Acute hemolytic anemia

• When the onset of anemia is abrupt, children may present acutely with
  • pallor
  • fatigue
  • exercise intolerance.
• Jaundice and dark urine are often seen, and occasionally hemoglobinuria is present due to the rapidity of red blood cell (RBC) destruction.
• Physical examination findings often include:
  •  tachycardia with a flow murmur, with or without a gallop
  • splenomegaly with or without hepatomegaly.
• With fulminant hemolysis, decreased oxygen-carrying capacity and severe anemia may be life-threatening, and the child may appear acutely ill or even moribund, with tachycardia, tachypnea, signs of hypoxemia, and even cardiovascular collapse.

Classification is based on:

• Site of hemolysis
  • intravascular: red cell fragmentation syndromes, PNH, immediate transfusion reactions. Look for schistocytes and urine hemoglobin/hemosiderin/heme+ (sensitive).
  • extravascular: RBCs destroyed by the reticuloendothelial system.
• Intrinsic (RBC defect) vs. an acquired extrinsic mechanism (where transfused cells will have a shortened life span).
  • Intrinsic defects: all are hereditary except PNH.
    • Membrane: Hereditary spherocytosis, hereditary elliptocytosis.
    • Enzyme: e.g. G6PD deficiency: normal smear and Coomb’s. Check G6PD levels, which may be normal after an acute hemolytic episode or post transfusion. Consider this in HIV patients, particularly African Americans, taking PCP prophylaxis. Although this is X-linked recessive, it may still occur in females due to lyonization.
    • Hemoglobinopathy: sickle cell, thalassemias, Hgb C, Hgb E.
    • Paroxysmal Nocturnal Hematuria: complement-mediated lysis. Consider with pancytopenia, unexplained thrombosis (especially intra-abdominal) and an elevated reticulocyte count and LDH. A rare diagnosis.
  • Extrinsic causes
    • Hypersplenism
    • Antibody-mediated: warm (IgG) vs. cold (IgM) think Mono, Mycoplasma;check Coomb’s. Spherocytes are on the smear. Drugs are a big offender as well.
    • Trauma/ Red Cell fragmentation: heart valve, hemodialysis, malignant HTN, vasculitis, HELLP, cardiopulmonary bypass, TTP/HUS, DIC. Look for schistocytes and helmet cells (even 1-2 per HPF), and spherocytes. Remember: DIC increases INR and PTT, HUS and TTP do not.
    • Infection/toxin: malaria, babesiosis, clostridia, brown-recluse, copper (Wilson’s disease).

Labs

• Send LDH, total and direct bilirubin, and possibly haptoglobin (level < 25 is 96% specific for hemolysis).
  • A normal LDH and haptoglobin > 25 helped rule out hemolysis in one small study. Haptoglobin overall is not very useful as it takes one week to return, is an acute phase reactant, and is very sensitive (leading to decreased specificity).

Laboratory findings typically include a normochromic, normocytic anemia with reticulocytosis or rarely reticulocytopenia. Occasionally, a high mean corpuscular volume may result from reticulocytosis or antibody-induced agglutination of erythrocytes. White blood cell count and platelet count are normal or slightly elevated. An indirect hyperbilirubinemia is usually present, but hepatic and renal functions are normal unless the patient has suffered cardiovascular collapse. Haptoglobin level < 25 is 96% specific for hemolysis, but it is an acute phase reactant and a very sensitive test.

Acute lymphoblastic leukemia typically presents with abnormalities of two or more hematologic cell lines, not with an isolated anemia, as described in the vignette. Also, the reticulocytosis demonstrates a normal and robust response to anemia, which would not be seen in acute leukemia, where normal hematopoiesis is replaced by an infiltration of leukemic blasts.

Although acute myocarditis may present with exercise intolerance and physical findings of congestive heart failure, severe anemia and hyperbilirubinemia would not be seen.

Patients who have underlying hemolytic anemias, such as sickle cell disease or hereditary spherocytosis, may develop severe anemia in the setting of infection with parvovirus B19. In these patients, this infection is characterized by an aplastic crisis, which may manifest as a change in exercise tolerance severe enough to warrant transfusion. However, the reticulocytosis described in  the vignette is not consistent with an aplastic crisis related to parvovirus B19 infection.

Children who have hemolytic-uremic syndrome may present with pallor, lethargy, and exercise intolerance. However, physical examination findings typically include hypertension, petechiae, and often edema. Laboratory evaluation reveals not only a hemolytic anemia, but also renal insufficiency and thrombocytopenia.

References:
Hochman JA, Balistreri WF. Chronic viral hepatitis. Always be current!
Pediatr Rev. 2003;24:399-410.
Full text available online for subscription or fee at

Mieli-Vergani G, Vergani D. Autoimmune hepatitis in children. Clin
Liver Dis. 2002;6:623-634.
Article available online at

Wolf AD, Lavine JE. Hepatomegaly in neonates and children. Pediatr
Rev. 2000;21:303-310.

Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease.
JAMA. 1980 May 16;243(19):1909-11.

http://medicine.ucsf.edu/housestaff/handbook/HospH2002_C7.htm