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Hemolysis is increased red blood cell (RBC) destruction with compensatory increased RBC production. The patient with hemolysis usually presents with symptoms of anemia and hyperbilirubinemia. However, chronic hemolysis may be an incidental finding when a complete blood count (CBC) is obtained for other reasons.
The causes of hemolysis can be classified as intrinsic or extrinsic. Intrinsic causes
are abnormalities that occur within the RBC (i.e., changes that involve the RBC membrane, enzymes, or hemoglobin). Extrinsic causes
involve damage to normal RBCs by any external process. A second classification system categorizes the causes of hemolysis according to whether RBC destruction occurs intravascularly or extravascularly
). A third classification is according to whether the cause of hemolysis is inherited or acquired.
DIFFERENTIAL DIAGNOSIS LIST
RBC Membrane Abnormalities
Hereditary spherocytosis (HS)
Hereditary elliptocytosis (HE)
Paroxysmal nocturnal hemoglobinuria
Embden-Meyerhof pathway defects—pyruvate kinase deficiency
Nucleotide metabolism defects—pyrimidine-5-nucleotidase deficiency
Hexose monophosphate shunt defects—glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemoglobinopathies—hemoglobin S, C, D, E
Thalassemia syndromes—α-thalassemia, β-thalassemia
Unstable hemoglobin syndromes—congenital Heinz-body hemolytic anemia, hemoglobin M disease
TABLE 40-1 Intravascular and Extravascular Causes of Hemolysis
Disseminated intravascular coagulation (DIC)
Hemolytic uremic syndrome
Acute hemolytic transfusion reactions
Organ graft rejection
Prosthetic heart valves
Acute G6PD deficiency
Paroxysmal nocturnal hemoglobinuria
Red blood cell (RBC) membrane abnormalities
RBC enzyme abnormalities
G6PD, glucose phosphate dehydrogenase.
Microangiopathic Hemolytic Anemia
Drugs (e.g., vitamin K, phenacetin, sulfones, benzenes, phenylhydralazine)
Bacteria (Clostridium perfringens, E. coli, Streptococcus)
Parasites (malaria, histoplasmosis)
DIFFERENTIAL DIAGNOSIS DISCUSSION
Hereditary spherocytosis (HS), the most common inherited RBC membrane defect, is most often seen in patients of northern European descent. Genetic mutations in genes encoding RBC skeletal proteins lead to skeletal protein anomalies, membrane instability, and subsequent hemolytic anemia in affected individuals. Although HS is inherited in an autosomal dominant fashion, 10% to 25% of all cases are sporadic.
The clinical severity depends on the severity of the hemolysis, which can be mild to severe, and on the degree of compensation by the patient. The classic clinical presentation of hemolytic anemia is jaundice, pallor, and splenomegaly. Patients may have hypersplenism, gallstones, worsening red cell destruction (hyperhemolysis) with infections, and transient red cell aplasia primarily caused by human parvovirus B19. Half of the patients have a history of neonatal hyperbilirubinemia.
The peripheral blood smear shows an increased number of spherocytes (i.e., small, round, dark-staining RBCs that lack central pallor). The mean corpuscular hemoglobin concentration is frequently elevated. Reticulocytosis is present. The osmotic fragility test demonstrates decreased resistance to osmotic lysis as compared with normal RBCs. The direct antibody test (DAT), often used to detect autoimmune hemolytic anemia (AIHA), is negative.
Hereditary elliptocytosis (HE), more common in people of African or Mediterranean descent, is caused by genetic mutations that lead to red cell cytoskeleton instability. Similar to HS, HE is inherited in an autosomal dominant pattern, but sporadic mutations are not as common.
Most children with HE are asymptomatic, but they may present for evaluation with a transient aplastic episode or a hyperhemolytic episode.
The peripheral blood smear reveals >15% elliptocytes (i.e., elongated, cigarshaped, or oval RBCs). The peripheral blood smear in normal patients may contain up to 15% elliptocytes.
The differential diagnosis of HE includes iron-deficiency anemia.
G6PD deficiency, inherited in an X-linked pattern, is the most common enzyme deficiency of the hexose monophosphate shunt. Affected patients are either heterozygous males or homozygous females. There is an increased incidence of G6PD deficiency in people of African and Mediterranean descent. Affected children may have drug-induced hemolysis or a chronic hemolytic process.
Medications and substances that can induce hemolysis in G6PD-deficient patients include acetanilid, doxorubicin, methylene blue, naphthalene, nitrofurantoin, primaquine, pamaquine, and sulfa drugs.
Presentation depends on the type of G6PD deficiency variant inherited.
Patients with the African variant of G6PD deficiency rarely present for evaluation with neonatal jaundice or chronic hemolytic anemia. They are usually identified when they present for evaluation following drug (or other substance) exposure. Drug-induced hemolysis can be severe, involving the sudden onset of pallor, malaise, scleral icterus, dark urine, and abdominal or back pain.
Patients with the Mediterranean variant of G6PD deficiency usually have a more severe form of G6PD deficiency and may present for evaluation with signs and symptoms of neonatal hyperbilirubinemia, chronic hemolytic anemia, or drug-induced hemolysis.
If G6PD deficiency is suspected, a blood sample should be sent for analysis of G6PD enzyme activity. “Bite” or “blister” cells (RBCs with small outpouchings or blisters on the outer rim) may be identified on the peripheral blood smear. Genetic testing is also available and included in the newborn screen in some states.
Sickle Cell Disease
Hemoglobin S (Hb S) is the predominant hemoglobin in the group of genetic disorders that encompass sickle cell disease (SCD). Hb S is an abnormal hemoglobin caused by a single nucleotide base substitution: Valine replaces glutamic acid in the sixth position of the β globin chain, resulting in structural changes in the RBC membrane. SCD variants include SCD-SS, SCD-SC, SCD-S β-thalassemia, and others. SCD is inherited in a recessive fashion with homozygous and compound heterozygous forms.
Patients with SCD disorders have hemolytic anemia and vaso-occlusive complications and are at an increased risk of infection. People with sickle cell trait are generally asymptomatic but may have occasional hematuria, rarely splenic infarction, and possibly pregnancy-related complications. Currently, most patients are identified through newborn screening for hemoglobinopathies. Others, not identified through newborn screening, present with signs and symptoms of SCD complications:
Infection. Children with SCD, especially those <3 years of age, are at an increased risk for the development of bacterial infections as a result of splenic hypofunction and other immunologic abnormalities. Streptococcus pneumoniae is the most commonly implicated microorganism; however, meningococcal organisms, Haemophilus influenzae, E. coli, Salmonella species, and Staphylococcus aureus are common pathogens in patients with SCD as well. Pneumococcal sepsis can be rapidly fatal in these patients, despite the use of penicillin prophylaxis and immunization with polyvalent pneumococcal vaccines.
Osteomyelitis. Patients with SCD are at an increased risk of osteomyelitis; therefore, any child with SCD, bone pain, and fever, or soft tissue swelling should be evaluated for the presence of osteomyelitis. The most common organisms causing osteomyelitis in this patient population are Salmonella and S. aureus. It is difficult to discriminate between osteomyelitis and a vaso-occlusive episode in the child with SCD. Evaluation should include radiographic studies and orthopedic evaluation.
Stroke. Children with SCD, particularly types SS and S β-thalassemia, may develop hemorrhagic or infarctive strokes. The clinical presentation includes seizures, hemiplegia, difficulty in speaking, or a change in mental status; however, subtle intermittent neurologic symptoms or severe headaches may indicate neurologic complications as well. Transcranial Doppler (TCD) ultrasonography screening identifies young children and adolescents who are at an increased risk of infarctive stroke.
Acute chest syndrome (ACS), classically defined as a new infiltrate on chest radiograph, is one of the leading causes of morbidity and mortality in patients with SCD. The cause of ACS may be multifactorial in an individual patient and includes infection, pulmonary vascular damage, infarction, and cytokine release.
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