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Chapter 47 Extrinsic Nonimmune Hemolytic Anemias 665

Fig. 47.2 MORPHOLOGIC CHANGES ARE PRODUCED BY HEATING NORMAL RED BLOOD
CELLS AT THE INDICATED TEMPERATURES. Budding begins abruptly at 50°C (122°F) and eventually
leads to spherocytosis.

Thrombotic microangiopathic hemolytic anemia can also be the circumstances, temperatures sufficient to cause heat denaturation of
presenting feature of severe, systemic infection, including viral RBCs have been generated. Occasionally, cell warmers used with
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(cytomegalovirus [CMV], HIV), fungal, and bacterial infections. transfusions in cold agglutinin disease have malfunctioned and
Whether infection “triggers” the development of TTP or instead the cooked the RBCs about to be transfused. In one case, a patient’s
presentation remains debatable. mother warmed the RBCs with a hot water bottle, reasoning that
In one large series, 10 of 351 (2.8%) patients diagnosed with TTP such cells would cause less vein irritation to her child. Such transfu-
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were subsequently diagnosed with disseminated malignancy. Symp- sion was followed by evidence of intravascular and extravascular
toms suggesting an underlying malignancy include dyspnea, cough, hemolysis, and the peripheral smear showed RBC budding and
atypical pain, and poor response to plasma exchange. The diagnosis fragmentation (Fig. 47.2). Presumably, similar events can lead to
was made by bone marrow biopsy in six of the 10 patients, and all hemolysis in patients who have sustained very extensive burns. In
patients died shortly after the diagnosis of malignancy was made. patients with heat stroke, the temperature usually is below 42°C
A current review highlights four hereditary and four acquired (108°F), a temperature at which little RBC denaturation occurs.
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disorders that lead to thrombotic microangiopathy. TTP may be
hereditary, due to mutations in ADAMTS13, or acquired, due to
autoantibody inhibition of ADAMTS13 activity. In addition, comple- Mechanical Trauma
ment mutations causing uncontrolled activation of the alternative
pathway, mutations in components of cobalamin metabolism, and The classic example of RBC damage caused by mechanical trauma
mutations in a protein kinase C-associated protein, diacylglycerol is march hemoglobinuria, which occurs in soldiers after a long
kinase, are other hereditary causes of thrombotic microangiopathy. march, in joggers after running on a hard road, or in karate or
Acquired causes in addition to autoantibodies to ADAMTS13 conga drumming enthusiasts after practice. Anemia is rare, and
include shiga toxin (hemolytic uremic syndrome), drug mediated on reticulocytosis is uncommon. Evidence of typical intravascular RBC
an immune basis (i.e., quinine), drug mediated on a toxic, dose- destruction is present and is thought to be caused by direct trauma
related basis (i.e., gemcitabine, cyclosporine), and acquired antibodies to RBCs in the vessels of the feet or hands. Switching jogging
to complement factor H. paths or wearing better footwear often relieves the problem. Some
cases show evidence of an underlying RBC membrane abnormal-
ity. Strenuous exercise may induce oxidant stress, as evidenced by
Therapy increased levels of malonyldialdehyde, a marker of lipid peroxidation,
in marathon runners after a race. Occasionally, malfunction of the
Management is primarily directed toward the underlying disease or cell savers used during abdominal or thoracic surgery mechanically
event. Compensation of RBC production should be optimized by injures RBCs.
replacing iron or folic acid if the patient is deficient in these nutrients.
Occasionally, removal or repair of a damaged native or prosthetic
heart valve is necessary when the hemolysis produces a disabling Cardiopulmonary Bypass
transfusion requirement. Treatment of TTP with plasma exchange
has been found to be superior to plasma infusions, with fresh-frozen Postperfusion syndrome occurs in some patients after cardiopulmo-
plasma and cryo-free plasma appearing to have equal efficacy. Throm- nary bypass. The syndrome includes acute intravascular hemolysis
botic microangiopathy associated with cyclosporine is often reversible and leukopenia as part of a febrile, inflammatory clinical picture.
with cessation of cyclosporine. Affected patients may develop pulmonary distress and even adult or
acute respiratory distress syndrome. Visible hemoglobinemia occurs,
OTHER FORMS OF MECHANICAL DAMAGE TO with rising plasma hemoglobin levels, and is associated with an
increase in lysed RBC ghosts seen in the whole blood and plasma.
RED BLOOD CELLS These ghosts are coated with the complement complex C5bC9 (see
Chapter 24). Presumably, the complement pathway is activated as the
Heat Denaturation blood passes through the oxygenator. The reason why complement
activation results in lytic attack on RBCs (and granulocytes) is
Normal RBCs undergo budding and fragmentation when exposed to unknown. Free hemoglobin released into the plasma secondary to
a temperature of 49°C (120°F) in vitro (Fig. 47.1B). In some of the intravascular hemolysis may contribute to acute kidney injury after
hereditary hemolytic anemias, this process occurs at temperatures cardiopulmonary bypass. Treatment involves knowledge of the
as low as 46°C (115°F; see Chapter 45). Under some clinical process and requisite support until the situation corrects itself.