Viral, bacterial, and parasitic infections can all cause anemia. Multiple mechanisms leading to hemolysis have been described. As mentioned earlier in this chapter, parvovirus B19 selectively infects erythroblasts through interaction with globoside, which encodes the P blood group antigen and temporarily shuts down erythropoiesis. Although this infection is tolerated well by healthy patients, it can lead to severe, at times life-threatening, aplastic crises in patients with anemias because of premature erythrocyte destruction. As one might predict, parvo virus cannot invade erythroblasts of the rare P-negative individuals.
Most infections cause hemolytic anemias triggered by several dis tinct, and at times overlapping, mechanisms. Plasmodium, Babesia, and Bartonella species directly attack the membrane and lyse the red cells. Some bacteria, such as Clostridium perfringens, elaborate hemolytic toxins or phospholipases that damage the membrane. Other infectious agents trigger the occasional production of autoantibodies against red cell membrane components, which in turn leads to auto immune hemolytic anemia. Finally, many sepsis syndromes are associated with anemia because of disseminated intravascular coagulation.
Malaria and the Erythrocyte Membrane
The red cell membrane defects described earlier in this chapter cause mild to severe hemolytic anemias. At the same time, many red cell membrane alterations have developed as a defense against microorganisms and parasites invading and lysing red cells. This is especially true for malarial para sites. Although four different species of the malaria parasite Plasmodium, including P. falciparum, Plasmodium ovale, Plasmodium vivax, and Plasmodium malariae, infect humans, almost all of the 1.5 to 2 million annual deaths caused by malaria are attributable to P. falciparum.
Because malaria coexisted with humans over the course of human evolution, it comes as no surprise that multiple erythroid genotypes were selected that confer some level of resistance to infection or mitigate disease severity. The ensuing heritable phenotypes include, among others, resistance to red cell adhesion and/or invasion, slower intraerythrocytic growth, decreased or increased adhesion of infected red cells to vascular endothelium, and increased phagocytosis of parasitized red cells.
Malaria and other infections causing hemolytic anemias are described in more detail in Chapter 158, which also discusses hemoglobinopathies and red cell enzyme variants that reduce invasion and/ or retard parasite growth. Consequently, we focus here on the heritable erythrocyte membrane alterations that developed as a defense against malaria.
Erythrocyte Preference
Two parasites, P. vivax and P. ovale, selectively infect reticulocytes, whereas P. malariae infects older erythrocytes. In contrast, P. falciparum infects red cells of all ages. This fact and the tendency of P. falciparum-infected erythrocytes to sequester in circulation explain the markedly higher severity of P. falciparum malaria.
Attachment and Invasion
Duffy Antigen
The P. vivax merozoite is completely dependent on attachment to the Duffy blood group antigen (also known as the Duffy antigen receptor for chemokines [DARC]) for erythrocyte invasion, and consequently, it 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 expression in erythroid cells, leaving its expression in other tissues intact. Elucidation of this mutation explained a long standing conundrum of transfusion medicine: why individuals with the Duffy-negative phenotype never develop antibodies against the Duffy antigen.
Glycophorins
All major erythrocyte glycophorins, A, B, and C/D, are involved in the attachment of P. falciparum to the RBC membrane. Consequently, invasion of P. falciparum into red cells from patients lacking glycophorin A (En[a−]), glycophorin B (S-s-U−), or glycophorins C and D (Gerbich negative, Ge−) is diminished. As noted earlier, the Gerbich-negative phenotype is associated with mild, asymptomatic ovalocytosis.
Protein 4.1R and Spectrin
Deficiency of protein 4.1R or self-association defects of spectrin are associated with elliptocytosis of varying severity. Both phenotypes appear to reduce the burden of RBC invasion.
Band 3 and Southeast Asian Ovalocytosis
Conflicting explanations of the basis of the protective phenotype of SAO (described earlier) from malaria have been described. Initial 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 virulent P. falciparum strains. This may explain the apparent contradiction with the reports of comparable parasitemias in SAO carriers and patients with a normal red cell phenotype from Papua New Guinea.
The protection from cerebral malaria afforded by SAO erythrocytes is likely because of the reduced cytoadherence of SAO red cells to the cerebral vasculature. Under conditions of flow, P. falciparum infected ovalocytes adhere more strongly than normal infected red cells to the endothelial receptor CD36. Because this receptor is not expressed in the brain, this raises a possibility that ovalocytosis protects from cerebral malaria by diminishing the number of parasitized red cells available for adhesion to the cerebral vasculature via alternative receptors. Moreover, ovalocytes appeared resistant to invasion by parasite strains that tend to bind to intracellular adhesion molecule I (ICAM1), the likely receptor for cytoadherence in the brain, but the exact mechanism is not yet known.
Knops Blood Group System
Severe malaria, particularly cerebral malaria, has been associated with the formation of rosettes, clumps of cells formed by the adhesion of malaria-infected erythrocytes to complement receptor 1 (CR1) on uninfected erythrocytes. Identification of the Knops blood group antigens on CR1, followed by observations that frequencies of various Knops antigens varied significantly in Whites and individuals of 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 conflicting results, but several have linked low-expression CR1 alleles with malaria resistance. Further studies have shown that the expression of CR1 and other complement proteins increases with age.
Together these data suggest that genetic and age-related differences in complement protein expression contribute to the variability observed in individuals with severe 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 malaria has not been fully elucidated for any of them. Malaria has clearly had a profound impact on the genetic makeup of populations living in endemic areas and provided us with multiple clues about the host parasite relationship. Better understanding of these natural defenses might eventually be converted into effective therapeutic interventions.
