1289

Chapter 48 - Acquired Hemolytic Anemias

Resulting from Direct Effects of
Infectious, Chemical, or Physical
Agents
G. Richard Lee
Infectious Agents
Malaria
Etiology and Epidemiology
Manifestations
Pathogenesis
Diagnosis
Management
Other Protozoan Infections
Bartonellosis
Clostridial Sepsis
Other Bacterial Infections
Chemical Agents, Drugs, and Venoms
Oxidant Drugs and Chemicals
Oxygen
Chemicals Producing Hemolysis by Nonoxidant Mechanisms
Arsine
Trimellitic Anhydride
Copper
Water
Hemodialysis
Other Agents
Venoms
Spider Bites
Snake Venoms
Bee Stings
Physical Agents
Thermal Injury
Ionizing Irradiation
Hypophosphatemia

Hemolytic anemia may develop as a result of exposure to a variety of

infectious, chemical, or physical agents (see Chapter 41 , Table 41.3) .
In most such instances, evidence of humoral antibodies directed
against host erythrocytes can be demonstrated (see Chapter 47) . In
addition, infections and certain "oxidant" drugs and chemicals may
precipitate hemolysis in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency (see Chapter 44) or in those with
unstable hemoglobin disease (see Chapter 53) . Acquired forms of
hemolytic anemia remain in which the red cells appear to be injured
directly by infectious, chemical, or physical agents without clear
evidence of an intrinsic red cell defect or an antibody directed against

red cells. However, the possibility of immunologic reaction cannot be

completely excluded in some instances.

Infectious Agents
Malaria
Etiology and Epidemiology

Malaria is an acute, chronic, or recurrent febrile disease caused in

humans by four species of Plasmodia: P. vivax, P. falciparum,
1290

P. malariae, and P. ovale. These protozoan microorganisms are capable of parasitizing erythrocytes and
certain other body tissues.

Malaria is spread by mosquitoes of the genus Anopheles. The sexual

phase of the Plasmodium life cycle takes place within the vector.
Malarial sporozoites are transmitted to mammals by the bite of the
female mosquito. The semitropical and tropical endemic distribution of
malaria corresponds to the distribution of the vector.
On a worldwide basis, malaria is the most prevalent of all serious
diseases; 300 to 500 million people are affected, and 1.5 to 2.7 million
die each year . Ninety percent of the deaths are in African children .
In the late 1950s World Health Organization programs directed at
eradication of the vector with the insecticide DDT were highly
effective. Mosquito-borne malaria disappeared from temperate zones,
and its incidence decreased markedly in tropical areas. Unfortunately,
a dramatic resurgence of the disease has occurred, its prevalence
more than doubling and its incidence approaching previous levels .
The reasons for the resurgence are complex. They include the
development of vector resistance to DDT combined with the lack of an
equally effective and inexpensive insecticide, political upheaval with
the associated deterioration of social and administrative support for
malaria eradication programs, and the development of drug-resistant
organisms. An example illustrating many of these factors is the
epidemic in Tadjikistan in 1995 .
Malaria has not been endemic in the United States since the 1940s, but
approximately 1000 cases have been reported each year since 1985
(Fig. 48.1) . About one-half of these cases are accounted for by recent
immigrants and visitors . Five areas are the sources of most of these
cases: sub-Saharan Africa, Mexico-Central America, Haiti, Southeast
Asia, and India
. Americans returning from Southeast Asia during
the Vietnam war accounted for an increased number of cases in the
early 1970s. Later, Southeast Asian refugees became an important
source of imported malaria, resulting in a peak incidence of over 2000
reported cases in 1980
. European
[1]

[2]

[3]

[4]

[5]

[6] [7] [8]

[8] [9]

Figure 48-1 Reported cases of malaria in the United States by year. (From the U.S.

Centers for Disease Control and Prevention.)

experience with imported malaria has been similar to that in the United States [10] .

Introduced malaria refers to mosquito-borne disease in a nonendemic

area. Only 13 cases of introduced malaria were reported in the United
States between 1952 and 1981, but since then 63 cases have
occurred, with local outbreaks in California , New Jersey , New York,
Florida, Texas, and Michigan . P. vivax is the organism in about 80%
of locally acquired cases. The Michigan reports in 1995 represent the
first malaria seen that far north since 1972.
Malaria can also be transmitted by blood transfusion
. Between
1972 and 1981, 26 cases of transfusion malaria were reported in the
United States, with an estimated rate of 0.25 cases per million donor
units. Nine additional cases were reported in 1982, the highest number
in 25 years . Careful adherence to standards for screening blood
donors could eliminate perhaps one-half of the cases of transfused
malaria. Malaria can also be transmitted by sharing needles among
intravenous drug abusers .
[6]

[11]

[12]

[13] [14]

[15]

[16]

Manifestations

Occasionally, patients are completely free of symptoms and are

detected fortuitously. In others, malaria often has a nonspecific, flulike
onset that mimics a viral illness . Classically, the most prominent
clinical manifestations are recurrent paroxysms of chills and fever with
temperatures as high as 105 to 106F (40.5 to 41C) associated with
malaise, headache, vomiting, and other systemic symptoms. The
paroxysms tend to recur regularly every 36 to 72 hours. They are most
prominent with P. malariae infections and least prominent with P.
falciparum. Only about 25% of patients have classic paroxysmal
disease ; some develop sustained or irregular fever, others have little
or none. Splenomegaly is noted in about one-half of patients with early
stages of disease and becomes even more common later. Jaundice
and hepatomegaly may develop in later stages of the illness.
Of the various species, P. falciparum infection causes the most
morbidity and mortality. In the acute stage it can be associated with
increasing parasitemia, hypotension, malignant hyperthermia, and
death. In addition, P. falciparum malaria is associated with cerebral,
pulmonary, and renal complications . The overall mortality in 1844
children with malaria in Kenya was 3.5% . The most important
prognostic factors were impaired consciousness, respiratory distress,
hypoglycemia, and jaundice. Severe anemia alone did not affect
prognosis . Between 1959 and 1987, 68 people died of P. falciparum
malaria in the United States . The overall mortality rate was 3.8%,
but the rate increased dramatically with age, reaching 30% in patients
older than 70 years. Delay in instituting effective therapy was an
important cause of increased mortality.
[17]

[18]

[17]

[19]

[20]

[2]

[21]

Anemia is a common sign of malaria . It is particularly characteristic

of P. falciparum malaria because of the greater extent of red cell
parasitization with this species. The prevalence and degree of anemia
also depend on the immune status of the patient, the nutritional
background, and other complicating factors . With uncomplicated P.
falciparum malaria, moderately severe anemia (hematocrit less than
[22]

[23]

1291

Figure 48-2 (Figure Not Available) An episode of acute hemolytic anemia with
hemoglobinuria (blackwater fever) after quinine therapy for P. falciparum malaria. In
this patient, reaction to the direct antiglobulin (Coombs) test was positive during
early phases of the episode. (From Adner M, et al: Coombs positive hemolytic disease
in malaria. Ann Intern Med 1968;68:33.)
0.35) is seen in approximately 20% of previously healthy patients during or after the first infection [24] . In
tropical areas, anemia tends to be most prevalent and most severe in children from 1 to 5 years of age [25] ,
whereas only moderate anemia is usually noted in adolescents and adults. These age differences may reflect
immune status.

Leukocyte numbers may be normal, but patients often have

leukopenia. Thrombocytopenia has been observed in about two-thirds
of patients with P. falciparum malaria
, often associated with
splenomegaly . Its cause has not been established. One suggestion is
that disseminated intravascular coagulation is a cause. Another
hypothesis holds that adenosine diphosphate (ADP) released from
infected red cells activates circulating platelets, which leads to a series
of reactions culminating in platelet removal by the spleen .
The most serious hematologic complication of malaria is acute
intravascular hemolytic anemia (blackwater fever), which occurs as a
rare event in the course of infection by P. falciparum (Fig. 48.2) (Figure
Not Available) . The clinical manifestations are fulminating, the
intravascular hemolysis being associated with prostration, vomiting,
chills, and pyrexia. Hemoglobinemia, methemalbuminemia,
hemoglobinuria, and hyperbilirubinemia are consistent features. In the
most severe episodes, acute oliguric renal failure supervenes.
[19] [25]

[26]

[27]

Pathogenesis

Most of the hematologic manifestations of malaria are related to the

invasion of erythrocytes by the organism. The ability of the various
Plasmodia to infect specific mammalian species is probably related to
their attachment to specific red cell membrane sites or receptors. Of
the species that infect humans, P. vivax and P. ovale invade only
reticulocytes P. malariae invades only mature cells, and P. falciparum
invades erythrocytes of all ages. As a result, the proportion of cells
parasitized in P. vivax malaria rarely exceeds 1%, whereas as many as
50% of cells may be affected in P. falciparum malaria. These patterns
of invasion suggest that the various plasmodial species use different
receptors.

The invasion process, which lasts only 20 seconds, takes place in

several well-defined steps
. First, the merozoite attaches to the
red cell at any point on the microorganism; then it reorients so that the
site of attachment is at its apical end. Next, a junction forms between
the parasite and the erythrocyte . The entire red cell becomes
deformed and an invagination develops at the attachment site as the
parasite moves more deeply into the cell. Finally, the membrane
reseals at the neck of the invagination, leaving the organism within a
vacuole lined by erythrocyte membrane. The Duffy blood group
antigen and membrane protein 3 (see Chapter 10) are required for
invasion by P. knowlesi
, which infects rhesus monkeys, and
clinical evidence in humans suggests similar requirements for P. vivax.
P. falciparum apparently has two receptors: one that binds to sialic acid
groups on the erythrocyte membrane protein glycophorin and another
that binds to a trypsin-sensitive, nonsialated ligand
.
Within the erythrocyte, the malarial organisms divide asexually to
produce a schizont containing 6 to 32 merozoites. In the process, they
use 25 to 75% of the hemoglobin of the cell. The intraerythrocytic
phase lasts 24 to 72 hours, depending on the species. Then the
schizonts lyse, the cell ruptures, and the merozoites are released to
invade other cells.
Erythrocytes parasitized by certain strains of P. falciparum develop
electron-dense knobs that mediate the attachment of the infected red
cells to venules
. The knobs develop only during the trophozoite
and schizont stages of development, and the formation of the knobs
may explain the absence of these stages in the circulating blood of
patients with P. falciparum infection. The sequestration in venules also
prevents the cells from entering the splenic circulation, thereby
evading destruction and enhancing merozoite development. The knobs
attach to endothelial cells and amelanotic melanoma cells in culture,
possibly through a specific receptor-ligand interaction. The sequestered
cells are effectively removed from the circulation, and this
phenomenon may be a factor in the rapid development of anemia in
severe infections .
Excessive destruction of red cells is the most important factor in the
pathogenesis of the anemia . Erythrocyte life span is shortened ,
haptoglobin disappears from the serum , and osmotic fragility is
increased . Hemoglobin digestion and cell disruption by the
parasite are obvious causes of hemolysis. In addition, parasitization
apparently alters erythrocyte membrane lipids, possibly leading to
increased permeability . Once inside the red cell, the parasite rapidly
digests the hemoglobin and uses it as a nutrient . This process
occurs within an acidic digestive vacuole that buds from the parasite.
Hemoglobin digestion follows an orderly pathway that begins with an
aspartic protease that
[3] [25] [28] [29]

[30]

[29] [31] [32]

[33] [34] [35]

[3] [36] [37]

[38]

[22]

[39]

[40]

[41]

[42]

[43]

[44]

1292

cleaves the hemoglobin at a hinge region of the alpha-chain, leaving the molecule exposed to further
proteolysis [45] . Hemoglobin from infected erythrocytes is altered in ways that increase its oxygen affinity,
enhance the Bohr effect, and reduce sensitivity to 2,3 DPG. Thus, oxygen delivery is compromised not only
by the anemia, but by hemoglobin destruction and defective oxygen delivery by residual hemoglobin.

The spleen also plays an important role in erythrocyte destruction,

both by removing and destroying invaded cells and by "pitting" the
parasite from the erythrocyte, with consequent damage to the cell
. Parasitized cells are less deformable than normal cells, thereby
contributing to splenic sequestration . Loss of deformability is mild in
cells containing ring forms and severe in those containing trophozoites
and schizonts. Surprisingly, however, nonparasitized erythrocytes are
also destroyed at increased rates . Even after complete clearance of
the parasites, hemolysis may persist for 4 to 5 weeks . A
complement-mediated immune process may be responsible in part,
and sometimes the result of the antiglobulin test is positive. Malarial
antigens may attach to the red cell surface whether or not the cell
harbors parasites. Subsequently, antibodies and complement attach to
the cell-bound antigens and lead to splenic phagocytosis of the coated
cells.
Anemia associated with malaria probably also results in part from
relative marrow failure, as occurs in association with other forms of
infection (see Chapter 35) . Tumor necrosis factor, a possible
cytokine mediator of the anemia of chronic disorders, tends to be
increased in patients with severe P. falciparum malaria . The
percentage of reticulocytes tends to be low during active infection and
to increase transiently after effective treatment. In P. vivax malaria,
however, the low reticulocyte count may be explained in part by the
increased affinity of the organism for reticulocytes . One group of
investigators found that erythropoietin secretion was impaired in
malaria but another group did not . In an experimental model of
malaria in mice, erythropoietin secretion was increased, but the
cellularity of the marrow and its content of pluripotent stem cells (CFUS) decreased as parasitemia increased . On the basis of these
observations, stem cell depletion may be a partial explanation for the
marrow failure in malaria.
The pathogenesis of blackwater fever remains uncertain, and the
present-day rarity of this complication has made adequate study by
modern techniques difficult. Blackwater fever does not appear to
reflect an unusual degree of parasitemia; in fact, characteristic ring
forms often are absent from erythrocytes during the attack .
Europeans who have had repeated attacks of malaria and who have
taken quinine irregularly have been the chief victims of the
complication
. Often, the disease appears to be precipitated by
quinine ingestion, suggesting an immunologic reaction of the "innocent
bystander" variety (see Chapter 44) . Cases involving untreated
individuals, however, have been reported . Evidence supporting an
[46] [47]

[48]

[49]

[19]

[50]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[56] [57]

[19]

autoimmune explanation for blackwater fever is largely indirect

because most attempts to demonstrate red cell antibodies have failed,
but a few instances associated with positive reactions to antiglobulin
tests have been reported . Some episodes thought to represent
blackwater fever may have resulted from the use of primaquine-like
drugs in G6PD-deficient people although this occurrence could explain
only a few cases because this complication was observed long before
such drugs were available.
Certain inherited red cell diseases appear to confer resistance to
parasitization by malarial organisms, either by inhibiting the invasion
process or by slowing intracellular growth. These phenomena may
contribute to enhanced prevalence of such inherited diseases because
of their effects on survival (balanced polymorphism). The most studied
and best-established of these illnesses is sickle cell trait (see Chapter
51) . Others include G6PD deficiency
, thalassemia
, certain
other abnormal hemoglobin disorders
, ovalocytosis of the
Melanesian (Malayan) type , diphosphoglycerate mutase (DPGM)
deficiency , and lack of the Duffy blood group antigen . High levels
of fetal hemoglobin may account for the resistance to the disease in
infants .
[58]

[59]

[23] [60] [61]

[62] [63]

[64] [65]

[66]

[67]

[31]

[68]

Diagnosis

Diagnosis of malaria in the United States is often delayed because

physicians fail to suspect it
. Such delays are dangerous because
the early mortality rate from P. falciparum malaria approaches 10%,
deaths that can be completely prevented with adequate treatment.
The disease should be considered in the differential diagnosis of any
febrile patient returning from an endemic zone. Common misdiagnoses
are hepatitis and gastroenteritis .
Diagnosis has traditionally required identification of parasites on the
blood smear (Fig. 48.3) . They can be recognized on ordinary Wrightstained smears, but the chances of detection and identification of
species are enhanced by the use of thick smears. Single negative
smears do not exclude the disease with certainty in patients with lowgrade infections. Parasites may be detected in blood during any phase
of the illness, but the chances of detection are greatest during afebrile
periods.
Appropriate therapy requires that P. falciparum malaria be
distinguished from that caused by the other species because of
therapeutic considerations ; only P. falciparum infection results in
emergent situations with the potential for fatality. P. falciparum disease
is distinguished from that caused by other strains by heavy
parasitemia involving all ages of erythrocytes and by the lack of
trophozoites and schizonts; usually, only ring forms and the distinctive,
banana-shaped gametocytes are apparent (Fig. 48.3) . A simple test
[17] [69]

[69]

[19]

strip procedure for diagnosis in a drop of blood from the finger tip may
be as accurate as microscopy .
[70]

Management

Chemoprophylaxis should be recommended to all people traveling to

an endemic area
. Unfortunately, because of the spread of drugresistant strains of P. falciparum, no single regimen is completely
effective. Knowledge of the characteristics of the malaria strains in the
sites to be visited is essential. In addition to chemoprophylaxis,
methods to avoid infective mosquitoes are a part of appropriate
preventive measures.
[71] [72]

1293

Figure 48-3 Plasmodium falciparum. 1, Very young ring form trophozoite; 2, Double
infection of single cell with young trophozoites, one a marginal form, the other a
signet ring form; 3,4, Young trophozoites showing double chromatin dots; 5-7,
Developing trophozoites; 8, Three medium trophozoites in one cell; 9, Trophozoite
showing pigment in a cell containing Maurer's spots; 10,11, Two trophozoites in each
of two cells, showing variation of forms that parasites may assume; 12, Almost
mature trophozoite showing haze of pigment throughout cytoplasm; 13, Aestiveoautumnal slender forms; 14, Mature trophozoite, showing clumped pigment; 15,
Parasite in the process of initial chromatin division; 16-19, Various phases of the
development of the schizont; 20, Mature schizont; 21-24, Successive forms in the
development of the gametocyte, usually not found in the circulation; 25, Immature
macrogametocyte; 26, Mature macrogametocyte; 27, Immature microgametocyte;
28, Mature microgametocyte. (Reproduced from Wilcox A., Manual for the
microscopical diagnosis of malaria in man. National Institutes of Health Bulletin No.
180.) See Color Plate.

Chloroquine is the prophylactic drug of choice if chloroquine-resistant

strains have not been reported in the region. It is an ideal prophylactic
agent in several respects: It is nontoxic and inexpensive, and it
remains in the body long enough to be effective with a once-weekly
administration schedule. The dosage is 500 mg weekly (8.3 mg/kg in
children) beginning 1 to 2 weeks before departure and continuing for 4
weeks after return.
Unfortunately, chloroquine-resistant strains of P. falciparum are now
widespread. For most people (Fig. 48.4) , mefloquine is recommended
for chemoprophylaxis in such areas. Adults should take one 250-mg
tablet weekly beginning 1 week before departure and continuing for 4
weeks after leaving the area. The drug may cause disabling central
nervous system toxicity and should not be used in patients with a
history of epilepsy or psychiatric disease. Alternatives
1294

Figure 48-4 Worldwide distribution of malaria. Regions in black are areas where P
falciparum remains sensitive to chloroquine. Cross-hatched areas are areas of

chloroquine resistance.
to mefloquine include doxycycline alone, chloroguanide (proguanil) in combination with chloroquine, or
chloroquine alone with Fansidar (sulfadoxine and pyrimethamine) kept in reserve for use if febrile illness
occurs.

Because of changes in drug resistance and the development of new

agents, recommendations for chemoprophylaxis often change. Thus,
physicians are advised to become familiar with current
recommendations from the U.S. Centers for Disease Control and
Prevention (CDC), Atlanta, Georgia, before recommending a regimen to
a prospective traveler. The CDC maintains a 24-hour telephone service
for this purpose (404-639-1610).
Except for those with chloroquine-resistant P. falciparum malaria, all
new patients with uncomplicated malaria should receive 600 mg (10
mg/kg) chloroquine orally initially and at 24 hours, followed by 300 mg
(5 mg/kg) at 48 hours. A 36-hour regimen has also been described .
This treatment is effective against the parasites in the red cells. P.
vivax, P. malariae, and P. ovale infection require additional treatment
with primaquine (15 mg orally for 14 days) to eliminate the hepatic
phase of the disease.
Therapy of chloroquine-resistant P. falciparum malaria is not
completely satisfactory . For mild, uncomplicated disease, quinine
sulfate can be given in a dose of 650 mg (10 mg/kg) every 8 hours in
combination with tetracycline (250 mg four times daily) or doxycycline
(3 mg/kg once daily) for 7 days. For more severe illness, general
measures to deal with hydration and acidosis are important. Such
complications as hypoglycemia, seizures, pulmonary edema, and acute
renal failure require specific therapy directed at the complication.
Parenteral quinine or quinidine is administered until oral therapy can
begin. Exchange transfusion may be a valuable adjunct to
chemotherapy in very severe disease .
Artemisinin (qinghaosu) is a promising new agent with very rapid
action and effectiveness against chloroquine-resistant strains. Not yet
available in the United States, it is undergoing extensive trials and a
clear picture of its role in therapy will emerge shortly. It appears to be
well tolerated and to produce rapid clearance of parasites from the
blood. Less certain is whether it can materially reduce mortality.
The future prospects for controlling malaria with vaccines are
encouraging . Infecting sporozoites are covered with a membrane
protein, the circumsporozoite protein. In humans, naturally occurring
antibodies to the circumsporozoite protein apparently reduce the
prevalence of the disease in endemic areas. Monoclonal antibodies to
this protein completely protect mice from infection with a murine form
of malaria. A recombinant vaccine based on fusion of the
circumsporozoite protein with the hepatitis B surface antigen showed
considerable promise in trials with a small number of volunteers .
[71]

[73]

[74]

[75]

[76]

Field trials are planned. Another vaccine, based on pre-erythrocytic and

asexual blood state Plasmodium proteins, was somewhat effective in a
field trial .
[77]

Other Protozoan Infections

Infection by tickborne protozoans of the genus Babesia is rare in
humans; only about 200 cases have been reported . It can also be
transmitted by blood transfusion . It has been reported in islands off
the eastern U.S. shore and neighboring coastal areas, Connecticut,
Washington state, New Hampshire, Wisconsin, Georgia, and California
. In asplenic people it can produce serious, often fatal illness with
hemolytic anemia ; therefore, treatment with quinine and
clindamycin is recommended for asplenic people .
Hemolytic anemia is a regular feature of African trypanosomiasis
(sleeping sickness) . This often fatal illness is caused by T. brucei
gambiense or T. brucei rhodesiense. The diseases induced by the two
subspecies are similar except that T. brucei gambiense infection
pursues a more chronic course. The organisms are transmitted to
humans and domestic animals by the bite of the tsetse fly. Normocytic
anemia with reticulocytosis is prominent. Red cell survival is shortened
and autoagglutination of erythrocytes with accelerated erythrocyte
sedimentation characteristically is observed, probably the result of
macroglobulinemia. The results of the direct antiglobulin (Coombs) test
may be positive. Both toxic effects of the parasite and immunologic
mechanisms are implicated in the destruction of the red cells. The
intensity of the hemolytic anemia may fluctuate with the degree of
parasitemia, and transitory hepatosplenomegaly and decreases in
serum complement levels accompany the episodes. Marrow failure
often supervenes during the terminal phases of the illness. Diagnosis
depends on serologic tests or demonstration of the parasite in the
blood.
Hemolytic anemia with prominent erythroblastosis may occur in
association with congenital toxoplasmosis and has also been
reported in an adult with acquired toxoplasmosis . Normocytic
anemia is associated with shortened erythrocyte life span during the
active phase of kala azar (visceral leishmaniasis) (see Chapter 79)
, quite possibly as the result of an autoimmune mechanism .
[78]

[79]

[78]

[80]

[78]

[81]

[82]

[83]

[84]

[85]

[86]

Bartonellosis
A severe, acute hemolytic anemia is produced in humans by Bartonella
bacilliformis, an organism that was originally thought to be a
protozoan, but now is classified as a flagellated bacillus . The
infection occurs particularly in Peru, where it is transmitted by the
sandfly (Phlebotomus) and probably by other arthropods. After a 2- to
3-week incubation period, the acute phase of the illness, known as
Oroya fever, begins. It is marked by malaise, headache, muscle pains,
[87]

1295

remittent fever and chills, and rapidly developing anemia. The findings in the blood are characteristic of
acute, mostly extravascular blood destruction, and significant leukocytosis is noted [88] [89] . As viewed in
Wright- or Giemsa-stained blood smears, numerous Bartonella organisms are apparent on or in the
erythrocyte [88] . The organisms are rod-shaped (1 to 2 mum in length and 0.2 to 0.5 mum in width) or round
(0.3 to 1.0 mum in diameter). They appear singly, in pairs, or in end-to-end chains, which may assume a V
or a Y form.

In patients who recover from the acute phase, a quiescent period

ensues during which the organisms disappear from the blood. A
chronic, eruptive stage follows, verruca peruviana, a benign condition
characterized by wartlike lesions of the skin and no hematologic
manifestations. Oroya fever and verruca peruviana constitute the two
phases of Carrion disease, named after the medical student who lost
his life while investigating it. Bartonella infection can be controlled
effectively with penicillin and other antibiotics.
Bartonella muris is found in rats. Anemia caused by related organisms
has been described in the dog and other animals as well as in rats. An
interesting feature of the infection in animals is that anemia rarely
occurs in the normal animal; instead, it develops in splenectomized
rats or in dogs receiving a deficient diet or deprived of plasma
substances by plasmapheresis
. Results of studies in animals have
demonstrated clearly that the anemia is the result of blood destruction
.
[89]

[90]

[91] [92]

[87]

Clostridial Sepsis
Clostridium perfringens septicemia occurs after septic abortion
or
in association with a diseased biliary tree, traumatic wound infections,
cancer, leukemia, endocarditis, gastrointestinal arteriovenous
malformations, or the necrotizing enterocolitis of newborns
. In
a few cases, no underlying disease has been identified
.
Profound, often fatal hemolytic anemia is a regular feature of clostridial
sepsis. Signs of intravascular erythrocyte destruction are prominent,
and many microspherocytes are found in the blood. The hemolysis can
be rapid and massive, with hematocrit values falling to less than 0.10
in a matter of hours
; in one case, no detectable red cells were
found in the blood, all oxygen transport being provided by free
hemoglobin in plasma . The hemolysis probably results from the
elaboration of clostridial alpha-toxin
, a lecithinase that attacks
erythrocyte membrane lipids to form highly lytic lysolecithins.
The diagnosis should be suspected when fever, jaundice, and
intravascular hemolysis occur together. Culture will confirm the
diagnosis, but successful treatment cannot wait for culture results.
Clostridial infection responds to antibiotic therapy, but treatment must
be started quickly in order to affect outcome. Large doses of penicillin
are probably the best therapy, but cephalosporins, clindamycin,
metronidazole, and chloramphenicol are acceptable alternatives
.
[87] [93]

[94] [95] [96] [97]

[98] [99]

[98] [99] [100]

[95]

[101]

[100]

Other Bacterial Infections

Instances of hemolytic anemia have been encountered in association

with many other bacterial infections, especially severe ones. Hemolytic
anemia was found in 25 of 61 patients with bacterial septicemia
caused by either Gram-positive or Gram-negative organisms
. Seven
of these episodes were accompanied by reticulocytosis and by reduced
serum haptoglobin levels. In the remaining 18 patients, hemolysis was
inferred because the volume of packed red cells (VPRC) fell twice as
fast as could be accounted for by marrow depression alone.
Spherocytes and schistocytes were often found on blood smears.
Acute hemolytic anemia with bacterial infection is especially common
in childhood
. Of 96 children with infection-associated hemolysis,
72% of the episodes were not associated with autoantibodies. The
ages ranged from newborn to 16.8 years, with peaks in infancy and at
4 years. Usually the hemolytic process disappeared within 3 months,
but a chronic course was observed in some. Hemolysis has been
reported in children with streptococcal, staphylococcal, or
pneumococcal septicemia or endocarditis
. Hemolytic
anemia and thrombocytopenia were noted in a patent with
meningococcemia
.
Certain specific, Gram-negative bacillary infections occasionally have
been associated with hemolytic anemia. Intravascular hemolysis with
hemoglobinuria has been observed in patients with cholera
.
Hemoglobinuria can occur in patients with typhoid fever
, and a
milder hemolytic state is a well-known but uncommon complication of
this illness
. Hemolysis has only rarely been reported with other
Salmonella infections
or with E. coli infections
. E. coli 0157
gastroenteritis can cause the hemolytic-uremic syndrome (Chapter
49) , but can also bring about hemolytic anemia with no renal
involvement or red cell fragmentation
.
Severe hemolytic anemia is observed occasionally in patients with
tuberculosis. In several such cases, the tuberculosis was in the
generalized miliary stage
or involved the spleen
, but in others
it was confined to the chest
.
Certain spirochetal infections are occasionally associated with
hemolytic anemia, including relapsing fever caused by Borrelia
recurrentis
, and leptospirosis (Weil syndrome)
. The frequency of
hemolytic anemia in Weil syndrome is unknown, but it can be severe
and even fatal. Spiculated erythrocytes and erythrocyte fragments
have been observed on blood smears. Some authors propose that the
lipolytic properties of the leptospire cause hemolysis by attacking the
erythrocyte membrane
. Hemolytic anemia also has been noted in
leptospirosis in animals
.
Although the pathogenesis of the hemolytic anemia in most of the
cases just cited is uncertain, the possibility exists that in at least some
of these instances the anemia was the consequence of direct action of
the infecting agent or its products on the erythrocyte. Adsorption of
[102]

[103]

[104] [105] [106] [107] [108]

[109]

[110]

[111]

[111] [112]

[113] [114]

[115]

[116]

[106] [117]

[118]

[107] [119]

[120]

[121]

[121]

[122]

microbial antigens to red cells has been detected by

immunofluorescent techniques
. This phenomenon may lead to
phagocytosis or complement-mediated erythrocyte destruction. Often,
immunologic mechanisms (see Chapters 45 and 46)
, disseminated
intravascular coagulation (see Chapter 70) , and temporary marrow
failure (see Chapter 36) explain the anemia that is encountered in
patients with infections. Immunologic mechanisms are particularly
important in association with hemolytic anemias accompanying viral
infections
.
[103]

[123]

[124]

1296

Chemical Agents, Drugs, and Venoms

Oxidant Drugs and Chemicals
Certain chemical agents can bring about the oxidative denaturation of
hemoglobin, leading to the sequential formation of methemoglobin,
sulfhemoglobin, and Heinz bodies (see Chapter 10) . In some cases,
the chemical itself acts as an oxidizing agent; more often, however, it
interacts with oxygen to form free radicals
or peroxides
. These
free radicals or peroxides, if produced in quantities too great to be
detoxified by the glutathione-dependent reduction system, denature
hemoglobin and damage other cellular structures.
People deficient in G6PD or other components of glutathionedependent detoxification processes (see Chapter 43) are particularly
sensitive to the hemolytic effects of oxidant compounds (see Table
44.2) . However, some of these agents are powerful enough to
overcome the defense mechanisms of apparently normal erythrocytes.
Others produce hemolysis if given to normal subjects in higher than
usual doses or if renal failure leads to unusually high blood levels.
Another possibility is that the apparently normal erythrocytes in some
of these cases have as yet undescribed defects that are
inconsequential until an oxidant chemical is encountered.
Agents that reportedly can induce hemolytic anemia in apparently
normal subjects are listed in Table 48.1 . Many of these agents are
derivatives of aromatic organic compounds. From reports submitted to
the AMA registry on adverse drug reactions
, the most common
drugs and chemicals implicated in hemolysis in normal subjects are
naphthalene (mothballs), nitrofurantoin (Furadantin),
salicylazosulfidine (Azulfidine), sulfamethoxypyridine (Kinex),
aminosalicylic acid, and sodium sulfoxone. Dapsone and
phenazopyridine (Pyridium) also are associated with Heinz body
hemolysis.
Hemolytic anemia caused by oxidant drugs varies considerably in
severity. Usually the anemia is noted within 1 to 2 weeks after drug
therapy is initiated. The characteristic laboratory signs of hemolysis
[125]

[127]

[126]

are found, including anemia, reticulocytosis, hypohaptoglobinemia,

hyperbilirubinemia, and erythroid hyperplasia of the bone marrow. In
severe cases, hemoglobinemia and hemoglobinuria may be apparent.
Cyanosis with methemoglobinemia or sulfhemoglobinemia is
sometimes noted. The hemolytic process usually disappears within 1 to
3 weeks after use of the offending drug has been discontinued.
Several morphologic findings are characteristic of hemolytic anemia
caused by oxidant drugs and chemicals, and some are so unusual that
they strongly suggest the diagnosis. Heinz bodies are found whenever
the anemia is severe. They probably are formed in the milder cases,
but are removed so efficiently by the spleen that they may not be
detected in the circulation
. "Bite cells" (degmacytes) are
erythrocytes that look as if a semicircular bite has been taken from one
edge (Fig. 48.5)
. They may be caused either by the partial
phagocytosis that occurs when a splenic macrophage pits the Heinz
body from the cell or when the Heinz body is actively extruded without
splenic intervention
. Hemighosts
or eccentrocytes
are
erythrocytes that look as if the hemoglobin has shifted to one side of
the cell,
[128]

[130] [135] [149]

[180]

[140]

[181]

TABLE 48-1 -- Drugs and Chemicals that Cause Hemolytic Anemia in Patients with Apparently Normal
Erythrocytes
Oxidant drugs and toxins
Aromatic (cyclic) compounds
Sulfonamides [127] [128] [129] [130]
Sulfones [127] [131] [132] [133] [134]
Phenazopyridine (Pyridium) [130] [135] [136]
Nitrofurantoin (Furadantin) [127]
Phenacetin [137] [138]
Salicylates [127]
Phenol [121]
Cresol (Lysol, penetrating oil) [140] [141] [142]
Naphthalene (mothballs) [127] [143] [144] [145]
Nitrobenzene [146]
Resorcin [147]
Aniline [148]
Phenylsemicarbazide [149]
Phenylhydrazine [150] [151]
Chlorates [152] [153]
Nitrates [154] [155] [156]

Oxygen [157] [158]

Hydroxylamine [159]
Methylene blue (in infants) [160] [161]
Hematin [162]
Pentachlorophenol [163]
Cisplatin [164]
Nonoxidant chemicals
Arsine (AsH3) [165] [166] [167]
Pyrogallic acid
Stibine (SbH3)
Lead (168; see Chapter 36)
Trimellitic anhydride [169]
Copper [170] [171] [172]
Propylthiouracil [173]
Apiol [174]
Mephenesin [175]
Glycerol (intravenous) [176]
Zinc ethylene-bis-dithiocarbamate [177]
Water [178] [179]

leaving the other side clear (Fig. 48.5) . The cell may appear to contain
a large vacuole
. Electron microscopic analysis reveals that the clear
area is formed by bringing the membranes from the two sides of the
cell into apposition; the hemoglobin-containing area is spheroidal
.
Hemighosts appear only when hemolysis is brisk
, and they
probably indicate a particularly severe degree of oxidant damage.
[142]

[140]

[140] [130]

Oxygen

Molecular oxygen may cause hemolysis under certain circumstances

. A mild hemolytic reaction was observed in a patient treated for stroke
with oxygen at high pressure
. Over a 6-day period after the
exposure, the VPRC fell from 0.48 to 0.35 L/L, the reticulocytes
increased from 0.5 to 4.6%, and the bilirubin value rose to 1.6 mg/dL.
Hemolysis also has been induced in mice by exposure to oxygen, and
the intensity of the reaction was greatly exaggerated in vitamin Edeficient animals (see Chapter 11)
. In normal human

[157]

[158]

[182]

1297

subjects, only 4 hours of exposure to 100% oxygen induced an increase in plasma hemoglobin levels to
about 26 mg/dL, and abnormalities in erythrocyte osmotic fragility were detected [157] . The toxic effects of
oxygen probably are related to the generation of H2 O2 [158] [183] and the peroxidation of membrane lipids [182] [184]
[185]
.

Chemicals Producing Hemolysis by Nonoxidant Mechanisms

Arsine

Arsine (Arseniuretted hydrogen, AsH3 ) is a colorless, nonirritating,

highly toxic gas that is produced by the action of water on a metallic
arsenide. Arsine poisoning is associated most often with the use of
acids in refining, extracting, or otherwise processing crude metals that
contain arsenic as an impurity
. Such industrial processes as
galvanizing, soldering, etching, and lead plating can expose workers to
this noxious gas, and attempts to use geothermal and fossil fuel
energy sources probably will produce additional exposure
. Arsine is
also used in the transistor industry to stabilize silicon, and leakage
from cylinders in which the gas is transported can lead to accidental
poisoning
.
Manifestations of poisoning appear 2 to 24 hours after exposure and
include abdominal pain, nausea, and vomiting, the passage of dark-red
urine, jaundice, anemia, reticulocytosis, leukocytosis, and other signs
of acute hemolytic anemia. Hemoglobinemia and hemoglobinuria are
found, and acute, oliguric renal failure often ensues. The antiglobulin
test result is negative. The mortality rate approaches 22.5%
.A
more chronic form of arsine poisoning occurring in gold refiners was
associated with severe hemolytic anemia, prominent stippling,
erythroblastosis, and rapid recovery when exposure was interrupted
.
Arsine is believed to be fixed by hemoglobin in a nonvolatile form
within the red cell, after which lysis occurs
, perhaps as the
consequence of the action of compounds formed in the oxidation of
arsine
. The treatment of choice is exchange transfusion to remove
the arsenic-containing erythrocytes and to restore the blood
hemoglobin levels.
[166] [167]

[166]

[186]

[187]

[165]

[188]

[166]

Trimellitic Anhydride

Hemolytic anemia and respiratory symptoms, including hemoptysis,

have been reported after inhalation of trimellitic anhydride in industrial
settings
. This compound is an epoxy resin used in the manufacture
of plastics. Clinical
[168]

Figure 48-5 Bite cells and hemighosts in drug-induced hemolytic anemia. Top 6
photographs, Arrows indicate bite cells in ordinary blood smears. (From Ward PCJ,
Schwartz BS, White JG. Heinz-body anemia: "bite cell" variant--a light and electron
microscopic study. Am J Hematol 1982;15: 135.) Lower left, Hemighost ( single arrow)
and ghost ( double arrows) in an ordinary blood smear. Lower right, Scanning
electron micrograph of a hemighost. (From Chan TK, Chan WC, Weed RI. Erythrocyte
hemighosts: a hallmark of severe oxidative injury in vivo. Br J Haematol
1982;50:575.)

1298

improvement occurs spontaneously after exposure is terminated. The cause of the hemolysis is not known,
but immunologic mechanisms may play a role [169] . Adequate ventilation or the appropriate use of face
masks can prevent toxicity.
Copper

Hemolytic anemia can occur as a result of the direct effects of

inorganic copper on the red cell
. Such episodes have been noted
rarely in humans
and animals
exposed to toxic amounts of
copper sulfate. Copper also has been implicated in hemolytic episodes
after hemodialysis
.
When inorganic copper enters the blood in large amounts, much of it
accumulates in the red blood cells
. Several important cellular
metabolic functions may be disrupted by the excess copper. It may
accelerate the oxidation of hemoglobin, inactivate enzymes of the
pentose-phosphate and glycolytic pathways, and damage the cellular
membrane. Erythrocyte deformability becomes markedly reduced
coincident with exposure to toxic amounts of copper, and membrane
permeability and osmotic fragility increase
. Any of these
abnormalities may account for the shortened survival of the red cell.
The release of inorganic copper into the circulation also accounts for
the occurrence of hemolytic anemia in Wilson disease (hepatolenticular
degeneration)
. This inherited illness, characterized
by a lifelong tendency to accumulate copper, usually becomes
symptomatic in the teens or early twenties, when the copper
concentration in the liver or nervous system reaches toxic levels
.
Hemolytic anemia is associated with the early stages of Wilson disease
. It may be the first manifestation of disease
, or it may be
associated with hepatic decompensation
, but it is not characteristic
of the later, neurologic stages. However, it may appear late in the
course of the disease if therapy with penicillamine is discontinued
.
The hemolytic episodes in Wilson disease usually are transient and
self-limited, but they may be severe and recurrent. When they occur
with hepatic decompensation, the situation is serious, and death from
liver failure often follows
. Laboratory test findings include the usual
signs of hemolytic anemia; in addition, however, hemoglobin A2 may
be increased for reasons that are not clear
.
[172]

[170] [171]

[189] [190]

[191] [192]

[172] [193]

[194]

[195] [196] [197] [198] [199] [200] [201]

[199]

[202]

[203] [204] [205]

[198]

[195]

[198]

[197]

Often, the diagnosis of Wilson disease is made long after a hemolytic

episode occurs; consequently, the true incidence of this complication
has not been determined. Hemolysis was reported in 53% of the cases
in one series
, 15% of another
, and in only 1 of 54 patients in a
third
.
Indirect evidence suggests that hemolysis associated with Wilson
disease results from the effects of inorganic copper on the red cell
. Apparently, hepatic copper storage capacity is limited, and when
the limit is exceeded, copper is released into the blood and
redistributed to other organs. Much of it enters the red cells, where it
exerts the deleterious metabolic effects described previously.
[206]

[205]

[204]

[195] [196]

[199]

Water

Hemoglobinuria and even death from renal failure were observed in

association with transurethral resection of the prostate when distilled
water was used for irrigation. Apparently, the water entered the blood
stream by way of the lymphatic and venous channels opened during
the operation
.
Hemolysis also has been noted in survivors of near drowning in fresh
water
. The entry of more than 0.6 L of water into the circulation
produces hemoglobinemia and hemoglobinuria as a result of osmotic
hemolysis. In such situations, the normal mechanisms protecting
against hemolysis (see Chapters 5 and 8) are overwhelmed.
[178]

[179]

Hemodialysis

This procedure has been associated with the development of hemolytic

anemia as the result of the presence of chloramines (oxidant
compounds used as bactericidal agents in urban water supplies)
,
formaldehyde in a water filtration system
, overheated dialysate
,
or contaminants such as nitrates
or copper.
[207]

[208]

[209]

[210]

Other Agents

Other agents reported to cause nonoxidant hemolysis are listed in

Table 48.1 . Most represent reports of isolated cases.
Venoms
Spider Bites

Certain spider bites produce severe, necrotic, gangrenous lesions

("necrotic arachnidism") that are sometimes associated with hemolytic
anemia or disseminated intravascular coagulation. In South America
and the southern part of the United States, the spiders implicated are
the brown recluse spider ( Loxosceles reclusa) and other Loxosceles
species
. In the northwestern United States, a similar picture
follows the bite of the hobo spider, also (misleadingly) known as the
aggressive house spider, Tegenaria agrestis (Fig. 48.6)
.
Hemolytic anemia has not been clearly associated with Tegenaria
bites, but at least one patient died with pancytopenia and massive
[211] [212]

[213] [214] [215]

hemorrhage. In 1994, 9418 spider bites were reported to the U.S.

Centers for Disease Control
Figure 48-6 Distribution of venomous spiders causing necrotic arachnidism, United
States and Canada, 1996. (From the U.S. Centers for Disease Control and
Prevention.)

1299

and a disproportionate number of them came from the northwest. Of 246 bites in which the spider was
identified, 27% were from the brown recluse.
[213]

The initially painless Loxosceles bite develops into a painful,

edematous, necrotic lesion that may progress to an extensive, slowly
healing, gangrenous process (necrotic arachnidism)
. In a few
patients, systemic manifestations, including typical, acute,
intravascular, hemolytic anemia, develop within several hours to 5
days later. The symptoms may be more severe in children
.
Hemoglobinuria and severe anemia are characteristic findings;
spherocytes, anisopoikilocytosis, stippling, and leukocytosis are found
in the blood and mechanical and osmotic fragility of the erythrocytes is
increased. Less commonly, erythrophagocytosis and
leukoerythroblastosis are found
. Thrombocytopenia also has been
observed, possibly resulting from associated diffuse intravascular
coagulation
. In some cases, the red cells are coated with
complement and the results of the antiglobulin (Coombs) test are
positive
. Most often, the hemolytic episode subsides
spontaneously in about 1 week, but a few severe reactions have
occurred, with ensuing renal failure and death.
Pathogenesis of the syndrome is incompletely understood, but some
progress has been made on the causative factors in the necrotic lesion
. The venom primarily attacks endothelium and secondarily
activates granulocytes with adhesion and discharge of their granular
contents. Granulocytes are required for the necrotic process to ensue.
The spider venom is capable of lysing erythrocytes
, but
complement activation and diffuse intravascular coagulation also may
be involved in the attack on the red cell
. Some authors suggest that
people who experience the systemic reactions are hypersensitive to
the venom
. Indeed, remarkably variable responses to Loxosceles
bites have been observed
; however, no biochemical basis for an
underlying hypersensitivity has been identified.
Treatment is largely supportive. Some clinicians recommend the
administration of moderately large doses of adrenal steroids (for
example, 100 mg prednisone per day), but evidence that such therapy
is effective is equivocal
. Dapsone may prevent the early skin lesion
from progressing to a necrotic stage
. An antivenom to Loxosceles
toxin has been produced, but is not commercially available
.
[211] [216] [217]

[218]

[219]

[218]

[217] [219]

[220]

[216]

[219]

[211]

[218]

[218]

[221]

[217]

Snake Venoms

Snake venoms, especially cobra venom, hemolyze red cells in vitro, the
hemolytic activity depending on two constituents, a phospholipase and
a basic protein called direct lytic factor
. Hemolytic anemia is an
uncommon manifestation of cobra bites, possibly because critical
amounts of venom are not often injected into the bloodstream. Of 47
patients bitten by a cobra, only 6 developed systemic toxicity. Three of
these patients developed mild to moderate hemolytic anemia
characterized by a fall in blood hemoglobin concentration of 3 to 4
g/dL, reticulocytosis, hyperbilirubinemia, and leukocytosis
. No signs
of intravascular hemolysis were observed. On the other hand, red cell
abnormalities were found in all of 5 patients bitten by vipers or cobras
in India
. Spherocytes were prominent, constituting 30 to 50% of red
cells by 3 to 4 days after the patients were bitten. The plasma
hemoglobin value ranged from 0.02 to 0.06 g/dL, and hemoglobinuria
occurred in 2 patients. Other abnormalities included falsely positive
reactions to antiglobulin tests, acanthocytosis, Heinz bodies, and
erythroblastosis. Blood hemoglobin levels decreased to as low as 10
g/dL. Hemolytic anemia also has reportedly occurred after the bite of
the Australian king brown snake
and the Tunisian saw-scaled
(carpet) viper
.
[222]

[223]

[224]

[225]

[226]

Bee Stings

Hemolytic reactions to bee stings appear to be rare. In one instance, a

3-year-old child stung 200 to 300 times by honeybees died after the
development of intravascular hemolysis and oliguric renal failure
. In
another case, hemolytic anemia caused by a hornet sting was
associated with diffuse intravascular coagulation
.
[227]

[228]

Physical Agents
Thermal Injury
Acute hemolytic anemia has been observed after extensive thermal
burns
. Signs of intravascular hemolysis are associated with
schistocytes, spherocytes, and echinocytes in the blood along with
increased osmotic and mechanical fragility of the erythrocytes
.
The severity of the reaction is related to the area of the body surface
affected. In one series, hemoglobinuria was found in 11 of 14 patients
who were moderately to severely burned; in most of these patients
more than 15% of the body surface was involved
. In another series,
hemolysis was apparent in patients with third-degree burns affecting
more than 20% of the body surface
.
Hemolysis occurs during the first 24 to 48 hours after the burn
. As
much as 30% of the circulating red cell mass may be destroyed in this
2-day period in severely burned patients
. After the acute hemolytic
episode, anemia develops and may last for many weeks
, but signs
[229] [230]

[230] [231]

[230]

[232]

[231]

[233]

[229]

of hemolysis disappear, and this later stage of the anemia of thermal

injury is probably a form of the anemia of chronic disorders (see
Chapter 35)
.
The acute hemolytic reaction in burned patients results in part from the
direct effects of heat on erythrocytes. When red cells are heated to
temperatures greater than 47C, irreversible morphologic and
functional abnormalities occur, the severity of which is related to the
temperature and the duration of exposure
. The major alterations
are fragmentation of the cells and the development of spherocytes,
accompanied by an increase in osmotic and mechanical fragility.
Cellular deformability and elasticity are greatly reduced
. These
changes result from irreversible denaturation of the cytoskeletal
protein spectrin
. When thermally damaged cells were injected
into animals, hemoglobinemia and hemoglobinuria were observed
promptly, with selective removal of the abnormal cells within a few
hours
. Mildly heat-damaged erythrocytes are removed
predominantly by the spleen; with greater degrees of damage, the red
cells are destroyed in the liver
.
Extracorpuscular factors also may play a role in the erythrocyte
[234] [235] [236]

[237] [238]

[239]

[240] [241]

[237]

[238] [242]

1300

destruction found in burned patients. Results of cross-transfusion studies indicate decreased survival of
normal cells transfused into burned patients and normal survival of the patients' cells in normal recipients
[243]
. Echinocytes could be induced in vitro by incubating normal cells with plasma from a burned patient [244]
[245]
. Abnormalities of plasma lipids may be responsible for these phenomena [245] .

Another clinical circumstance resulting in thermal damage to red cells

is exposure to overheated dialysate during hemodialysis
. This
situation may occur because of failure of the thermostatic controls of
the dialysis equipment.
[209]

Ionizing Irradiation
High doses of total body irradiation (180 to 600 rad) resulted in
reduced erythrocyte survival in dogs
. This effect did not seem to
result from direct radiation-induced damage to red cells because
reduced survival of even donor cells occurred in previously irradiated
animals. In in vitro studies, red cells were found to be resistant to
radiation damage; doses in the range of 20,000 rad were required to
produce detectable effects
. In vivo radiation in mice, however,
resulted in a tendency of erythrocytes to agglutinate spontaneously in
saline solution and to undergo hemolysis in acidified serum
. Despite
these observations, no clear evidence exists that irradiation induces
hemolytic anemia in humans.
[246]

[247]

[248]

Hypophosphatemia
Severe hypophosphatemia can develop in patients undergoing
prolonged therapy with antacids, in those receiving intravenous

hyperalimentation without phosphorus supplementation, in debilitated

and starved people, and in alcoholics. In addition to confusion,
weakness, anorexia, malaise, paresthesias, and
electroencephalographic and electromyographic changes, hemolytic
anemia has been observed
. In reported cases, the serum
phosphorus concentration was low, less than 0.6 mg/dL. The
concentration of intracellular phosphorylated compounds was greatly
reduced and glycolysis was thought to be profoundly inhibited. Red cell
ATP and 2,3-diphosphoglycerate were among the phosphorylated
compounds found to be deficient, leading to reduced membrane
deformability and increased hemoglobin-oxygen affinity. Therapy with
parenterally administered phosphate corrected the abnormalities. In
hyperalimented dogs, the condition could be reproduced
experimentally, and a bleeding diathesis with faulty clot retraction and
thrombocytopenia with reduced platelet survival also developed
.
[249] [250] [251]

[250] [252]