RBCs, TRALI and Lipids: A role for Lipo reduction?

Since transfusion-related acute lung injury (TRALI) emerged as the leading cause of transfusion associated mortality, considerable effort has been spent to better understand the pathophysiology of TRALI and reduce its incidence. Many donor and product factors have been found to be involved with the pathogenesis of TRALI associated with the transfusion of platelet and plasma components, but TRALI due to the transfusion of RBC components has been more difficult to explain since RBC components prepared in additive/preservative solutions contain very little plasma. TRALI associated with RBC component transfusions is especially important because the large number of RBC transfusions result in an absolute number of TRALI cases approaching the total seen with plasma and platelet transfusions. The manuscript by Silliman et al in this issue of Transfusion, describes novel factors that accumulate during RBC storage which may help to explain how TRALI is caused by RBC transfusion.¹

TRALI is far more likely to occur following the transfusion of platelet concentrates and plasma products than RBC components.^2,3 This is likely due to the marked difference in the quantity of plasma in platelet and plasma components compared to RBC components stored in additive/preservative solutions. Many studies have shown that the transfusion of leukocyte antibodies in the plasma contained in the platelet and plasma components are an important cause of TRALI. Case-control studies have confirmed that TRALI is more likely to occur in recipients transfused with greater quantities of plasma or plasma-containing blood components.⁴ In addition, the transfusion of plasma and platelets from multiparous women is more likely to cause TRALI than is plasma from other donors, implying that alloimmunization is an important factor in the pathogenesis of TRALI.^3,5 Other case-control studies have found that the transfusion of platelet and plasma components from donors with antibodies directed to HLA Class II and neutrophil-specific antigens are more likely to develop TRALI.⁵ In addition, a recent multicenter retrospective cohort study has found a higher incidence of TRALI in recipients of components from donors with HLA antibodies than in recipients of control components, but the difference did not reach statistical significance.⁶

Factors related to the storage of platelet components can also cause TRALI. A platelet-derived proinflammatory factor, soluble CD40 ligand (sCD40L), accumulates in stored platelets, primes neutrophils and induces neutrophil-mediated damage to endothelial cells.⁷ A case-control study found that platelet components implicated in TRALI have greater levels of sCD40L than control components.⁷ However, sCD40L accumulates in non-leukocyte-reduced RBC components, but not in leukocyte-reduced RBC components, since leukocyte reduction filters also remove platelets.⁷

Many studies have shown that lipids accumulated during the storage of platelet and non-leukocyte-reduced RBC components prime neutrophils, are associated with TRALI, and induce lung injury in different animal models.^8–14 Lysophosphatidylcholines (lyso-PCs) accumulate during the storage of cellular blood components.^8,15 These lyso-PCs prime neutrophils so that they respond more robustly to activating stimuli or they are activated by stimuli that would normally not activate neutrophils. When animals are pretreated with lipopolysaccharide (LPS) the transfusion of plasma containing lyso-PCs results in acute lung injury.¹¹

It is difficult to know how frequently lyso-PCs and sCD40L are associated with TRALI because testing for these agents is not widely available to transfusion services or blood centers and samples from implicated units are not always available for testing. No doubt, lyso-PCs and sCD40L are responsible for some cases of TRAL due to the transfusion of platelet components. However, neither lyso-PCs nor sCD40L accumulates in RBC components that have been leukocyte-reduced. In addition, leukocyte-reduced RBC concentrates stored in additive solutions contain very little plasma so leukocyte antibodies are likely a much less important cause of TRALI for RBC components then for platelet and plasma components. A recent study found that the transfusion of RBC components from female donors is no more likely to cause TRALI than the transfusion of RBC components from male donors.³ Still, despite the absence of these TRALI initiating factors in leukocyte-reduced RBC components, the transfusion of leukocyte-reduced RBC components are well-documented as a cause of TRALI.^2,3

In this issue of Transfusion, Silliman and colleagues report that non-polar lipids accumulate in stored leukocyte reduced RBC components.¹ These non-polar lipids include arachidonic acid, hydroxyeicosatetranoic acid (HETE), 12-HETE and 15-HETE. Like lyso-PC, non-polar lipids prime neutrophils and can cause acute lung injury in rats primed with LPS. Silliman and collegues found that non-polar lipids are elevated in RBC components after 14 days of storage, reach higher levels by 28 days but then remain relatively stable until day 42. These findings are tantalizing and potentially important, but the role of non-polar lipid as a cause of TRALI needs to be confirmed by clinical studies. As a first step, case-control studies are needed to determine if RBC components that have been associated with TRALI have higher levels of non-polar lipids than control components. Other issues that should be addressed include what proportion of TRALI cases are due the transfusion of RBC components with high levels of non-polar lipids. What concentration of non-polar lipid in stored RBC components places transfusion recipients at risk for TRALI? How many days can RBCs components be stored before non-polar lipids reach concentrations sufficient to place a recipient at risk for TRALI? Is the rate of accumulation of non-polar lipids affected by the RBC storage solution and conditions?

Although the per unit risk of TRALI associated with RBC component transfusions is much lower that the risk associated with the transfusion of either platelet or plasma components, far more RBC components are transfused worldwide than platelet or plasma components and the incidence of TRALI due to RBC transfusions is similar to the incidence of TRALI due to platelet or plasma transfusions.² As a result it is important to better understand the mechanisms by which RBC components cause TRALI if we are to modify the component or its use to reduce this risk. While the report by Silliman is an important advancement in the field, more work is needed. Work by Vlaar et al recently published in Transfusion found that the production of lyso-PC by platelets and RBC components requires the presence of plasma, and lyso-PC levels accumulate more rapidly at 22°C compared to 4°C.¹⁶ They did not specifically study non-polar lipids, but these results suggest that RBC storage conditions could also affect the accumulations of lipids in RBC components. Others have hypothesized that RBC microparticles in stored blood components may mediate TRALI by fixing complement and IgG which activates neutrophils via the Fc receptors of neutrophils.¹⁷

The blood banking and transfusion medicine communities have had increasing success in reducing the risk of TRALI associated with the transfusion of plasma and platelet components. If accumulation of lipids during RBC storage turns out to increase the risk of TRALI, perhaps measures to prevent or reduce lipids might yield a safer and better component. Measures directed at RBC “lipo reduction” (or better yet, prevention), might result in better and safer RBC transfusions.