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Chapter 47 Extrinsic Nonimmune Hemolytic Anemias 669

prognosis. Transfusions are of limited efficacy because the membrane States, the two classes of venomous snakes are pit vipers (e.g., rattle-
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abnormalities are acquired by transfused RBCs. In one case, spur snakes, cottonmouths, moccasins, and copperheads) and coral snakes.
cell anemia occurred in a pediatric patient after orthotopic liver Pit viper venom affects hemostasis and may produce DIC with bleed-
transplantation and resolved after retransplantation. 19 ing but rarely hemolysis. Coral snake venom produces severe neuro-
Acute alcoholism can be associated with hypophosphatemia, logic impairment. Therapy consists of support and use of the
defined as levels less than 0.2 mg/dL. Such hypophosphatemia pre- appropriate antivenin and prophylactic antimicrobials, and tetanus
sumably interferes with RBC intermediary metabolism (see Chapters injections.
33 and 44), and RBC adenosine triphosphate (ATP) levels fall. Very
low ATP levels are associated with RBC rigidity, which leads to Drugs and Chemicals Exclusive of Those Producing
fragmentation, loss of surface area, and spheroidicity. The RBCs then
are further trapped in the spleen. This hypophosphatemia syndrome Oxidative Hemolysis
can also cause neuromuscular disorders, including weakness, pares-
thesias, tremors, and seizures. It should be treated aggressively with Potassium Chlorate
orally and intravenously administered phosphate supplements.
Hypophosphatemia also occurs in patients with cirrhosis, patients Potassium chlorate ingestion is listed as a cause of hemolysis, but this
receiving total parenteral nutrition whose phosphate intake is not compound is no longer available in hospital pharmacies and has no
carefully monitored, and patients taking large amounts of phosphate- currently recognized medical use. Arsine gas is generated in industrial
binding antacids. plants that engage in lead plating, galvanizing, etching, and soldering.
Stomatocytosis can occur in severe liver disease and is thought to Inhalation of a toxic amount produces a severe intravascular hemolysis
be a sign of acute alcoholic intoxication. The change in RBC shape of unknown pathogenesis and may require urgent RBC and plasma
can also be seen in acute pancreatitis. The stomatocyte is a cell well exchange.
on its way to becoming a spherocyte. The reduction in SA:V leads to
trapping in the microvasculature of the spleen and other organs of
the monocyte–macrophage system, producing various degrees of Copper
hemolysis.
The idea that copper can produce human hemolytic disease is best
supported by observations of episodes of severe hemolysis and acute
Renal Disease liver failure in patients with Wilson disease. The patient usually is a
child, adolescent, or young adult for whom the diagnosis of Wilson
The anemia in renal disease is multifactorial. A major component is disease has not yet been made. The initial clinical presentation is
impaired RBC production, which can be well controlled with eryth- usually dominated by Coombs-negative hemolytic anemia accompa-
ropoietin. Renal disease also impairs platelet function, which may nied by weakness and dark urine. Associated findings include coagu-
lead to occult blood loss. However, hemolysis also can occur and is lopathy, a rapid progression to renal failure, relatively modest rises in
multifactorial. Disease of the small renal arterioles can produce serum aminotransferases, and a low alkaline phosphatase level. In
fragmentation hemolysis of the sort seen in TTP–HUS, preeclampsia, addition to the presence of a brisk reticulocytosis, the typical findings
and malignant hypertension (see the box on Causes of Red Blood of intravascular hemolysis may be present, including elevated lactate
Cell Fragmentation Hemolysis). Otherwise, whether uremia produces dehydrogenase, low haptoglobin, and markedly elevated bilirubin
significant shortening of RBC survival is not clear. Patients with levels. Review of the peripheral smear may not reveal any specific
chronic renal failure who are undergoing hemodialysis may be par- morphologic findings, although both stomatocytosis and blister cells
ticularly susceptible to oxidative damage to their RBCs. RBC gluta- consistent with oxidant injury have been described. In one reported
thione is reduced in some patients, and the activity of the enzymes patient with concomitant transfusion-dependent hemoglobin E/β
G6PD and glutathione peroxidase is relatively low. The ability of thalassemia, the acute hemolysis led to a severe unexpected drop in
these RBCs to deal with generation of peroxides probably is impaired. the posttransfusion hemoglobin level. Because of the hereditary
deficiency in the copper-binding protein ceruloplasmin, urine and
serum nonceruloplasmin–bound copper levels in patients with
Venoms, Bites, Stings, and Toxins hemolysis are very high.
Free copper can interfere with glucose metabolism by hexoki-
The best-known example of toxin-caused hemolysis is discussed in nase inhibition and alternatively can generate oxidative hemolysis,
the earlier section, Bacterial Products Causing Hemolysis by Direct perhaps by acting as a Fenton reagent. It is important to establish
Damage to Red Blood Cells. the diagnosis promptly. When this condition is suspected, the prac-
titioner should look for Kayser–Fleischer rings on physical exami-
nation, and measure serum and urine copper and ceruloplasmin
Insect, Spider, and Snake Bites levels. Treatment with penicillamine or trientine plus zinc reduces
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the serum copper level and stops the hemolysis. In the case of
Hemolysis occurs after bee and wasp stings, snake bites, and spider acute liver failure, the treatment is urgent liver transplantation.
bites. Isolated cases of acute intravascular hemolysis after bee and Plasmapheresis and hemofiltration may be beneficial in reducing the
wasp stings have been reported. Two kinds of dangerous spiders live copper level and can serve as a bridge to transplant. In some cases,
in the United States: the southern black widow and the brown recluse plasmapheresis in combination with chelation therapy or the use of
spider. Both sexes of the black widow produce the venom, but only a fractionated plasma separation and adsorption dialysis system may
the female has fangs capable of penetrating human skin. Black widow avert the need for transplant in impending acute liver failure. Other
spider bites produce generalized muscle pain and muscular rigidity. forms of copper poisoning may cause hemolysis in patients who do
Hemolysis is not common. Brown recluse spider bites cause a con- not have underlying Wilson disease. The amount of copper ingested
siderable local reaction, called the volcano lesion. DIC and hemolysis would have to exceed the copper-binding capacity of normal ceru-
may occur after a lag of 24–48 hours. Envenomation results in loplasmin levels.
cleavage of RBC glycophorins, presumably making the RBCs more
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susceptible. Corticosteroids may be beneficial. The hemolysis
appears to be self-limiting, but RBC transfusion support may be Lead
needed.
In some parts of the world, cobra bites can cause intravascular There are at least two general forms of lead intoxication. One type
hemolysis because the venom contains phospholipases. In the United is chronic, slow cumulative poisoning (i.e., saturnism). An example