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Chapter 47 Extrinsic Nonimmune Hemolytic Anemias 667

TABLE Mechanisms by Which Infection Can as a consequence of direct parasitic destruction, extravascularly as a
47.2 Cause Hemolysis consequence of changes in the splenic microvasculature and in the
activation state of the monocyte–macrophage system. Treatment
Mechanism Example consists of the use of appropriate antimalarials and the support of
Direct parasitization of red Malaria, babesiosis erythropoiesis, including the use of RBC transfusion or exchange (or
cells both) when indicated.
The anemia of malarial infections also involves mechanisms dis-
Immune mechanisms Cold agglutinin hemolysis after tinct from lysis of parasitized RBCs. Erythropoiesis is suppressed,
infectious mononucleosis or leading to suppression of erythroid precursors and inadequate reticu-
mycoplasmal pneumonia (see locytosis during acute infection. This inadequate hematopoietic
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Chapter 46)
response may be exacerbated by underlying iron deficiency, hemoglo-
Induction of hypersplenism Malaria, schistosomiasis binopathies, or concomitant infection (e.g., HIV), all potential
Altered red cell surface Haemophilus influenzae infection contributors to the severity of anemia. In addition, loss of uninfected
topology erythrocytes plays a major role in the development of anemia, with
an 8- to 10-fold greater loss of unparasitized RBCs compared with
Release of toxins and Clostridial infection causing thrombotic parasitized cells. Uninfected RBCs have reduced deformability, and
enzymes thrombocytopenic purpura–hemolytic the degree of reduced deformability correlates with the severity of
uremic syndrome, Escherichia coli infection. Poorly deformable RBCs likely are cleared by the spleen.
0197, HIV infection
A recent study in rats indicates that CD8 T-cell–dependent parasite
clearance in the spleen is involved in the damage of uninfected RBCs
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and their subsequent destruction. Evidence of in vivo removal of
immature malarial forms prompts the question of whether “unin-
Infection fected” cells that are lost represent previously infected cells that
nevertheless remain abnormal. Insertion of a merozoite rhoptry
Infection can cause hemolytic anemia via several pathophysiologic protein, ring surface protein 2, on RBCs in which infection was
mechanisms (Table 47.2). aborted has been implicated in the clearance of unparasitized erythro-
cytes and erythroid progenitors. In addition, uninfected RBCs
demonstrate increased binding of Igs that are probably nonspecific
Parasite Infections immune complexes. Acute malarial infection, particularly with P.
falciparum, also leads to alteration in splenic function that incites
The classic example of direct parasitization is infection by Plasmodium premature destruction of uninfected RBCs. 13
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falciparum (Fig. 47.1C), Plasmodium vivax, or Plasmodium malariae. The lifespan of transfused RBCs is likewise decreased. Cr-labeled
Infection with malaria, primarily P. falciparum, is a major health normal RBCs infused into patients infected with malaria demonstrate
problem in the developing world, causing an estimated 300–500 a shorter lifespan than in normal control participants; this effect may
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million infections and 1–3 million deaths annually. The burden of persist after clearance of the parasitemia. Alternatively, parasites can
disease rests most heavily on young children and pregnant women. be removed from RBCs along with the RBC membrane by the
Falciparum malaria can cause a life-threatening anemia, with severe process of pitting, producing parasite-free spherocytes. This mecha-
anemia defined as hemoglobin less than 5 g/dL associated with para- nism potentially explains the observed disparity between anemia and
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sitemia and a normocytic blood film. Malaria is primarily a disease parasitemia.
of the tropical developing world but is still seen in the United States Other infections that have somewhat similar pathophysiologies
and its territories, primarily as an import from outside the United include Carrión disease (i.e., bartonellosis), in which a bite from the
States. Of the 1298 cases reported in the United States in 2008, 117 sandfly injects Bartonella bacilliformis, which attaches to the RBC
(9%) were classified as severe, two of which were fatal. In each of the surface of up to 80% of erythrocytes and causes lysis, leading to the
malarias, sporozoites injected by the mosquito in its saliva make their massive hemolysis that characterizes acute infection. It appears that
way to liver cells. After 1–2 weeks, they become merozoites, which invasion of RBCs partly depends on the flagella of Bartonella spp.
burst out of the liver cells and into the bloodstream. Then, in a Incubation with antiflagellin antiserum reduces invasion of RBCs.
remarkable process, the parasite, by means of its apical end and The bacteria also secrete deformin, a factor that leads to deep pitting
related organelles called rhoptries, attaches to a specific receptor on on the surface of RBCs, presumably providing a portal of entry into
the RBC surface. For P. vivax, the Duffy blood group antigen appears the erythrocyte. There also may be a role for splenic clearance of
to be involved. infected cells, and prior splenectomy appeared to protect a patient
P. falciparum binds to sialic acid residues on the RBC surface from hemolysis during acute infection.
that are on glycophorin A. After specific attachment, a convulsive Babesia organisms also directly invade RBCs by mechanisms
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movement occurs during which the RBC engulfs the parasite by a somewhat resembling those seen is malaria, producing fever and
process resembling receptor-mediated endocytosis. Upon invasion hemolytic anemia. The parasite is transmitted by ticks and transfu-
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of the RBC, the malarial parasite starts digesting the hemoglobin, sions of infected blood products, and can be transmitted vertically.
depositing the undigested heme in the form of hemozoin. Knobs Most tick-borne cases occur on the West Coast, particularly in
appear on the RBC surface, and the RBC becomes a sphere. Many Washington and California, and in the northern portion of the
proteins of parasitic origin are inserted into the RBC membrane, Midwest; cases occurring on the East Coast are concentrated in
and some appear to cluster underneath these knobs. A parasite Massachusetts and Nantucket Island. However, transfusion-associated
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protein called mature parasite-infected erythrocyte surface antigen cases have been reported throughout the United States. In one
binds to membrane protein 4.1, and another parasite protein called report of transfusion-associated babesiosis, the median interval from
ring-infected erythrocyte surface antigen binds to β spectrin. Both transfusion to onset of clinical manifestations was 37 days. The
spectrin and protein 4.1 are integral components of the membrane organisms can be seen invading RBCs on smear examination, some-
skeleton, and the consequence of the binding of malarial proteins is what like P. falciparum malaria, but these organisms produce no
RBC membrane stabilization. Thus stabilized, the parasitized RBC pigment. The highest risk of death from babesiosis occurs in indi-
can continue to survive while the parasite continues to digest its viduals who are older than 50 years or are immunocompromised
contents. 10 because of acquired immunodeficiency syndrome (AIDS), drugs,
The parasite recruits the RBC’s metabolic machinery, degrades transplantation, or asplenism. Sporadic reports indicate that acquired
and ingests hemoglobin, and grows, eventually bursting out of the chronic toxoplasmosis is occasionally associated with hemolytic
RBC, and the cycle begins again. The RBCs are lysed intravascularly anemia.