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832 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 833

and insidious over several months, but occasionally a patient has sud- LABORATORY FEATURES
den onset of symptoms of severe anemia and jaundice over a period of a
few days. In secondary AHA, the symptoms and signs of the underlying GENERAL FEATURES
disease may overshadow the hemolytic anemia and associated features.
In idiopathic AHA with only mild anemia, results of physical By definition, patients with AHA present with anemia, the sever-
examination may be normal. Even patients with relatively severe hemo- ity of which ranges from life-threatening to very mild. Patients with
lytic anemia may have only modest splenomegaly. However, in very warm-antibody AHA may present with hematocrit levels less than 10
severe cases, particularly those of acute onset, patients may present with percent or may have compensated hemolytic anemia and a near-normal
fever, pallor, jaundice, hepatosplenomegaly, hyperpnea, tachycardia, hematocrit. For the latter patients, the predominant laboratory features
angina, or heart failure. are an increased reticulocyte count and a positive DAT. Occasionally,
10,235
Clinical warm-antibody AHA may be aggravated or first become the patient has leukopenia and neutropenia. Platelet counts typ-
apparent during pregnancy. 166,233,234 Most cases are mild, however, and ically are normal. Rarely, severe immune thrombocytopenia is asso-
the prognosis for the fetus is generally good, provided the mother is ciated with warm-antibody AHA. This constellation is termed Evans
236
treated early. 233 syndrome. In this syndrome, the RBC and platelet antibodies are
apparently distinct. 237
Patients with classic chronic cold agglutinin disease exhibit mild to
COLD-ANTIBODY AUTOIMMUNE HEMOLYTIC moderate, fairly stable anemia, with hematocrit levels only occasionally
ANEMIA as low as 15 to 20 percent. In contrast, patients with paroxysmal cold
Most patients with cold agglutinin hemolytic anemia have chronic hemoglobinuria have hematocrit levels that decrease rapidly during a
hemolytic anemia with or without jaundice. In other patients, the prin- paroxysm. During a paroxysm, leukopenia is noted early, followed by
cipal feature is episodic, acute hemolysis with hemoglobinuria induced leukocytosis. Complement titers frequently are depressed because of
by chilling (see discussion of thermal amplitude in “Pathogenic Effects consumption of complement proteins during hemolysis.
of Cold Agglutinins and Hemolysins” above). Combinations of these In drug-induced immune hemolytic anemia of the hapten/drug
clinical features may occur. Acrocyanosis and other cold-mediated adsorption and true autoantibody types, the hematologic findings are
vasoocclusive phenomena affecting the fingers, toes, nose, and ears are similar to those described for spontaneously occurring warm-antibody
associated with sludging of RBCs in the cutaneous microvasculature. AHA. Most patients exhibit anemia and reticulocytosis. Leukopenia
Skin ulceration and necrosis are distinctly unusual. Hemolysis occur- and thrombocytopenia may be noted in cases of ternary complex-
ring in M. pneumoniae infections is acute in onset, typically appearing mediated hemolysis.
as the patient is recovering from pneumonia and coincident with peak Evaluation of the blood film can reveal several features related to
titers of cold agglutinins. The hemolysis is self-limited, lasting 1 to 3 all types of AHA (Fig. 54–2). Polychromasia indicates a reticulocyto-
weeks. Hemolytic anemia in infectious mononucleosis develops either sis, reflecting an increased rate of reticulocyte egress from the marrow.
11
at the onset of symptoms or within the first 3 weeks of illness. 128 Spherocytes are seen in patients with moderate to severe hemolytic
Other physical findings are variable, depending upon the presence anemia. If hereditary spherocytosis can be excluded, this finding sug-
of an underlying disease. Splenomegaly, a characteristic finding in lym- gests an immune hemolytic process. RBC fragments, nucleated RBCs,
phoproliferative diseases or infectious mononucleosis, may be observed and occasionally erythrophagocytosis by monocytes may be seen in
in idiopathic cold agglutinin disease. severe cases (Fig. 54–2). Most patients have mild leukocytosis and neu-
In paroxysmal cold hemoglobinuria, constitutional symptoms are trophilia. Additionally, patients with cold-antibody AHA may exhibit
prominent during a paroxysm. A few minutes to several hours after cold RBC autoagglutination in the blood film and in chilled anticoagulated
exposure, the patient develops aching pains in the back or legs, abdomi- blood (Fig. 54–3).
nal cramps, and perhaps headaches. Chills and fever usually follow. The The reticulocyte count usually is elevated. Nevertheless, early in
first urine passed after onset of symptoms typically contains hemoglo- the course of the disease, more than one-third of all patients may have
bin. The constitutional symptoms and hemoglobinuria generally last a transient reticulocytopenia despite a normal or hyperplastic erythroid
238–241
few hours. Raynaud phenomenon and cold urticaria sometimes occur marrow. The mechanism is unknown, but autoantibodies reactive
during an attack; jaundice may follow. against antigens on reticulocytes are speculated to lead to their selec-
tive destruction. One unusual patient with warm-antibody AHA,
239
reticulocytopenia, and marrow erythroid aplasia had a serum autoanti-
DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA body that inhibited erythroid colony formation in vitro. The aplastic
242
A careful history of drug exposure should be obtained from all patients crisis remitted after the serum IgG level was lowered by immunoad-
with hemolytic anemia and/or a positive DAT. As in idiopathic AHA, sorption. Reticulocytopenia also may be seen in patients with marrow
the clinical picture in drug-induced immune hemolytic anemia is quite function compromised by an underlying disease, parvovirus infection,
variable. The severity of symptoms largely depends upon the rate of toxic chemicals, or nutritional deficiency. Marrow examination usually
hemolysis. In general, patients with hapten/drug adsorption (e.g., pen- reveals erythroid hyperplasia and may provide evidence of an underly-
icillin) and autoimmune (e.g., α-methyldopa) types of drug-induced ing lymphoproliferative disorder.
hemolytic anemia exhibit mild to moderate hemolysis, with insidious Hyperbilirubinemia (chiefly unconjugated) is highly suggestive of
onset of symptoms developing over a period of days to weeks. In con- hemolytic anemia, although its absence does not exclude the diagnosis.
trast, the ternary complex mechanism (e.g., cephalosporins or quini- Total bilirubin is only modestly increased (up to 5 mg/dL) and, with rare
dine) often causes sudden, severe hemolysis with hemoglobinuria. In exceptions, the conjugated (direct) fraction constitutes less than 15 per-
the latter setting, hemolysis can occur after only one dose of the drug in cent of the total. Urinary urobilinogen is increased regularly, but bile is
a patient previously exposed to the drug. Acute renal failure may accom- not detected in the urine unless serum conjugated bilirubin is increased.
pany severe hemolysis by the ternary complex mechanism. 39,56,58,62,63,86 Usually, serum haptoglobin levels are low, and lactate dehydrogenase
Several reports indicate that second- and third-generation cephalo- levels are elevated. Hemoglobinuria is encountered in rare patients with
sporins may cause severe, even fatal, hemolysis by the ternary complex warm-antibody AHA and hyperacute hemolysis, more commonly in
mechanism. 37–39,64 patients with cold agglutinin disease, and characteristically in patients

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