Lowell, Clifford A.

BACKGROUNDIt is increasingly recognized that recipient risk factors play a prominent role in possible transfusion‐related acute lung injury (pTRALI) and transfusion‐associated circulatory overload (TACO). We hypothesized that both transfusion and recipient factors including natriuretic peptides could be used to distinguish TRALI from TACO and pTRALI.STUDY DESIGN AND METHODSWe performed a post hoc analysis of a case‐control study of pulmonary transfusion reactions conducted at the University of California at San Francisco and Mayo Clinic, Rochester. We evaluated clinical data and brain natriuretic peptides (BNP) levels drawn after transfusion in patients with TRALI (n = 21), pTRALI (n = 26), TACO (n = 22), and controls (n = 24). Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical and biomarker predictors in differentiating TRALI from TACO and pTRALI.RESULTSWe found that pTRALI and TACO were associated with older age, higher fluid balance, and elevated BNP levels relative to those of controls and TRALI. The following variables were useful in distinguishing cases of pTRALI and TACO from TRALI: age more than 70 years, BNP levels more than 1000 pg/mL, 24‐hour fluid balance of more than 3 L, and a lower number of transfused blood components. Using the above variables, our logistic model had a 91% negative predictive value in the differential diagnosis of TRALI.CONCLUSIONSModels incorporating readily available clinical and biomarker data can be used to differentiate transfusion‐related respiratory complications. Additional studies examining recipient risk factors and the likelihood of TRALI may be useful in decision making regarding donor white blood cell antibody testing.

BACKGROUND Pulmonary transfusion reactions are important complications of blood transfusion, yet differentiating these clinical syndromes is diagnostically challenging. We hypothesized that biologic markers of inflammation could be used in conjunction with clinical predictors to distinguish transfusion‐related acute lung injury (TRALI), transfusion‐associated circulatory overload (TACO), and possible TRALI. STUDY DESIGN AND METHODS In a nested case‐control study performed at the University of California at San Francisco and Mayo Clinic, Rochester, we evaluated clinical data and blood samples drawn before and after transfusion in patients with TRALI (n = 70), possible TRALI (n = 48), TACO (n = 29), and controls (n = 147). Cytokines measured included granulocyte‐macrophage–colony‐stimulating factor, interleukin (IL)‐6, IL‐8, IL‐10, and tumor necrosis factor‐α. Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical predictors and laboratory markers in differentiating TACO, TRALI, and possible TRALI. RESULTS Before and after transfusion, IL‐6 and IL‐8 were elevated in patients with TRALI and possible TRALI relative to controls, and IL‐10 was elevated in patients with TACO and possible TRALI relative to that of TRALI and controls. For all pulmonary transfusion reactions, the combination of clinical variables and cytokine measurements displayed optimal diagnostic performance, and the model comparing TACO and TRALI correctly classified 92% of cases relative to expert panel diagnoses. CONCLUSIONS Before transfusion, there is evidence of systemic inflammation in patients who develop TRALI and possible TRALI but not TACO. A predictive model incorporating readily available clinical and cytokine data effectively differentiated transfusion‐related respiratory complications such as TRALI and TACO.

Background Possible transfusion‐related acute lung injury (p TRALI ) cases by definition have a clear temporal relationship to an alternative recipient risk factor for acute respiratory distress syndrome ( ARDS ). We questioned whether transfusion factors are important for the development of p TRALI . Study Design and Methods In this nested case‐control study, we prospectively identified 145 consecutive patients with p TRALI and randomly selected 163 transfused controls over a 4‐year period at the U niversity of C alifornia at S an F rancisco and the M ayo C linic ( R ochester, M innesota). Results For p TRALI , we found evidence against transfusion being important: receipt of plasma from female donors (odds ratio [ OR ], 0.82; 95% confidence interval [ CI ], 0.29‐2.3; p = 0.70), total number of units transfused ( OR , 0.99; 95% CI , 0.89‐1.10; p = 0.86), and number of red blood cell and whole blood units transfused ( OR , 0.78; 95% CI , 0.59‐1.03; p = 0.079). In contrast, we found that risk for p TRALI was associated with additional recipient factors: chronic alcohol abuse ( OR , 12.5; 95% CI , 2.8‐55; p < 0.001), current smoker ( OR , 4.2; 95% CI , 1.67‐10.8; p = 0.0024), shock before transfusion ( OR , 4.6; 95% CI , 2.0‐10.7; p < 0.001), and positive fluid balance before transfusion ( OR , 1.32/ L ; 95% CI , 1.20‐1.44; p < 0.001). Conclusion Recipient risk factors for ARDS rather than transfusion risk factors predominate in p TRALI .

AbstractTransfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality. To determine TRALI incidence by prospective, active surveillance and to identify risk factors by a case-control study, 2 academic medical centers enrolled 89 cases and 164 transfused controls. Recipient risk factors identified by multivariate analysis were higher IL-8 levels, liver surgery, chronic alcohol abuse, shock, higher peak airway pressure while being mechanically ventilated, current smoking, and positive fluid balance. Transfusion risk factors were receipt of plasma or whole blood from female donors (odds ratio = 4.5, 95% confidence interval [CI], 1.85-11.2, P = .001), volume of HLA class II antibody with normalized background ratio more than 27.5 (OR = 1.92/100 mL, 95% CI, 1.08-3.4, P = .03), and volume of anti–human neutrophil antigen positive by granulocyte immunofluoresence test (OR = 1.71/100 mL, 95% CI, 1.18-2.5, P = .004). Little or no risk was associated with older red blood cell units, noncognate or weak cognate class II antibody, or class I antibody. Reduced transfusion of plasma from female donors was concurrent with reduced TRALI incidence: 2.57 (95% CI, 1.72-3.86) in 2006 versus 0.81 (95% CI, 0.44-1.49) in 2009 per 10 000 transfused units (P = .002). The identified risk factors provide potential targets for reducing residual TRALI.

AbstractAlthough current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet–dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.