Transfusion medicine

Transfusion reactions & complications

Transfusion related immunomodulation (TRIM)



Last staff update: 6 March 2024 (update in progress)

Copyright: 2024, PathologyOutlines.com, Inc.

PubMed Search: Transfusion related immunomodulation

Devon D. Mahoney, M.D.
Evelyn M. Potochny, D.O.
Page views in 2024 to date: 52
Cite this page: Mahoney DD, Potochny EM. Transfusion related immunomodulation (TRIM). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedtrim.html. Accessed March 29th, 2024.
Definition / general
  • Transfusion related immunomodulation (TRIM) refers to the capability of transfused allogeneic blood products to interact with and impact recipient immune cell function
  • Immunosuppressive or proinflammatory effects of transfusion have the potential to negatively impact patient outcomes
Essential features
  • Existence and extent of the impact of TRIM is somewhat controversial
  • Leukoreduction is a key strategy to mitigate TRIM effects
    • However, TRIM has also been documented despite leukoreduction and may occur in a leukocyte independent manner
  • Potential adverse effects related to TRIM include increased risk for infection, organ dysfunction and recurrence or progression of cancer
    • Positive impacts, such as lower rejection rates of transplanted organs, have also been described
Terminology
  • Immunomodulation by blood transfusions
  • Immunomodulatory effects of blood transfusions
  • Transfusion associated immunomodulation
Pathophysiology
  • There are many proposed mechanisms by which donor blood products may interact with the recipient's immune system (Transfusion 2018;58:804)
  • White blood cell mediated
    • Donor antigen presenting cells expressing major histocompatibility complex (MHC) II molecules interact with recipient lymphocytes
      • Engagement of recipient T cells without costimulatory signals leads to antigen specific anergy and shifts to immunosuppressive T helper type 2 (Th2) type response
    • Donor white blood cells (WBCs) undergoing apoptosis during collection or storage
      • Exposes phosphatidylserine on dying cell membranes, which interacts with recipient immune cells
        • Recipient immune cells generate immunosuppressive signals (i.e., increased IL10 and TGFβ)
    • Donor WBCs producing soluble mediators including cytokines, degranulation products, soluble human leukocyte antigen (HLA) molecules
      • May induce recipient immune cell apoptosis, impair chemotaxis, decrease natural killer (NK) cell activity
  • Red blood cell mediated
    • Hemolysis during storage and transfusion leading to release of metabolic wastes, microparticles, free iron and free heme
      • Upregulation of proinflammatory cytokines
      • Bias of macrophage phenotype from inflammatory M1 to immunosuppressive M2
    • While it has been proposed that longer storage duration of red blood cell units may increase these effects, studies to date have not supported the clinical impact of longer red blood cell storage in the general population (N Engl J Med 2016;375:1937)
  • Platelet mediated
    • In vitro work has suggested platelet derived microparticles are capable of immune system modulation
    • In vivo contribution is unknown
  • Bioactive lipid mediated
    • Polyunsaturated fatty acids (arachidonic acid, linoleic acid, etc.) remain in blood products after leukoreduction
      • In vitro studies have demonstrated a capability to prime neutrophils
      • Rat models transfused with these lipids have shown transfusion related lung injury-like effects
    • In vivo contribution is unknown
  • Extracellular vesicle mediated
    • In vitro studies have demonstrated a variety of proinflammatory and immunosuppressive interactions with monocytes, macrophages and neutrophils
    • In vivo contribution is unknown
Clinical features
  • Critically ill patients and patients with cancer may be at increased risk for complications of TRIM due to already dysregulated immune signaling (Sci Rep 2018;8:10186)
  • Studies reporting seemingly paradoxical proinflammatory and immunosuppressive impacts from transfusion could be explained by recipient specific and contextual influences at the time of transfusion
    • Immune response to critical illness is dynamic
Transmission
  • Mononuclear cells and soluble mediators from white blood cells in nonleukoreduced allogeneic blood products
    • Leukoreduction reduces the quantities of these but some residual white blood cells remain
    • Soluble mediators also may persist despite removal of white blood cells
  • Effect is still demonstrable in leukoreduced units and may be due to contributions from red blood cells, platelets, bioactive lipids and extracellular vesicles
  • Reference: Best Pract Res Clin Anaesthesiol 2023;37:495
Symptoms
Laboratory
  • No specific findings
  • In vitro features of an inappropriately paralyzed immune response to critical illness may be present (Transfusion 2017;57:195)
    • Downregulated monocyte HLA-DR expression
    • Reduced ex vivo production of TNFα in response to lipopolysaccharide (LPS) challenge
    • Lymphocyte hyporeactivity with decreased IFNγ production in response to phytohemagglutinin or anti-CD3
  • Can see changes related to complications of TRIM, such as infection or organ dysfunction
Case reports
  • 9 year old boy with acute lymphoblastic leukemia (ALL), frequent blood transfusions and endogenous fungal endophthalmitis (BMC Ophthalmol 2011;11:30)
Treatment
  • Leukoreduction of blood components is a key mitigation strategy
  • Treatment of complications, such as infection or cancer progression, as otherwise clinically indicated
Sample assessment & plan
  • Assessment:
    • The patient is a 16 year old girl with osteosarcoma undergoing chemotherapy admitted with symptomatic anemia. She received 2 units of nonleukoreduced packed red blood cells. Within 72 hours of the transfusion, she developed a fever (39 °C), lactic acidosis and hypotension requiring vasopressor support. Despite aggressive antibiotic therapy, she developed acute kidney injury and hypoxic respiratory failure requiring ventilator support. Blood cultures are positive for fungal organisms.
  • Impression:
    • Multiple organ dysfunction from sepsis induced systemic inflammation and mitochondrial energy failure. Contributing factors including transfusion related immunomodulation from recent blood transfusion.
  • Plan:
    • Restrictive transfusion strategy with leukoreduced units
    • Antibiotics and supportive care
Differential diagnosis
  • Contributions solely from underlying disease
Board review style question #1
Which of the following modifications to blood products can help to reduce the risk of nosocomial infection development due to immunosuppression after allogeneic blood transfusion in the critically ill?

  1. Concentration of units
  2. Human leukocyte antigen (HLA) matching
  3. Leukoreduction
  4. Washing
Board review style answer #1
C. Leukoreduction. Leukoreduction is a key strategy to mitigate transfusion related immunomodulation (TRIM) effects. Answers D and A are incorrect because while washing and concentration will remove residual plasma from units and may decrease residual soluble mediators found in the plasma, leukoreduction has been associated with a multifold reduction in the quantity of immunosuppressive interleukins posttransfusion. Answer B is incorrect because HLA matching will not reduce the risk of TRIM.

Comment Here

Reference: Transfusion related immunomodulation (TRIM)
Board review style question #2
Which of the following has been implicated as a mechanism of transfusion related immunomodulation (TRIM)?

  1. Downregulation of cytokines
  2. Intracellular vesicles
  3. Neutrophil priming via bioactivated lipids
  4. Upregulation of serotonin
Board review style answer #2
C. Neutrophil priming via bioactivated lipids. Neutrophil priming via bioactivated lipids is one of several mechanisms thought to lead to TRIM. Answer A is incorrect because upregulation of cytokines has been implicated in TRIM. Answer B is incorrect because extracellular vesicles, not intracellular, have been implicated in TRIM. Answer D is incorrect because upregulation of serotonin has not been associated with TRIM.

Comment Here

Reference: Transfusion related immunomodulation (TRIM)
Back to top
Image 01 Image 02