Wednesday, June 11, 2014

TRIMming Transfusions

The Gist:  Transfusions aren't benign and Transfusion Related Immunomodulation (TRIM) may play a role in complications associated with transfusions.  Data suggest that allogenic blood transfusions (ABTs) may have immunosuppressive properties [1-6]. Yet, TRIM is a vague controversial entity without easily identifiable clinical markers or pathogenesis and is predominantly based on observational and animal data [3,8].   Keep this entity in mind, not withholding blood products when indicated, but when contemplating the risks and benefits for those patients with borderline indications.  Give the patient all the blood they need, but not one drop more.

Free Open Access Medical education (FOAM) sources have increasingly mentioned this entity, TRIM, over the past few years, including this recent Maryland Critical Care Project podcast.  On a recent FOAMcastwe reviewed the core content associated with adverse effects of transfusions; yet, we did not encounter TRIM overtly in the review of Rosen's and Tintinalli.  Thus, I needed to find out more about this entity I had only learned about through podcasts.

TRIM has not made its way into many classrooms, likely secondary to the lack of understanding of the clinical significance and etiology of TRIM.  The development of pneumonia in the weeks following a transfusion is more difficult to attribute to a single etiology than a hemolytic reaction occurring during the transfusion.  Furthermore, much of the data are observational are observational and animal based with uncertain clinical implications.  As we see transfusion triggers decrease with equivalent or superior outcomes, it may be helpful to keep an eye on TRIM and, when we are tempted to transfuse individuals who are just above the transfusion threshold or give 2 units of red cells empirically, recall that blood product transfusions are actually transplants.  Perhaps we should have the same obsession with transfusions as we do fluid responsiveness summed up eloquently in the words of Dr. Paul Marik, "give that patient all the fluid they need, but not one drop more."

Clinical effects attributed to TRIM

Increased risk of infection
  • Contamination of blood products with infectious particles is not common and ranges from 1 in 1-3 million for HIV and hepatitis C, to 1 in 2000 for bacteria in platelets [11].  Studies, including the recent JAMA meta-analysis by Rhode et al, demonstrate more infections in individuals with higher transfusion targets.  Thus, some postulate that the increase in infections is a result of the immunomodulatory effects of transfusions. 
Tumor growth/Cancer - The roots of this notion, particularly an association with lymphoma, lie in retrospective and observational studies [6]
  • Randomized controlled trials (RCTs) looking at leukoreduced blood products did not demonstrate an increase in cancer  [1,2,6]
Multi-organ failure - this is one of the effects we care about most clinically and studies of various quality demonstrate an association between multi-organ failure/short-term mortality and transfusion [1].
  • Studies confounded by the underlying severity of illness of the patients, which itself predisposes the patients to multiorgan failure. 
  • The most consistent effects of TRIM are in RCTs involving cardiac surgery patients [1]
Improved survival in renal transplants - In the 1970's, patients awaiting renal transplants were given one or more ABT, leading to increased graft survival [1].
  • Immunosuppressive pharmaceuticals such as cyclosporine have replaced this practice.
Decreased spontaneous abortions [2]

Pathophysiology of TRIM -   These are postulated theories and associations since the exact etiology isn't clear.  Texts tend to agree that TRIM is the result of a complex inflammatory and immunosuppressive happenings that may result from downregulation of cellular immunity, induction of humoral immunity, and altered inflammatory responses. TRIM may depend on:

Degree of contamination of transfused blood with leukocytes - this is one of the reasons the FDA recommends leukoreduction of all blood [12].  Transfusions with leukoreduced blood have demonstrated varying results.
  • The beneficial effects of TRIM have been attributed to donor dendritic cells (or Allogeneic Mononuclear Cells - AMCs), which may invoke a tolerance among recipient cells and downregulate T cells.
  • Leukocytes release reactive oxygen species and proteolytic chemicals that may cause an inflammatory cascade and tissue injury [1].
  • Not the the sole culprit as trials in which one group received leukoreduced blood do not consistently demonstrate a difference [2].
Soluble components or "mediators" - This includes things like histamine, cytokines, and proteins in the plasma or released from the white cell membranes and granules are released upon degradation.  Also, there's some thought that plasma contains soluble class I HLA molecules, which may be partially responsible.
  • These "soluble mediators" may inhibit proper T cell function and ability of neutrophils to work properly [1].  
  • Higher levels of cytokines such as IL-10 have been demonstrated in patients receiving more blood in the peri-operative period.  It's theorized that these cytokines, whether they're generated by the recipient in response to a stimulus or from the donor, play an immunosuppressive effect [7].
  • However, filtration of these products before storage has not demonstrate a difference in "TRIM effects" (OR 1.06 (0.91-1.24)p>0.05), indicating that these are not the sole mediator of TRIM [2]. 
Storage time - This is not an exact etiology but may amplify the effects of the above proposed mediators.  This is purported secondary to the release of soluble mediators during storage of blood products.  Some studies have found increased infection, morbidity, or mortality with older red blood cells (RBCs) but the totality of the literature is inconclusive. Most of the studies have small numbers, have differing definitions of "old" RBCs, and are retrospective or observational in nature; however, results from the RCTs ABLE and RECESS may clarify [13].
  • Leukocytes degrade during the first two weeks of storage and release chemicals called soluble mediators.  RCTs that filtered leukoreduced and non-leukoreduced blood still demonstrated an increased incidence of infection in the non-leukoreduced blood (OR 2.25 (1.12-4.25) p<0.05) [2]
  • Free Iron - blood undergoes a degree of hemolysis during prolonged storage, freeing iron which is biologically reactive.   
So, we're not sure precisely what TRIM is, whether TRIM is clinically significant, or what may cause TRIM.  The bottom line is that transfusions likely have effects beyond what we currently understand, so it is prudent to treat this type of transplant with respect.

1. Vamvakas EC, Blajchman MA. Transfusion-related immunomodulation (TRIM): an update. Blood Rev. 2007;21(6):327–48. 
2. Blajchman MA, Vamvakas EC.  (2009).  Transfusion-related immunomodulation In Pamphilon DH (ed). Practical Transfusion Medicine (pp. 98-106).  Blackwell Publishing
3. Zimring JC, Nester T.  (2013). Transfusion Related Immunomodulation In Shaz BH (ed.) Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects, Elsevier Science, Chapter 69.
4.  Chen W, Lee S, Colby J, et al.The impact of pre-transplant red blood cell transfusions in renal allograft rejection. Rockville, MD, USA: Agency for Healthcare Research and Quality. Technology Assessment Report; Project ID RENT0610; 2012.
5. Scornik JC, Bromberg JS, Norman DJ et al. An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survivalBMC Nephrology 2013, 14:217 
6. Gilliss BM, Looney MR, Gropper MA. Reducing noninfectious risks of blood transfusion. Anesthesiology. 2011;115(3):635–49. 
7. Theodoraki K, Markatou M, Rizos D, et al. The impact of two different transfusion strategies on patient immune response during major abdominal surgery: a preliminary report. J Immunol Res. 2014;2014:945829. 
8.  Geiger T. Transfusion-associated immune modulation: a reason to TRIM platelet transfusions? Transfusion. 2008 Sep;48(9):1772-3.  doi: 10.1111/j.1537-2995.2008.01860.x.
9. Rohde JM, Dimcheff DE, Blumberg N et al. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014 Apr 2;311(13):1317-26. 
10. Sparrow RL. Red blood cell storage and transfusion-related immunomodulation. Blood Transfus. 2010;8 Suppl 3:s26–30.
11.Hillyer CD, Josephson CD, Blajchman CJ et al.  Bacterial Contamination of Blood Components: Risks, Strategies, and Regulation.  ASH Education Book January 1, 2003 vol. 2003 no. 1 575-589
12. Food and Drug Administration.   Guidance for Industry: Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion. U.S. Department of Health and Human Services, Center for Biologics Evaluation and Research.  September 2012
13.Aubron et al. Age of red blood cells and transfusion in critically ill patients.  Annals of Intensive Care 2013, 3:2


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  2. Here's a recent review with a different point of view from some cited.

    Lannan KL 1 ,
    Sahler J ,
    Spinelli SL ,
    Phipps RP ,
    Blumberg N
    Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
    Blood Cells, Molecules & Diseases [2013, 50(1):61-68]
    Type: research-article, Journal Article, Review, Research Support, N.I.H., Extramural
    DOI: 10.1016/j.bcmd.2012.08.009
    During the last three decades, a growing body of clinical, basic science and animal model data has demonstrated that blood transfusions have important effects on the immune system. These effects include: dysregulation of inflammation and innate immunity leading to susceptibility to microbial infection, down-regulation of cellular (T and NK cell) host defenses against tumors, and enhanced B cell function that leads to alloimmunization to blood group, histocompatibility and other transfused antigens. Furthermore, transfusions alter the balance between hemostasis and thrombosis through inflammation, nitric oxide scavenging, altered rheologic properties of the blood, immune complex formation and, no doubt, several mechanisms not yet elucidated. The net effects are rarely beneficial to patients, unless they are in imminent danger of death due to exsanguination or life threatening anemia. These findings have led to appeals for more conservative transfusion practice, buttressed by randomized trials showing that patients do not benefit from aggressive transfusion practices. At the risk of hyperbole, one might suggest that if the 18th and 19th centuries were characterized by physicians unwittingly harming patients through venesection and bleeding, the 20th century was characterized by physicians unwittingly harming patients through current transfusion practices. In addition to the movement to more parsimonious use of blood transfusions, an effort has been made to reduce the toxic effects of blood transfusions through modifications such as leukoreduction and saline washing. More recently, there is early evidence that reducing the storage period of red cells transfused might be a strategy for minimizing adverse outcomes such as infection, thrombosis, organ failure and mortality in critically ill patients particularly at risk for these hypothesized effects. The present review will focus on two approaches, leukoreduction and saline washing, as means to reduce adverse transfusion outcomes.