Clinical Features. Hemolysis typically develops 2 or 3 days after drug exposure and is of variable severity. Because G6PD is X-linked, the red cells of affected males are uniformly deficient and vulnerable to oxidant injury. By contrast, random inactivation of one X chromosome in heterozygous females (Chapter 7) creates two populations of red cells, one normal and the other G6PD-deficient. Most carrier females are unaffected except for those with a large proportion of deficient red cells (a chance situation known as unfavorable lyonization). In the case of the G6PD A− variant, it is mainly older red cells that are susceptible to lysis. Because the marrow compensates for the anemia by increasing its production of new red cells with adequate levels of G6PD, the hemolysis abates even if the drug exposure continues. In other variants such as G6PD Mediterranean, found mainly in the Middle East, the enzyme deficiency and the hemolysis that occur on exposure to oxidants are more severe.
Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic anemia that stems from acquired mutations in PIGA, a gene required for the synthesis of phosphatidylinositol glycan (PIG), which serves as a membrane anchor for many proteins. Because PIGA is X-linked, normal cells have only one active PIGA gene, a mutation of which is sufficient to cause PIGA deficiency. The pathogenic mutations in PNH occur in an early hematopoietic progenitor that is capable of giving rise to red cells, leukocytes, and platelets. Progeny of the PIGA-mutated clone lack the ability to make “PIG-tailed” proteins, including several that limit the activity of complement; as a result, red cells derived from PIGA-deficient precursors are inordinately sensitive to lysis by the complement C5b-C9 membrane attack complex. Leukocytes share the same deficiency but are less sensitive to complement than are red cells, and so red cells take the brunt of the attack. The nocturnal hemolysis that gives PNH its name occurs because complement fixation is enhanced by the decrease in blood pH that accompanies sleep (owing to CO2 retention). However, most patients present less dramatically with anemia and iron deficiency resulting from chronic intravascular hemolysis.
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The most feared complication of PNH is thrombosis, which often occurs within abdominal vessels such as the portal vein and the hepatic vein. The prothrombotic state also is somehow related to excessive complement activity, as Eculizimab, an antibody that binds C5 and inhibits the assembly of the C5b–C9 membrane attack complex, greatly lessens the incidence of thrombosis as well as the degree of intravascular hemolysis. Eculizimab has no effect on early stages of complement fixation, and treated patients continue to have varying degrees of extravascular hemolysis because of the deposition of C3b on red cell surfaces. Loss of C5b-C9 activity in patients receiving Eculizimab poses a risk for Neisseria infections, particularly meningococcal sepsis; thus, all treated patients must be vaccinated against
N. meningococcus.
Immunohemolytic anemia is caused by antibodies that bind to determinants on red cell membranes. These antibodies may arise spontaneously or be induced by exogenous agents such as drugs or chemicals. Immunohemolytic anemia is uncommon and is classified based on (1) the nature of the antibody and (2) the presence of predisposing conditions (summarized in
Table 12.4