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Chapter 47 Extrinsic Nonimmune Hemolytic Anemias 671

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reduced to nitrites in the infant gut. Nitrites bind to hemoglobin,
Agents That Cause Oxidative Hemolysis
producing methemoglobinemia, which may be so profound as to
• Therapeutic agents produce coma. If methylene blue infusion does not quickly turn the
• Nitrofurantoin (Furadantin) chocolate color of blood back to normal, the physician must consider
• Sulfasalazine (Azulfidine) the possibility that the patient is G6PD deficient and therefore unable
• p-Aminosalicylic acid to generate adequate amounts of NADPH (discussed earlier in the
• Phenazopyridine (Pyridium) section Drug-Induced Oxidative Hemolysis: General Concepts). In
• Clotrimoxazole that case, exchange transfusion may be lifesaving. Benzocaine topical
• Quinolones anesthesia in the form of a spray or cream can cause severe methe-
• Phenacetin moglobinemia, with cyanosis and dyspnea requiring methylene blue
• Rasburicase treatment.
• Dapsone and other sulfones
• Primaquine Pyridium (phenazopyridine) can cause oxidative hemolysis even in
• Recreational drugs the absence of renal disease. This agent is commonly used for treat-
• Isobutyl nitrate ment of bladder irritation. The Physician’s Desk Reference recommends
• Amyl nitrite maximum therapy of 2 days. However, patients not uncommonly are
• Miscellaneous agents given a prescription for 1–4 weeks of therapy.
• Naphthalene mothballs It has been recognized for more than 130 years that therapy
• Methylene Blue with dapsone causes oxidative hemolysis. In the past, dapsone
• Paraquat was used primarily to treat leprosy and dermatitis herpetiformis,
• Hydrogen peroxide
and was not often encountered as a cause of oxidative hemolysis.
Dapsone has come into more widespread use in some communities
as a very effective prophylactic agent against Pneumocystis carinii
pneumonia in patients with AIDS. The reduced levels of glutathi-
one reported in patients with AIDS may enhance dapsone toxicity.
high as 50% to 60% of total hemoglobin. The hemichromes, by Dapsone is also used in the treatment of malaria where it regularly
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themselves or with their iron portions acting as a Fenton reagent, causes hemolytic anemia in G6PD-deficient patients. Some clinics
mediate the generation of hydroxyl free radicals, which add their screen potential recipients for G6PD deficiency (see Chapter 44)
effect to that of superoxide and hydrogen peroxide. Lipid peroxida- and, if results are negative, proceed with dapsone therapy. However,
tion may take place, leading to membrane blebbing and cell lysis, dapsone can cause oxidative attack on normal RBCs, leading
as well as loss of asymmetry of the phospholipid membrane bilayer. sequentially to methemoglobinemia, Heinz bodies, and hemolysis,
Movement of phosphatidylserine and phosphatidylethanolamine all occurring at generally accepted standard doses. Dapsone is
to the outer bilayer of the membrane results in increased recogni- metabolized to a hydroxylamine derivative that is directly toxic
tion by macrophages in the reticuloendothelial system. Membrane to RBCs.
proteins may be crosslinked, with binding of denatured, oxidized
hemoglobin to the membrane cytoskeleton, which may increase
splenic macrophage recognition. In addition, the RBCs are rigid MISCELLANEOUS, POORLY CHARACTERIZED CAUSES OF
and susceptible to trapping in sinusoidal structures, whether or EXTRINSIC HEMOLYTIC ANEMIAS
not they have Heinz bodies lying against the membrane. In vitro
evidence suggests that oxidized RBCs are increasingly susceptible to Interferon-α as a Cause of Hemolytic Anemia
phagocytosis by macrophages. These features may account for extra-
vascular destruction. The oxidative lesions can be severe enough to Both microangiopathic and autoimmune hemolysis have been
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cause intravascular destruction as well, producing hemoglobinemia reported with IFN-α use. Zuber et al reported eight patients with
and hemoglobinuria. chronic myeloid leukemia who developed thrombotic microan-
The smear may show bite cells, which look as if a macrophage giopathy confirmed by renal biopsy. Seven of these patients had
had taken a bite, removing a Heinz body-containing segment of identifiable hemolysis, and three had thrombocytopenia. They also
membrane. RBC rigidity may result in irregularly shaped cells because reviewed 13 other cases of microangiopathy associated with IFN-α
these undeformable cells are unable to undergo elastic recoil after reported in the literature and observed that most cases occurred in
fighting their way through the sinus wall. Recurrent loss of membrane the setting of prolonged therapy in chronic myeloid leukemia. Two
material may produce spherocytes. Severe hemolysis may produce the cases of chronic hepatitis with microangiopathy were notable for
kind of circulating ghost or hemighost called a blister cell or bite cell. having received unusually high doses of IFN for this indication.
These RBCs have an empty veil of membrane on one side and Cases of autoimmune hemolysis have been reported with IFN-α
puddled hemoglobin on the other. A Heinz body preparation may therapy in the setting of chronic myeloid leukemia or chronic
be positive. However, the absence of bite cells does not rule out the hepatitis C.
diagnosis.
The clinical picture is determined by the specific agent used.
Screening for G6PD deficiency or a related disorder using an enzyme Hemolysis With Intravenous Immunoglobulin G
assay or the ascorbate cyanide test may be useful. Although any defect
in the antioxidant defense mechanisms, such as G6PD deficiency, Strictly speaking, hemolysis with intravenous IgG is a form of
considerably increases the susceptibility to hemolysis, many agents immune hemolysis. However, preparations of IgG contain anti-A
can produce oxidant hemolysis even in persons with normal defense and anti-B antibodies, and rarely cause an alloimmune hemolytic
mechanisms (see box on Agents That Cause Oxidative Hemolysis). anemia, as described in two young women undergoing treatment for
Paraquat ingestion has occurred inadvertently and in suicide attempts. idiopathic thrombocytopenic purpura. If this situation occurs and
Profound cyanosis with methemoglobinemia can occur within hours, more intravenous IgG is needed, performing a minor cross-match
with levels of 120% or higher. The condition may be succeeded and choosing a preparation of intravenous IgG that gives no reaction
by hemolysis, with Heinz bodies seen in appropriate preparations is recommended. In addition to isoantibody production, anemia has
of RBCs. been reported with intravenous IgG because of immune complex-
Toxic ingestion or inhalation of nitrites may occur in suicide mediated complement activation.
attempts from industrial exposures; via diets high in pickled or For hemolytic anemia with large granular lymphocyte leukemia,
smoked foods; through intentional recreational use; or in infants see box on Hemolytic Anemia in Chronic Large Granular Lympho-
from formulas prepared using well water high in nitrates, which are cytic Leukemia.