Hemolysis
Kim Smith-Whitley
INTRODUCTION
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 (Table 40-1). A third classification is according to whether the cause of hemolysis is inherited or acquired.
DIFFERENTIAL DIAGNOSIS LISTRBC Membrane Abnormalities
Hereditary spherocytosis (HS)
Hereditary elliptocytosis (HE)
Hereditary pyropoikilocytosis
Infantile pyknocytosis
Paroxysmal nocturnal hemoglobinuria
Enzyme Defects
Embden-Meyerhof pathway defects—pyruvate kinase deficiency
Nucleotide metabolism defects—pyrimidine-5-nucleotidase deficiency
Hexose monophosphate shunt defects—glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemoglobin Disorders
Hemoglobinopathies—hemoglobin S, C, D, E
Thalassemia syndromes—α-thalassemia, β-thalassemia
Unstable hemoglobin syndromes—congenital Heinz-body hemolytic anemia, hemoglobin M disease
Alloimmune Causes
Hemolytic disease of the newborn
Hemolytic transfusion reaction
Autoimmune Causes
Warm-Reactive Antibodies
Idiopathic
Neoplastic Causes
Immunodeficiency
Infectious Causes
Viruses (e.g., cytomegalovirus, hepatitis, influenza, coxsackievirus, HIV)
Bacteria (e.g., Streptococcus, Escherichia coli, Salmonella typhi)
Postimmunization (e.g., diphtheria-tetanus-pertussis, polio, typhoid)
Toxic Causes
Antibiotics—penicillin, cephalothin, tetracycline, rifampin, and sulfonamides
Phenacetin
5-Aminosalicylic acid
Quinine and quinidine
Insulin
Lead
Chlorpromazine
Collagen Vascular Disease
Systemic lupus erythematosus
Scleroderma
Juvenile rheumatoid arthritis
Polyarteritis nodosa
Dermatomyositis
Cold-Reactive Antibodies
Infectious Causes
Mycoplasma
Epstein-Barr virus (EBV)
HIV
Neoplastic Causes
Lymphoproliferative disease
TABLE 40-1 Intravascular and Extravascular Causes of Hemolysis | ||||||||||||||||||||||
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Nonimmune Causes
DIFFERENTIAL DIAGNOSIS DISCUSSION
Hereditary Spherocytosis
Etiology
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.
Clinical Features
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.
Evaluation
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.
Treatment
Treatment of HS is supportive. Although transfusion of RBCs may be necessary for acute exacerbation of anemia, only a small number of patients depend on RBC transfusions. Splenectomy is used to decrease the extravascular red cell destruction and should be considered in children with poor growth or increased RBC transfusion requirements.
Hereditary Elliptocytosis
Etiology
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.
Clinical Features
Most children with HE are asymptomatic, but they may present for evaluation with a transient aplastic episode or a hyperhemolytic episode.
Evaluation
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.
Treatment
Splenectomy is curative but is not indicated unless anemia is profound.
G6PD Deficiency
Etiology
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.
Clinical Features
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.
Evaluation
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.
Treatment
Drug-induced intravascular hemolysis is self-limited and reversible when the offending drug is discontinued. Children with chronic hemolysis may require RBC transfusions for exacerbations of anemia characterized by cardiovascular compromise.
Sickle Cell Disease
Etiology
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.
Clinical Features
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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