Page 759 - Hematology_ Basic Principles and Practice ( PDFDrive )

646 Part V Red Blood Cells

antigen and temporarily shuts down erythropoiesis. Although this invasion of P. falciparum into red cells from patients lacking gly-
infection is tolerated well by healthy patients, it can lead to severe, cophorin A (En[a−]), glycophorin B (S-s-U−), or glycophorins C and
at times life-threatening, aplastic crises in patients with anemias D (Gerbich negative, Ge−) is diminished. As noted earlier, the
because of premature erythrocyte destruction. As one might predict, Gerbich-negative phenotype is associated with mild, asymptomatic
parvovirus cannot invade erythroblasts of the rare P-negative ovalocytosis.
individuals.
Most infections cause hemolytic anemias triggered by several dis- Protein 4.1R and Spectrin
tinct, and at times overlapping, mechanisms. Plasmodium, Babesia, and Deficiency of protein 4.1R or self-association defects of spectrin are
Bartonella species directly attack the membrane and lyse the red cells. associated with elliptocytosis of varying severity. Both phenotypes
Some bacteria, such as Clostridium perfringens, elaborate hemolytic appear to reduce the burden of RBC invasion.
toxins or phospholipases that damage the membrane. Other infectious
agents trigger occasional production of autoantibodies against red Band 3 and Southeast Asian Ovalocytosis
cell membrane components, which in turn leads to autoimmune Conflicting explanations of the basis of the protective phenotype of
hemolytic anemia. Finally, many sepsis syndromes are associated with SAO (described earlier) from malaria have been described. Initial
anemia because of disseminated intravascular coagulation. reports suggested that SAO erythrocytes were resistant to malarial
invasion. These results were repeatedly questioned until recent studies
demonstrated SAO cells to be resistant to invasion by the more viru-
Malaria and the Erythrocyte Membrane lent P. falciparum strains. This may explain the apparent contradiction
with the reports of comparable parasitemias in SAO carriers and
The red cell membrane defects described earlier in this chapter cause patients with a normal red cell phenotype from Papua New Guinea.
mild to severe hemolytic anemias. At the same time, many red cell The protection from cerebral malaria afforded by SAO erythro-
membrane alterations have developed as a defense against microor- cytes is likely because of reduced cytoadherence of SAO red cells to
ganisms and parasites invading and lysing red cells. This is especially the cerebral vasculature. Under conditions of flow, P. falciparum-
true for malarial parasites. Although four different species of the infected ovalocytes adhere more strongly than normal infected red
malaria parasite Plasmodium, including P. falciparum, P. ovale, P. vivax, cells to the endothelial receptor CD36. Because this receptor is not
and P. malariae, infect humans, almost all of the 1.5 to 2 million expressed in the brain, this raises a possibility that ovalocytosis pro-
annual deaths caused by malaria are attributable to P. falciparum. tects from cerebral malaria by diminishing the number of parasitized
Because malaria coexisted with humans over the course of human red cells available for adhesion to the cerebral vasculature via alterna-
evolution, it comes as no surprise that multiple erythroid genotypes tive receptors. Moreover, ovalocytes appeared resistant to invasion by
were selected that confer some level of resistance to infection or miti- parasite strains that tend to bind to intracellular adhesion molecule
gate disease severity. The ensuing heritable phenotypes include, I (ICAM1), the likely receptor for cytoadherence in the brain, but
among others, resistance to red cell adhesion and/or invasion, slower the exact mechanism is not yet known.
intraerythrocytic growth, decreased or increased adhesion of infected
red cells to vascular endothelium, and increased phagocytosis of para- Knops Blood Group System
sitized red cells. Severe malaria, particularly cerebral malaria, has been associated with
Malaria and other infections causing hemolytic anemias are the formation of rosettes, clumps of cells formed by the adhesion of
described in more detail in Chapter 158, which also discusses hemo- malaria-infected erythrocytes to complement receptor 1 (CR1) on
globinopathies and red cell enzyme variants that reduce invasion and/ uninfected erythrocytes. Identification of the Knops blood group
or retard parasite growth. Consequently, we focus here on the heri- antigens on CR1, followed by observations that frequencies of various
table erythrocyte membrane alterations that developed as a defense Knops antigens varied significantly in whites and individuals of
against malaria. African ancestry, led to the hypothesis that some Knops group anti-
gens might be protective from rosetting and severe malaria. Case
control studies with genotyping and/or flow cytometry have yielded
Erythrocyte Preference conflicting results, but several have linked low-expression CR1 alleles
with malaria resistance. Further studies have shown that the expres-
Two parasites, P. vivax and P. ovale, selectively infect reticulocytes, sion of CR1 and other complement proteins increases with age.
whereas P. malariae infects older erythrocytes. In contrast, P. falci- Together these data suggest that genetic and age-related differences
parum infects red cells of all ages. This fact and the tendency of P. in complement protein expression contribute to the variability
falciparum-infected erythrocytes to sequester in circulation explain observed in individuals with severe malaria.
the markedly higher severity of P. falciparum malaria. Although these erythrocyte membrane polymorphisms offer
fascinating insight into natural defenses against one of the most
serious diseases affecting humans, the mechanism of resistance to
Attachment and Invasion malaria has not been fully elucidated for any of them. Malaria has
clearly had a profound impact on the genetic makeup of populations
Duffy Antigen living in endemic areas and provided us with multiple clues about
The P. vivax merozoite is completely dependent on attachment to the the host-parasite relationship. Better understanding of these natural
Duffy blood group antigen (also known as the Duffy antigen receptor defenses might eventually be converted into effective therapeutic
for chemokines [DARC]) for erythrocyte invasion, and consequently it interventions.
cannot invade Duffy-negative RBCs. It has been hypothesized that
this is why the Duffy-negative phenotype is common in large areas
of Africa. The Duffy-negative phenotype is caused by mutation in
a GATA1 motif in the Duffy antigen gene promoter, preventing its SUGGESTED READINGS
expression in erythroid cells, leaving its expression in other tissues
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phenotype never develop antibodies against the Duffy antigen. 31681, 2014.
Barcellini W, Bianchi P, Fermo E, et al: Hereditary red cell membrane defects:
Glycophorins diagnostic and clinical aspects. Blood Transfus 9:274–277, 2011.
All major erythrocyte glycophorins, A, B, and C/D, are involved in Basu A, Chakrabarti A: Defects in erythrocyte membrane skeletal architec-
attachment of P. falciparum to the RBC membrane. Consequently, ture. Adv Exp Med Biol 842:41–59, 2015.