Autoimmune hemolytic anemia in solid organ transplantation-The role of immunosuppression

Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe hemolytic anemia (HA) and death. About 125 drugs have been implicated as the cause. The HA can be caused by drug-independent antibodies that are indistinguishable, in vitro and in vivo, from autoantibodies causing idiopathic warm type autoimmune hemolytic anemia (AIHA). More commonly, the antibodies are drug-dependent (i.e., will only react in vitro in the presence of the drug). The most common drugs to cause DIIHA are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin), which are associated with drug-dependent antibodies. The most common drug to cause AIHA is fludarabine. Finding out which drug is causing the problem and stopping that drug is the first approach to therapy. It is not easy to identify the drug interactions accurately in vitro; laboratories specializing in this area can be of great help. Copyright 2010 Elsevier Ltd. All rights reserved.

FK-506 and cyclosporin A (CsA) are potent immunosuppressive agents used clinically to prevent tissue rejection. Interest in the development of more effective immunosuppressive drugs has led to an intense effort toward understanding their biochemical mechanism of action with the result that these compounds have now become powerful tools used in deciphering the signal transduction events in T lymphocyte activation. Although chemically unrelated, FK-506 and CsA exert nearly identical biological effects in cells by inhibiting the same subset of early calcium-associated events involved in lymphokine expression, apoptosis, and degranulation. FK-506 binds to a family of intracellular receptors termed the FK-506 binding proteins (FKBPs). CsA binds to another family of intracellular receptors, the cyclophilins (Cyps), distinct from the FKBPs. The similarities between the mechanisms of action of CsA and FK-506 converge upon the calcium- and calmodulin-dependent serine-threonine protein phosphatase calcineurin (CaN). Both the FKBP/FK-506 complex and the Cyp/CsA complex can bind to calcineurin, thereby inhibiting its phosphatase activity. Calcineurin, a component of the signal transduction pathway resulting in IL-2 expression, catalyzes critical dephosphorylation events required for early lymphokine gene transcription.

Limitations in donor availability for stem cell or organ transplantation require that ABO-incompatible donors be used. Crossing ABO lines can have immune consequences characterized by immediate or delayed hemolysis. The use of peripheral blood as a stem cell source has essentially eliminated the risk for ABO-mediated hemolysis during infusion. Delayed red cell engraftment is expected after a major ABO-incompatible transplant and may be associated with pure red cell aplasia. The incidence of hemolysis associated with minor ABO incompatibility, the passenger lymphocyte syndrome, is waning because anti-B-cell immunosuppressive therapy is increasingly a component of graft versus host disease prophylaxis. The impact of ABO mismatching on stem cell recipient survival remains an area of active investigation. Although major ABO-incompatible organs are not used routinely for transplantation, minor ABO-incompatible organs are frequently used to meet the demand for organs. Passenger lymphocyte syndrome in this setting is a common complication, and has now been observed with every organ type and increasingly with non-ABO antibodies. Hemolysis can occur, but it is uncommonly severe. ABO-mismatched donors are commonly used for transplantation, and immune hemolysis remains the main complication. Clinicians must be vigilant in order to recognize hemolysis and implement appropriate therapy.