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CHAPTER 53 MALARIA

HEMOLYTIC ANEMIA EPIDEMIOLOGY
Known since antiquity, malaria is the world’s most common cause of
RESULTING FROM hemolytic anemia. Human malaria is caused by one of five species of a
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protozoan, Plasmodium. In 2012, an estimated 207 million episodes of
INFECTIONS WITH malaria occurred worldwide, resulting in approximately 627,000 deaths,
mainly children in sub-Saharan Africa. Severe malaria anemia is most
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commonly seen in young children and pregnant women.
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MICROORGANISMS the breeding sites of the Anopheles mosquito, the specific vector. Some
Malaria transmission depends on geography, rainfall patterns, and
regions have conditions that make malaria common throughout the
year, so-called endemic areas, whereas in other places there are seasonal
Marshall A. Lichtman peaks, usually the rainy season when mosquito breeding is enhanced.
Persons in Africa, Asia, the Middle East, and parts of Europe may be at
risk. Travelers to such places are at high risk because of lack of immu-
SUMMARY nity and because when they return home, the diagnosis might not be
considered promptly. Malaria may also be transmitted by blood trans-
Hemolytic anemia is a prominent part of the clinical presentation of patients fusion or organ donation from an infected donor.
infected with organisms such as the Plasmodium sp., Babesia, and Bartonella,
which directly invade the erythrocyte. Malaria is the most common cause of LIFE CYCLE
hemolytic anemia on a worldwide basis, and much has been learned about Sporozoites enter the circulation while the female Anopheles mosquito
how the parasite enters the erythrocyte and the mechanism of anemia. Falci- takes a blood meal. They invade and multiply in hepatocytes. The lat-
parum malaria, in particular, can cause severe and sometimes fatal hemolysis ter cells rupture when engorged and release merozoites that invade the
(blackwater fever). Other organisms cause hemolytic anemia by producing a red cell. In the red cell, the merozoites also cycle through these stages:
hemolysin (e.g., Clostridium perfringens), by stimulating an immune response trophozoites (ring-forms), which then can convert to schizonts. Mature
(e.g., Mycoplasma pneumoniae), by enhancing macrophage recognition and schizonts burst the red cells and release merozoites that invade other red
hemophagocytosis, or by as yet unknown mechanisms. The many different cells. The bursting and release coincides with the abrupt rises in temper-
infections that have been associated with hemolytic anemia are tabulated and ature and related signs and symptoms seen in malaria. A small fraction
references to the original studies provided. of merozoites in red cells convert to male and female gametocytes that
are ingested when the mosquito bites. In the mosquito, they fuse and
form an oocyst that divides asexually into numerous sporozoites. The
sporozoites migrate to the mosquito’s salivary glands from where they
reenter a victim’s blood upon the next bite, initiating a malarial infec-
Shortening of erythrocyte life span occurs commonly in the course of tion. Plasmodium vivax and Plasmodium ovale can persist in the liver
inflammatory and infectious diseases. This effect may occur particularly in a dormant stage (hypnozoites) and produce relapses months or years
in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency later.
(Chap. 47), splenomegaly (Chap. 56), and in the microvascular frag-
mentation syndrome (Chaps. 51 and 132). In some infections, however,
rapid destruction of erythrocytes represents a prominent part of the ALTERATIONS IN THE INFECTED RED CELL
overall clinical picture (Table 53–1). 1–49 This chapter deals only with the After the host is bitten by an infected female Anopheles mosquito, the
latter states. sporozoites invade the liver and possibly other internal organs in the
Several distinct mechanisms may lead to hemolysis during infec- asymptomatic tissue stage of malaria. Merozoites, emerging at first from
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tions. These include direct invasion of or injury to the erythrocytes the tissues and later from previously parasitized red cells, use specialized
by the infecting organism, as in malaria, babesiosis, and bartonello- invasion proteins such as the erythrocyte binding-like (EBA) and retic-
sis; elaboration of hemolytic toxins, as by Clostridium perfringens; and ulocyte homology (RH) protein families, which bind to receptors on the
development of antibodies, either autoantibodies against red cell anti- erythrocyte surface, including glycophorins A/B/C, CR1 (CD35), and
gens or deposition of microbial antigens or immune complexes on ery- basigin (CD147). 53–55 A complex series of events eventuates in invasion
throcytes, which result in hemolytic anemia. 50
of the interior of the red cell by the parasite. 35,53 Having entered the ery-
throcyte, the parasite grows intracellularly, nourished by the cell’s con-
tents, and modifies the host cell by exporting hundreds of proteins into
the cytoplasm, some of which are inserted into the red cell membrane. 56
Erythrocytes infected with Plasmodium falciparum develop sur-
face knobs that contain receptors, especially the P. falciparum ery-
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Acronyms and Abbreviations: CR1, complement receptor 1; EBA, erythrocyte- throcyte membrane protein-1 (PfEMP-1), for endothelial proteins.
binding antigen; G6PD, glucose-6-phosphate dehydrogenase; ICAM, intercellular All parasites bind to CD36 antigen (platelet glycoprotein IV) and
adhesion molecule; PfEMP, Plasmodium falciparum erythrocyte membrane protein; thrombospondin found on endothelial surfaces, whereas some bind
RSP-2, ring surface protein 2; VCAM, vascular cell adhesion molecule. to the intercellular adhesion molecule-1 (ICAM-1), and a few bind
to the vascular cell adhesion molecule (VCAM) 58–62 and mediate the

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