Hemolytic anemia mechanisms

GSH-S deficiency is a more frequent cause of GSH deficiency (HI7), and more than 20 families with this enzyme deficiency have been reported since the first report by Oort et al. (05). There are two distinct types of GSH-S deficiency with different clinical pictures. In the red blood cell type, the enzyme defect is limited to red blood cells and the only clinical presentation is mild hemolysis. In the generalized type, the deficiency is also found in tissues other than red blood cells, and the patients show not only chronic hemolytic anemia but also metabolic acidosis with marked 5-oxoprolinuria and neurologic manifestations including mental retardation. The precise mechanism of these two different phenotypes remains to be elucidated, because the existence of tissue-specific isozymes is not clear. Seven mutations at the GSH-S locus on six alleles—four missense mutations, two deletions, and one splice site mutation—have been identified (S14). 

OSHA (Occupational Safety and Health Administration). 1999. OSHA Chemical Sampling Information. ChemSamp. [On-line] Available http //www.osha-slc.gov/ ChemSamp data. Pemis, B., and M.Magistretti. 1999. A study of mechanisms of acute hemolytic anemia from arsine. Med. Lavaro 51 37-41. 

Dl. Dawson, J. P., Thayer, W. W., and Desforges, J. F., Acute hemolytic anemia in the newborn infant due to naphthalene poisoning Report of two cases with investigations into the mechanism of the disease. Blood 13, 1113-1125 (1958). 

Cells differ considerably in their use of the pentose f phosphate pathway. In muscle, a tissue in which carbohydrates are utilized almost exclusively for generation of mechanical energy, the enzymes of the pentose phosphate pathway are lacking. By contrast, red blood cells are totally dependent on the pentose phosphate pathway as a source of NADPH for which they need to keep the iron of hemoglobin in its normal +2 valence state. A deficiency in glucose-6-phosphate dehydrogenase, the first enzyme in the pentose phosphate pathway, can lead to the wholesale destruction of red blood cells and a condition known as hemolytic anemia. 

Mechanism of primaquine-induced hemolytic anemia. GSH, reduced glutathione GSSG, oxidized glutathione NADPH, reduced nicotinamide adenine dinucleotide phosphate. 

Autoimmune diseases have been reported to be more frequent in human subjects treated with several recombinant cytokines [38], For instance, increased titers or the new occurrence of autoantibodies have been observed in hepatitis C patients treated with the recombinant interferons-alpha (IFNa). Quite a few clinical case reports describe the development of organ-specific as well as systemic autoimmune diseases including systemic lupus erythematosus, insulin-dependent type I diabetes mellitus, autoimmune thrombocytopenia, autoimmune hemolytic anemia, myasthenia gravis, and autoimmune thyroiditis in patients under IFNa therapy. Although the mechanism involved is not fully elucidated, the available data support the pathogenic potential of IFNa in autoimmunity [31]. In contrast, autoimmune effects associated with IFNp therapy are thought to be of lesser concern based on the current clinical evidence [38], Thyroid autoimmunity in contrast to other autoimmune diseases is frequent in patients treated with recombinant interleukin-2 (rIL-2). Thus, among 281 previously euthyroid cancer patients treated with rIL-2, up to 41%... 

Non-IgE-antibody-mediated immunological reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products is thought to be the cause of the formation of antierythrocyte antibodies and the development of a positive Coombs test implicated in the development of immune hemolytic anemia (211). About 3% of patients receiving large doses of intravenous penicillin (10-20 million units/ day) will develop a positive direct Coombs test (212). However, only a small fraction of Coombs positive patients will develop frank hemolytic anemia (213). Antibody-coated erythrocytes are probably eliminated by the reticuloendothelial system (extravascular hemolysis) (214), or less often by complement-mediated intravascular erythrocyte destruction (215). Another mechanism implicates circulating immune complexes (anti-beta-lactam antibody/beta-lactam complexes), resulting in erythrocyte elimination by an innocent bystander mechanism (82). Similar mechanisms have been implicated in thrombocytopenia associated with beta-lactam antibiotics (216,217). 

Levine B, Redmond A. Immunochemical mechanisms of penicilhn induced Coombs positivity and hemolytic anemia in man. Int Arch Allergy Appl Immunol 1967 31(6) 594-606. 

Kerr RO, Cardamone J, Dalmasso AP, Kaplan ME. Two mechanisms of erythrocyte destruction in penicillin-induced hemolytic anemia. N Engl J Med 1972 287(26) 1322-5. 

The interpretation of delayed transfusion reactions can be difficult, as the occurrence of low-grade warm acquired hemolytic anemia can resemble this form of transfusion reaction (78). Careful elution of antibody, its identification, and elucidation of its relation to the transfused erythrocytes are required to establish the nature of the reaction. If the indirect antiglobulin test is negative, autoimmune hemolysis is the likely pathogenic mechanism (79). 

Autoimmune hemolytic anemia has rarely been reported with the older cephalosporins, including cefalexin (40), cefalotin (41,42), cefazolin (43), and cefaloridine (44). The main laboratory findings correspond to the drug adsorption mechanism classically found in benzylpenicil-lin-induced immune hemolysis. Antibodies cross-reacting with cefalotin and benzylpenicillin were found in both benzylpenicillin-induced and cefalotin-induced hemolysis (43,45) Cases have also been reported with cefamandole (46), cefalexin (47), ceftriaxone (48), cefotaxime (49,50), cefotetan (51,52) and ceftazidime (53). 

A 48-year-old woman who had been given ceftriaxone 2 g/day intravenously for 7 days for Lyme disease developed severe hemolytic anemia (59). She had previously been given ceftriaxone twice without any adverse effects. An immune complex mechanism was suggested. 

Shulman lA, Arndt PA, McGehee W, Garratty G. Cefotaxime-induced immune hemolytic anemia due to antibodies reacting in vitro by more than one mechanism. Transfusion 1990 30(3) 263-6. 

Eckrich RJ, Fox S, Mallory D. Cefotetan-induced immune hemolytic anemia due to the drug-adsorption mechanism. Immunohematol 1994 10(2) 51-4. 

Acute hemolytic anemia, probably as part of an allergic reaction (SED-9, 154) (4,5), leukopenia through an unknown mechanism, and thrombocytopenic purpura with hemorrhage have been documented (6). 

Severe acute hemolysis due to acquisition of red cell alloantibodies from donor serum has been reported (67-69). In other cases, the suggested mechanism of hemolytic anemia after high dosages of intravenous immunoglobulin was the presence of anti-A and/or anti-B antibodies in the plasma product (70). 

Rapid exacerbation (1-21 days) or delayed (3-38 months) de novo appearance of immune hemolytic anemia has been reported after initiation of interferon alfa treatment in nine patients with lymphoproliferative disorders (220). However, this rare event was identified in only 1% of 581 patients receiving interferon alfa alone or as part of a chemotherapeutic regimen for chronic myelogenous leukemia (221). A mechanism close to that observed with alpha-methyldopa has been thought to be involved (208). The direct antiglobulin test was positive in 32% of 28 chronic myeloid leukemia patients after a median of 1 year of treatment with interferon alfa (222). 

Nitrofurantoin prodnces oxidant stress and cellnlar damage by different mechanisms (43). It can distnrb folate metabolism, leading to a megaloblastic component in pre-existing (mostly hemolytic) anemia, which responds to folic acid treatment. 

An immunologically induced hemolytic anemia due to penicillin or its congeners occurs but is rare (44—47). It typically occurs during treatment with high doses (over 10 million units/day) of penicillin for more than 2 weeks (44,45,48). The dose- and time-dependence of this reaction appear to be explained by the underlying mechanism. 

Besides this hapten or penicillin-type of drug-induced hemolysis, a second less frequent mechanism, the so-called innocent bystander mechanism can occur (46,49,50). Penicillin-antibody complexes are only loosely bound to erythrocytes and activate complement, which can be detected on the erythrocyte surface with the complement antiglobulin test ( complement or nongamma type). This mechanism plays a part in immune hemolytic anemias due to various drugs other than penicillins. The hemolytic reaction can continue for weeks after withdrawal of penicillin, that is as long as sufficient penicillin-coated erythrocytes and specific antibodies remain in circulation. 

Harris JW. Studies on the mechanism of a drug-induced hemolytic anemia. J Lab Clin Med 1956 47(5) 760-75. 

Ribavirin accnmnlates in erythrocytes, resnlting in hemolysis by an nnknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. Time-dependent and dose-dependent hemolytic anemia (eventnaUy associated with hyperbilirubinemia and a high reticnlocyte connt) is the only major toxic effect associated with oral or intravenons ribavirin and is reversible on withdrawal. There was a fall in hemoglobin concentrations below 10.0 g/dl in 9% of patients with hepatitis C treated with ribavirin and interferon alfa (6,7). 

Sulfonamides rarely have adverse effects on erythrocytes. However, there are various mechanisms by which sulfonamide-induced hemolytic anemia can occur (61) ... 

Sideroblastic anemia is characterized by the accumulation of iron in the mitochondria of erythroblasts. In a Phase I study in 35 patients with refractory tumors, eight taking CMT-3 developed anemia without leukopenia or thrombocytopenia (54). Three of these patients underwent bone-marrow examination and each had ringed side-roblasts. The authors referred to several cases of aplastic anemia, megaloblastic anemia, and hemolytic anemia in which members of the tetracycline family have been implicated. However, they stated that there has been no previous reports of sideroblastic anemia associated with any tetracycline derivative and that the molecular mechanisms by which CMT-3 might cause sideroblastic anemia are unclear. 

Around 50 families with GPI deficiency have been described worldwide. In total, 29 mutations are characterized at the molecular level, of which 24 were missense mutations, 3 nonsense, and 2 splice site mutations. Mapping of these mutations in the crystal structure of human GPI gives insight into the molecular mechanisms causing hemolytic anemia in this disorder. Mutations could be placed in three groups the first affecting the precise structure of the enzyme, the second those that disrupt the dimer interface, and the third those mutants that directly affect the active site. ... 

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