocyte count. With a rapid fall in Hgb, as in acute autoimmune hemolytic anemia, the reticulocyte count may be low at the start, rise in response to anemia, and fall during recovery. Thrombocytopenia should raise suspicions about TTP or HUS.

Test: Peripheral blood smear
Significance: Fragmented RBCs, schistocytes, and helmet cells are seen in DIC, TTP, HUS, and cardiac valve hemolysis. Other findings on the smear that may be helpful in the diagnosis are spherocytes (HS and warm AIHA), target cells (hemoglobin C and thalassemias), and acanthocytes (anorexia nervosa).

Test: Bilirubin
Significance: Total and unconjugated bilirubins are elevated in most cases.

Test: Urinalysis
Significance: Hemoglobinuria is present in intravascular hemolysis. This is established by a urine dipstick positive for heme with no intact red cells microscopically. Myoglobinuria can also give this picture.

Test: Coombs test
Significance: Direct Coombs test (direct antiglobulin test or DAT) detects antibodies or complement fragments present on the patient’s RBCs, while the indirect antiglobulin test detects antibodies in the patient’s serum that can bind normal RBCs. The DAT provides direct evidence of immune mediated hemolysis. Warm antibody AIHA is caused by an IgG antibody that coats RBCs, which are subsequently removed by the spleen. Cold antibody AIHA is caused by an IgM antibody that binds RBCs, fixes complement, and can cause both extravascular as well as intravascular hemolysis.

Test: Haptoglobin, hemopexin, and LDH
Significance: In intravascular hemolysis, haptoglobin levels may be undetectable, hemopexin is reduced and LDH is significantly increased. In extravascular hemolysis, haptoglobin is decreased (but detectable) and LDH may be increased, but not to the level seen in intravascular hemolysis.

Test: Bone marrow aspiration
Significance: Rarely indicated, but if performed, erythroid hyperplasia should be present.

• Hemoglobin under 5 g/dL, especially with signs of cardiovascular compromise, requires immediate attention. Attempts to stabilize cardiovascular compromise with volume should be undertaken with care, as hemodilution may occur. Transfusion may be difficult in autoimmune hemolysis because of potential problems with crossmatching.
• Renal failure may accompany severe hemolysis in TTP or HUS.
• Hemolysis in the neonatal period secondary to ABO or Rh incompatibility may require exchange transfusion either for anemia or for hyperbilirubinemia.

Q: When are blood transfusions indicated in patients with active hemolysis?
A: Patients with severe, acute hemolysis that is causing cardiovascular compromise may require a transfusion if the process cannot be stopped with standard therapy (steroids for warm AIHA, plasmapheresis for TTP, etc.). Transfusions must be given slowly if the hemolytic process has been chronic and the patient’s blood volume is expanded.

Q: Can hemolysis always be identified on a peripheral blood smear?
A: No. Schistocytes, fragments, spherocytes, targets, or other morphology may provide clues to specific diagnoses but are not always present. The presence of a hemolytic process is inferred from a fall in hemoglobin, rise in the reticulocyte count and elevation of the bilirubin and LDH levels.

• Most patients with severe, acute hemolysis, either primary or due to an underlying chronic hemolytic disorder, will need to be evaluated by a hematologist.
• Suspected RBC membrane and enzyme defects, as well as hemoglobinopathies, should be referred at least for initial evaluation. Ongoing involvement of a hematologist will depend on the ultimate diagnosis.
• A CBC with a reticulocyte count is the most important screening test. Other tests depend on clinical suspicion of the underlying etiology but may include a direct and indirect Coomb test.

• Hereditary RBC membrane defects may be mild and may be diagnosed at an older age. Although these disorders are autosomal dominant, 20% of these patients represent new spontaneous mutations and have no affected family members.
• Blood for diagnostic RBC enzyme studies must be drawn prior to transfusion.

Berkowitz FE. Hemolysis and infection: categories and mechanisms of their interrelationship. Rev Infect Dis 1991;13(6):1151–1162.

Tabbara IA. Hemolytic anemias. Diagnosis and management. Med Clin North Am 1992;76(3):649–668.