Joanna M. Heal

Transfusion-related acute lung injury (TRALI) is a form of posttransfusion acute pulmonary insufficiency that has been linked to the infusion of biologic response modifiers (BRMs), including antileukocyte antibodies and lipids. Soluble CD40 ligand (sCD40L) is a platelet-derived proinflammatory mediator that accumulates during platelet storage. We hypothesized that human polymorpho-nuclear leukocytes (PMNs) express CD40, CD40 ligation rapidly primes PMNs, and sCD40L induces PMN-mediated cytotoxicity of human pulmonary microvascular endothelial cells (HMVECs). Levels of sCD40L were measured in blood components and in platelet concentrates (PCs) implicated in TRALI or control PCs that did not elicit a transfusion reaction. All blood components contained higher levels of sCD40L than fresh plasma, with apheresis PCs evidencing the highest concentration of sCD40L followed by PCs from whole blood, whole blood, and packed red blood cells (PRBCs). PCs implicated in TRALI reactions contained significantly higher sCD40L levels than control PCs. PMNs express functional CD40 on the plasma membrane, and recombinant sCD40L (10 ng/mL-1 mug/mL) rapidly (5 minutes) primed the PMN oxidase. Soluble CD40L promoted PMN-mediated cytotoxicity of HMVECs as the second event in a 2-event in vitro model of TRALI. We concluded that sCD40L, which accumulates during blood component storage, has the capacity to activate adherent PMNs, causing endothelial damage and possibly TRALI in predisposed patients.

The paradigm related to the immunologic consequences of allogeneic blood transfusions has been extended from humoral allosensitization to the effects of transfusion on cellular immune function. This includes downregulation of effector cells, activation of latent viral infection, and the prolonged circulation of donor immunocompetent cells, as seen in graft-vs-host disease. There are now extensive data showing conclusively that allogeneic transfusions are associated with increases in cancer recurrence rates (80% in colorectal cancer) and postoperative bacterial infections (as much as 200% to 1000% in some studies). Whether these associations are causal or not remains in doubt. Based on animal and clinical studies, we believe these associations are likely, in part, due to immune dysregulation caused by transfusion, perhaps augmented by the effects of hemorrhage, anesthesia, and surgical stress. The most likely mechanism underlying transfusion-induced immunosuppression is anergy due to presentation of large amounts of antigen through the intravenous route. This favors presentation of antigen by "nonprofessional" antigen-presenting cells, a situation that usually leads to anergy or tolerance rather than immune activation. Two additional hypothetical mechanisms proposed for immune dysregulation after allogeneic transfusion are (1) prolonged circulation of donor cells causing subclinical graft-vs-host disease, and (2) reactivation of immunosuppressive viruses latently present in recipient white blood cells. Results of some initial interventional studies, employing autologous transfusions or removing white blood cells from allogenic donor blood suggest that relatively simple, cost-effective strategies to ameliorate these complications may be at hand.

Homologous blood transfusions have been associated in both animals and humans with an increased risk of acute postoperative infectious complications. Eighty-four patients who underwent hip replacement surgery and were transfused with 2 or 3 units of blood were analyzed to determine whether those receiving homologous transfusions had different outcomes than those receiving autologous blood only. Only patients free of other risks for postoperative infection were studied. Those receiving homologous blood had a 32 percent (16/50) rate of proven or suspected infections, which was significantly higher than the 3 percent (1/34) rate in patients receiving autologous blood (p = 0.0029). Wound infections accounted for only a minority (6/17) of the proven or suspected infections, which suggests that nonsurgical factors contributed to these complications. The patients identified as being infected required significantly more antibiotic therapy (mean, 7.6 days) and lengthier hospital stays (mean, 15.5 days) than the patients who remained free of evidence of infection (means: 2.3 days of antibiotics and 12.3 days in the hospital) (p = 0.0001 for each variable). Other potential risk factors for infection, such as duration of surgical procedure, advanced patient age, amount of blood loss, type of anesthesia, surgeon performing the operation, use of a cemented versus porous-coat prosthesis, leukocytopenia, anemia, and underlying medical diagnosis, did not account for the differences in infection rates seen in those receiving homologous and autologous transfusions. These results confirm previous reports of an increased risk of postoperative infection in patients receiving homologous transfusions. Homologous transfusion may contribute to an increased risk of infection by immunologic modulation of the recipient.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Cardiopulmonary adverse events after transfusion include transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), which are potentially lethal and incompletely understood. STUDY DESIGN AND METHODS: To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective, before-and-after study of acute transfusion reactions for the 7years before and after introduction of universal leukoreduction in 2000, involving 778,559 blood components. RESULTS: Substantial decreases occurred in the rates of TRALI (-83%; from 2.8 cases per 100,000 components before to 0.48 after universal leukoreduction; p=0.01), TACO (-49%; 7.4 to 3.8 cases per 100,000; p=0.03), and febrile reactions (-35%; 11.4 to 7.4 cases per 10,000; p<0.0001). The incidence of allergic reactions remained unchanged (7.0 per 100,000 before and after universal leukoreduction). These outcomes were primarily attributable to decreased TRALI and/or TACO associated with red blood cell (RBC) and platelet (PLT) transfusions (-64%) with notably smaller decreases associated with fresh-frozen plasma or cryoprecipitate transfusions (-29%). The incidence of TRALI and/or TACO after 28,120 washed RBC and 69,325 washed transfusions was zero. CONCLUSION: These data suggest novel hypotheses for further testing in animal models, in prospective clinical trials, and via the new US hemovigilance system: 1) Is TACO or TRALI mitigated by leukoreduction? 2) Is the mechanism of TACO more complex than excessive blood volume? and 3) Does washing mitigate TRALI and TACO due to PLT and RBC transfusions?