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Addresss correspondence to Magali Fontaine, M.D., Ph.D., Department of Pathology, Stanford University Medical Center, 300 Pasteur Drive, H1402, Stanford, CA 94305, USA; tel 650 736 4250; fax 650 723 9178; e-mail: magalif{at}stanford.edu.
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Abstract |
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 Top Abstract IntroductionMethodsCase ReportsResults of Laboratory...DiscussionReferences |
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Keywords: platelet transfusion, anti-HLA antibodies, anti-neutrophil antibodies, acute lung injury, diagnostic guidelines
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Introduction |
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TopAbstractIntroductionMethodsCase ReportsResults of Laboratory...DiscussionReferences |
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Methods |
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TopAbstractIntroductionMethodsCase ReportsResults of Laboratory...DiscussionReferences |
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If the symptoms indicate hypoxemia and/or respiratory failure, the diagnosis of TRALI is suspected; all blood products related to the implicated unit are quarantined and the TS Medical Director is notified. Following review of the clinical history and presentation of the reaction, the TS physician evaluates the suspected TRALI reaction based on a definition of acute lung injury (ALI) used by the international pulmonary and critical care community [4]. ALI is characterized by (i) acute onset of hypoxemia (oxygen saturation <90% by pulse oximetry) for a patient who is breathing room air, or a PaO2/FiO2 
300 mmHg, (ii) bilateral infiltrates on frontal chest x-ray (CXR), and (iii) no evidence of circulatory overload. The TS physician reports the reactions as (1) "TRALI" if ALI occurred within 6 hr post-transfusion with no temporal relationship to another risk factor for ALI, (2) "Possible TRALI" if ALI occurred within 6 hr post-transfusion, but with alternative risk factors for ALI, or (3) "Not TRALI" [3].
Laboratory tests. In accordance with the Canadian consensus panel’s recommendations [3], the complete laboratory TRALI investigation is initiated for all patients diagnosed as "TRALI." For patients diagnosed as "Possible TRALI," the laboratory investigation is initiated at the discretion of the blood collection center. For the complete laboratory TRALI investigation, donor samples are tested at the Stanford Medical School Blood Center HLA Laboratory for HLA Class I and Class II antibodies using the Flow PRA (One Lambda, Canoga Park, CA) for screening, as well as the single antigen flow bead (One Lambda) for identification of antibody specificities. Neutrophil antibodies are identified at the Southeastern Wisconsin Blood Center using standard flow cytometry. Recipients are HLA-typed at the Stanford Medical School Blood Center HLA Laboratory by a DNA-based low-resolution typing method using polymerase chain reaction amplification (Labtype, One Lambda).
Donor management The plateletpheresis donors of each case are first considered as "temporally associated donors" (within 6 hr) for the suspected TRALI reaction. Then, a "temporally associated donor" is considered an "implicated donor" for the TRALI reaction if antibodies to an HLA Class I or II antigen or human neutrophil antigen are present on the respective recipient’s granulocytes defined after genotyping.
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Case Reports |
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Case 2. This patient was a 55-yr-old man with a history of a plastic anemia treated with antithymocyte globulin and cyclosporine, who presented to the oncology clinic with neutropenic fever. Subsequently he was admitted to the hospital with sepsis and hypotension and transferred to the ICU for respiratory and cardiovascular support. On admission his blood hemoglobin concentration was 7.5 gm/dl, hematocrit 21.3%, WBC 500/µl, and platelet count 7,000/µl. The patient received 2 units of packed red blood cells and 2 plateletpheresis units. Approximately 2 hr after completion of the second plateletpheresis transfusion, he exhibited worsening respiratory function with tachypnea and abrupt arterial hypoxemia with a decline in the PaO2 from 132 mmHg to 53 mmHg. The CXR showed diffuse bilateral opacities, a right pleural effusion, and no evidence of left atrial hypertension. Blood and urine cultures were negative at the time of the reaction. Despite intense respiratory and cardiovascular support, the patient’s condition progressively worsened and he died on day 21 of his admission. The etiology of respiratory failure was considered by the TS team as "Possible TRALI."
Case 3. This patient was a 1-yr-old male who presented to the oncology clinic with a history of a small blue cell tumor on the left anterior thigh, along with pulmonary metastases. After 4 cycles of chemotherapy, he received radiation therapy to his chest and thigh. During a routine check of his blood cell count, the patient was found to have a blood hemoglobin concentration of 6.4 gm/dl and a platelet count of 7,000/µl. He was transfused with 1 whole plateletpheresis unit. Approximately 1 hr after completion of the platelet transfusion, the patient presented with increased respiratory rate from 32 to 72, cyanosis, and hypoxemia with a PaO2 of 57 mmHg. The CXR showed bilateral pulmonary infiltrates consistent with pulmonary edema, as well as bilateral pleural effusions. The patient was admitted to the hospital for investigation and treatment of respiratory failure. The differential diagnosis at the time of admission for respiratory distress included: (1) intrinsic pulmonary pathology secondary to metastases, (2) transfusion-associated circulatory overload, (3) pneumonia, and/or (4) TRALI. The patient was intensely treated with iv furosemide to induce diuresis. Although he remained O2-dependent via nasal cannula for about 2 weeks, he responded well to the diuretic treatment, which ameliorated the pulmonary edema on CXR. Cultures of blood, urine, and bronchoalveolar lavage were negative. It was concluded that his respiratory distress and pleural effusions were not due to infection, but more likely attributable to a combination of TACO (in the setting of slowly progressive radiation pneumonitis) and "Possible TRALI."
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Results of Laboratory Investigations |
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Patient #1 had the following HLA phenotype: A25, AX; B8, B18, Bw4; DR15(2), DR17(3), DR51, DR52; DQ2, DQ6. For patient #1, the associated donor was a para-1 female who had both HLA Class I and Class II antibodies, but no antineutrophil antibodies. HLA antibodies were first screened by ID flow bead array, confirmed with the Luminex class I single antigen flow bead array, and identified for specific Class I as anti-B8, B39, B64, B65 strong reacting (8+) antibodies, as anti-B18, B35, B51, B75, B38, B71 and A25, A33, A68 weaker reacting (4+) antibodies, and as anti-B52, B53, B39, B41, B42, B54, B72, B77, B78, and A26, A66, and A69 marginally reacting (2+) antibodies.
Class II antibodies were also confirmed by single antigen flow beads and identified as DR1-DR18 but not DR7, DR51, DR52, DQ8 and DQ9. In conclusion, the complete TRALI investigation of patient #1 confirmed that the tested donor was implicated in the TRALI reaction experienced by this patient, with patient-specific antibodies identified against HLA class I (A25, B8, B18) and against HLA class II (DR15 and DR17).
For patient #3, the associated donor was a non-transfused male who tested negative for HLA antibodies and for IgG neutrophil antibody, but positive for IgM anti-neutrophil antibody. The IgM reactivity was not specific for any neutrophil alloantigen.
Based on these findings, the plateletpheresis donor #1 was permanently deferred. No action was taken for donor #2, as no laboratory investigation took place. Finally, donor #3 was disqualified from further donation of plasma products or platelets.
The 3 suspected cases of TRALI are summarized in Table 1
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Discussion |
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The strength of the clinical recognition of a TRALI diagnosis guides the transfusion service in investigating the associated blood donations, potentially preventing future TRALI reactions from the same donor, and/or preventing future TRALI reactions in the same patient. After careful review of the clinical presentation, a full laboratory investigation was performed in cases #1 and #3; donor #1 was confirmed as being implicated in a TRALI reaction and became permanently deferred; donor #2 was neither tested nor deferred; and donor #3 was disqualified from donating plasma or platelets.
When the TRALI reaction was initially described by Popovsky et al [5,6] in the early 1980s, the laboratory investigations were primarily a confirmatory test with a positive crossmatch between the donor serum and the patient’s granulocytes. The current guidelines of the concensus panel recommend making a definite diagnosis of TRALI based solely on clinical information [3]. Still the clinical diagnosis of a TRALI reaction remains a challenge both for the attending clinician and the Transfusion Service physician. The diagnosis in patient #2 was "Possible TRALI," due to underlying sepsis with respiratory failure prior to transfusion. Silliman et al [2] emphasizes that risk factors for ALI should not be regarded as criteria against TRALI, which should also be considered in patients with compromised respiratory function if worsening occurs after transfusion [2].
Thus, the laboratory investigation of a TRALI reaction does not merely confirm the TRALI reaction, but also provides an evaluation of the blood donors associated with the TRALI reaction. This evaluation should guide the blood donor center physician in managing the associated donors. The donor testing should be undertaken in all "TRALI" diagnoses made with no preexisting ALI in the patient prior to transfusion, as in case #1. Subsequently donor #1 was confirmed as implicated in TRALI reaction #1 as he had multiple HLA antibodies, some of which matched the recipient’s HLA antigens. In a lookback at the donations associated with case #1 (data not shown), we did not observe any TRALI reactions after blood transfusion from the 6 previous donations of the same donor implicated with case #1, including after transfusion of the case #1-related product, which was a double plateletapheresis unit.
Interestingly, Toy et al [7] found no evidence of TRALI after transfusion of blood products from one donor with multiple HLA antibodies into 103 recipients, 25% of whom had 
1 HLA antigen that matched the donor antibody. Kopko et al [8] reported the presence of a mild to severe respiratory syndrome in 35% of recipients receiving blood products from a donor with anti-human-neutrophil-antigen (HNA)-3a antibody. Therefore, a case of TRALI may represent an isolated event, but donor granulocyte antibodies rather than HLA antibodies seem likely to cause multiple cases of TRALI [8].
Hypothetically, TRALI reaction may be the result of two cumulative events: the first event being linked to the patient (ie, underlying sepsis, hematologic disease, and/or post-surgical status) and the second event being related to the transfusion of potential granulocyte primers (eg, inflammatory cytokines, active lipids and/or alloantibodies) [9,10]. In order to implement definite measures to prevent TRALI reactions, clinicians and transfusion specialists may have to define susceptibility criteria for TRALI in patients receiving blood transfusion.
A recent working group lead by Toy et al [11] from the National Heart, Lung, and Blood Institute (NHLBI) published guidelines to assist critical care physicians in recognizing TRALI. They limited the diagnosis of TRALI to patients with a new onset of severe hypoxemia and they recommended carefully assessing TRALI patients for pre-existing risk factors for ALI [11]. To facilitate TRALI diagnosis, Toy et al [11] gave a helpful list of TRALI-associated symptoms and laboratory findings, one of which is transient leukopenia concomitant to the onset of ALI. In patient #1, diagnosed with a "TRALI" reaction, the WBC remained within normal range, while patients #2 and #3 were neutropenic before the platelet transfusion. In response to the TRALI-Consensus Conference report [3] and the guidelines published by Toy et al [11], a new AABB interim standard was issued in June 2005 [12]. This interim standard (# 5.4.2.1 [EC] ) recommends evaluating blood donors implicated in TRALI or associated with multiple events of TRALI and reassessing their eligibility to donate [12].
In conclusion, application of recommended guidelines for TRALI diagnosis [3] have helped our Transfusion Service physicians to categorize the transfusion reactions in patients with symptoms of respiratory failure as "TRALI," "Possible TRALI," or "Not TRALI." Preventive measures such as donor deferral and/or disqualification for plasma donations have been implemented depending on the results of neutrophil and HLA antibody screening of the associated donors.
The lack of specificity of preventive measures targeting blood donors should encourage clinicians to adhere to blood component utilization guidelines and to minimize inappropriate use of blood products. Interestingly, the 3 patients reported here were severely thrombocytopenic; although none of them was actively bleeding, platelet transfusion was indicated due to the risk of intracranial bleeding with platelet counts 10,000/µl [13]. Ultimately, specific criteria for TRALI susceptibility will need to be defined as a preventive measure.
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