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Transfusion-related acute lung injury (TRALI) is a clinical syndrome that presents as acute hypoxemia and noncardiogenic pulmonary edema during or after a transfusion. The incidence of TRALI has been estimated to be approximately 1 in 5000 units transfused. If this estimate is accurate, then 5000 TRALI cases should be detected each year in the U.S., based on an annual transfusion volume of 25 million units. If the mortality rate is 6%, 300 deaths attributable to TRALI would occur annually. However, the FDA has only received between 8 and 21 reports of fatal TRALI cases per year between 1998 and 2003. The NHLBI Working Group on TRALI has officially defined this syndrome as a new episode of acute lung injury (ALI) that occurs during or within 6 hours after completion of a transfusion of one or more plasma containing blood components, which is not temporally related to another cause of ALI. Other causes of ALI include:
The recommended clinical criteria for diagnosis of TRALI include:
All blood components containing plasma have been implicated in TRALI cases, but the greatest risk is associated with those components containing the largest volume of plasma such as FFP, platelets and cryoprecipitate. TRALI in thrombocytopenic stem cell transplant patients with recovering neutrophils may be diagnosed as diffuse alveolar hemorrhage. Pathogenesis Two pathogenic mechanisms have been proposed: the leukocyte antibody hypothesis and the neutrophil priming hypothesis. Both mechanisms lead to a final common pathway of increased pulmonary capillary permeability, resulting in the exudation of protein-rich edema fluid. The leukocyte antibody hypothesis proposes that transfused antibodies bind to circulating WBCs, particularly neutrophils, promoting cellular activation. Activated neutrophils adhere to pulmonary capillary endothelial cells and release cytotoxic chemicals such as cytokines, leukotrienes or reactive oxygen radicals. These mediators cause pulmonary endothelial damage with subsequent pulmonary edema. In 90% of the cases in which antibody has been detected, an antibody present in the blood component reacts with recipient white blood cell (WBC) antigens. In 10% of cases, antibody present in the recipient reacts with antigens on transfused donor WBCs. Antibodies may be directed against HLA class I or Class II antigens or human neutrophil antigens (HNA). It is not clear from present data whether particular HLA specificities are more likely than others to cause TRALI. All 5 of currently identified HNA specificities have been associated with TRALI, but anti-HNA3a appears to cause the most severe cases. The antibody hypothesis has not been sufficient to explain all cases of TRALI. In one large series, leukocyte antibodies were detected in only 4% of TRALI cases. Also, some transfusions of components from donors with HLA or HNA antibodies have not caused TRALI. For this reason, a second hypothesis has been formulated, which is called the neutrophil priming hypothesis or the two-event hypothesis. The first event causes neutrophils to be primed and sequestered in the lungs. A second event causes activation of primed neutrophils, which then damage the pulmonary capillaries. The first event may be caused by the patient's underlying condition, such as infection, surgery or inflammation. The second event is caused by transfusion of bioactive substances, such as lipids or cytokines.  Prevention of TRALI Substantial circumstantial evidence indicates that the majority of cases of TRALI are caused by transfusion of plasma containing leukocyte antibodies. Many recipients who develop TRALI have received a donor unit containing antibodies directed against an antigen present on their leukocytes. Such antibodies may be directed against HLA Class I or Class II antigens or non-HLA neutrophil antigens (HNA). The highest frequency of leukocyte antibodies is found in female donors who have previously been pregnant. Overall, about 15 to 20% of female donors have HLA antibodies compared to < 1% of male donors. Several years ago, investigators from the United Kingdom (UK) Serious Hazards of Transfusion (SHOT) system determined that the rate of TRALI occurrence was 5 to 7-fold greater for blood components that contained high volumes of plasma such as FFP and platelets than for packed red blood cells. This data also showed that the majority of TRALI cases involved a leukocyte antibody-positive female donor. On the basis of the SHOT analysis, the UK adopted a policy to minimize the transfusion of FFP and platelets from female donors. Since the implementation of this policy in October 2003, the number of TRALI cases has decreased from 20 per year to 3. Recently, the American Red Cross analyzed cases of fatal TRALI reported between 2003 and 2005. Retrospective review of fatalities revealed 38 cases of probable TRALI, the majority of which (24 of 38) followed plasma transfusion. A female leukocyte antibody-positive donor was involved in 75% of cases involving plasma and in 60% of cases involving apheresis platelets. As a result of this compelling data, the American Association of Blood Banks (AABB) has recommended that all blood collecting facilities take steps to minimize the preparation of high plasma-volume components from donors known to be at increased risk of leukocyte alloimmunization. Accordingly, blood centers have begun supplying FFP from only male donors. They also must develop a plan to provide apheresis platelets from male donors by March 2008 and implement it by November 2008. Investigation of a suspected TRALI case 1. Adverse reaction is reported to hospital Transfusion Service 2. Medical Director of Transfusion Service determines if the adverse reaction meets the criteria for diagnosis of TRALI. Other adverse reactions to transfusion may produce similar signs and symptoms. The differential diagnosis includes:
4. Hospital transfusion service notifies the blood center. Testing for antibodies to HLA class I & II and HNA should be confined to donors whose components were transfused within 6 hours preceding the onset of TRALI. The most likely candidates include:
6. A donor will be classified as implicated in TRALI if they are found to have HLA I or II antibodies or HNA antibodies with specificity directed against antigens present on recipients WBCs. These donors should be permanently deferred from future donation. 7. When ALI is temporally related to both transfusion and at least one of these other risk factors, the reaction should be classified as "possible TRALI". 8. Fatal cases of TRALI must be reported to FDA and nonfatal cases to MedWatch. TRALI cases associated with antibody in the recipient reacting with donor WBCs are rare and usually occur after transfusion of nonleukocyte reduced units. Because of their low frequency, these cases do not require laboratory confirmation. Testing would not influence donor management. References AABB Association Bulletin #05-05, March 9, 2005 Boshkov, LK and Silliman CC. Transfusion-related acute lung injury. Blood Therapies in Medicine 2004;4:85-93. |
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