Transfusion medicine

Transfusion therapy

Irradiation



Topic Completed: 6 July 2021

Minor changes: 6 July 2021

Copyright: 2020-2021, PathologyOutlines.com, Inc.

PubMed Search: Irradiation[TI] transfusion[TI]

Mamie Thant, M.D.
Jansen N. Seheult, M.B.B.Ch., B.A.O., M.Sc., M.S., M.D.
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Cite this page: Thant M, Seheult JN. Irradiation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedirradiation.html. Accessed December 3rd, 2021.
Definition / general
  • Irradiation of cellular blood components is required for certain transfusion recipients to prevent transfusion associated graft versus host disease (TA-GVHD), a rare but usually fatal transfusion related complication
  • Populations at risk for TA-GVHD include those with severe impairment in cellular immunity, as well as recipients of donations from blood relatives due to shared human leukocyte antigen (HLA) haplotypes that render the recipient unable to recognize donor T lymphocytes as foreign
Essential features
  • Transfusion associated graft versus host disease (TA-GVHD) is a rare but usually fatal complication of transfusion, with an estimated mortality rate that exceeds 80%
  • There are limited viable treatment options for TA-GVHD and therefore, prevention is required for recipients identified to be at risk for this complication
  • Irradiation of cellular blood components is currently the cornerstone of prevention of TA-GVHD
  • There are minimum dosage requirements for blood product irradiation in the U.S. (see Clinical features) and Europe
  • Irradiation can cause lipid peroxidation of red cell membranes and an increase in extracellular potassium levels, which may lead to clinical hyperkalemia in at risk recipients, such as neonates
Terminology
  • Human leukocyte antigen (HLA)
  • Transfusion associated graft versus host disease (TA-GVHD)
Pathophysiology
  • TA-GVHD
    • Due to engraftment and proliferation of viable T lymphocytes from the donor in the transfusion recipient
    • Transfused donor T lymphocytes in cellular blood components recognize the recipient's tissues as foreign
    • Recipient's immune system is unable to recognize the donor T lymphocytes as foreign, thereby allowing the donor mediated immune attack on the recipient's tissues, especially the skin, bone marrow and gastrointestinal tract, to continue unchecked
    • Risk of TA-GVHD increases with:
      1. Number of viable lymphocytes in a transfused component
      2. Severity of impairment of cellular immunity of the recipient
      3. Number of HLA alleles shared by donor and recipient
    • Signs and symptoms typically appear 10 - 14 days after the transfusion or even later in the case of neonates; this may result in delayed recognition
    • Organ system manifestations are generally similar to GVHD associated with allogeneic stem cell transplant, including fever, skin rash, hepatitis or hepatomegaly and enterocolitis with diarrhea
    • However, TA-GVHD is uniquely associated with pancytopenia, due to marrow aplasia, leading to its mortality rate > 90% from neutropenic sepsis (Transfus Med 2013;23:416, Transfusion 2007;47:1405)
    • Transfusion recipients at risk for TA-GVHD include:
      • Patients with severe congenital or acquired immunodeficiency states, e.g. severe combined immune deficiency (SCID), DiGeorge syndrome, hematopoietic stem cell transplant (HSCT) recipients
      • Patients being treated with purine analogues (fludarabine, clofarabine, bendamustine), antithymocyte globulin or alemtuzumab (anti-CD52 therapy)
      • Fetuses and neonates: includes fetuses receiving intrauterine transfusion, premature infants and neonates requiring red cell exchange, due to their underdeveloped cellular immunity and the risk of as yet unrecognized congenital immunodeficiency (Transfusion 2011;51:916)
      • Partially HLA matched blood products, where the recipient and the donor share some but not all HLA antigens (haplotypes)
      • Patients receiving transfusions from blood relatives (directed donations) in geographical areas with genetically homogeneous populations, e.g. Japan (AABB: Standards for Blood Banks and Transfusion Services, 30th Edition, 2016)
      • Universal irradiation may be considered, as in one study, 50% of TA-GVHD cases occurred in patients who would not be predicted to be at risk for TA-GVHD by current guidelines for blood irradiation (Blood 2015;126:406)
    • Lack of donor recipient HLA disparity can lead to TA-GVHD among immunocompetent individuals in the following situation: the donor is homozygous for an HLA haplotype but the recipient is heterozygous for that haplotype, leading to a one way haplotype match in which the recipient is unable to recognize the donor as foreign but the donor reacts to the recipient as foreign (Blood 2015;126:406)
    • Universal irradiation may be considered, as in one systemic review of TA-GVHD cases, 50% of cases occurred in patients who would not be predicted to be at risk for TA-GVHD by current guidelines for blood irradiation; although in the cases for which HLA data were available, the vast majority were found to involve donor antigens not recognized as foreign by the recipient (Blood 2015;126:406)
      • Japan is one nation that uses universal irradiation of cellular blood components due to previously high rates of TA-GVHD among immunocompetent patients who happened to share HLA haplotypes (Transfus Med 2000;10:315)
Clinical features
  • Due to the high mortality rate and limited viable treatment options, risk mitigation strategies for prevention of TA-GVHD are required
    • Irradiation
      • Irradiation leads to DNA damage and cell cycle arrest
      • Dosage studies have established the radiation dosages necessary to inactivate T cells in a cellular blood component without impairing granulocyte function (Blood 1994;83:1683, Transfus Med 1996;6:261)
    • Other potential preventive measures:
      • In vitro and animal models have shown that pathogen inactivation methods involving photoactive compounds (e.g. synthetic psoralens or riboflavin) that damage DNA when exposed to UV light, also inactivate T cells with an efficacy comparable to irradiation (Transfusion 2018;58:1506, Bone Marrow Transplant 2009;44:205)
      • However, to date, irradiation and pathogen inactivation have not been directly compared in a clinical trial
      • Leukoreduction is not considered an effective preventive measure, due to incomplete removal of viable T lymphocytes; however, there is some evidence that leukoreduction may reduce the risk of TA-GVHD compared with no preventive measure
      • Blood products that have been subjected to a freeze thaw cycle confer a significantly lower risk of TA-GVHD, due to inactivation of donor lymphocytes
        • These products include fresh frozen plasma (FFP), thawed plasma, plasma frozen within 24 hours after collection (PF24), cryoprecipitate or frozen and deglycerolized RBC components
        • In contrast, liquid plasma contains potentially viable T lymphocytes that may cause TA-GVHD in at risk recipients, since it has never been subjected to a freeze thaw cycle
  • Red cell and whole blood units have most commonly been implicated in TA-GVHD, although there have been instances of TA-GVHD from platelets (Blood 2015;126:406)
  • Adverse effects of radiation include damage to cell membranes, affecting overall product recovery and potassium leak, particularly in the case of red cells (Vox Sang 2014;106:379)
  • Due to concerns about hyperkalemia in neonates, many institutions perform additional processing of irradiated units intended for pediatric patients, including washing or transfusion of fresher red cell units (Transfusion 2008;48:2302)
  • Expiration date on irradiated red cell components is 28 days or its original expiration date, whichever is earlier
  • Extracellular potassium concentration in the blood component increases with longer storage of the component postirradiation (Vox Sang 2015;108:141)
Symptoms
  • TA-GVHD typically presents 10 - 14 days after transfusion and is associated with fever, a maculopapular rash, diarrhea, hepatitis and occasionally jaundice
Screening
  • There is no specific investigation that detects whether a patient is at risk of TA-GVHD
Laboratory
  • Diagnosis of TA-GVHD is based primarily on characteristic clinical findings, although laboratory studies and tissue or bone marrow biopsy may be useful
    • Complete blood count (CBC) and differential will show pancytopenia
    • Peripheral blood smear will show decreases in all cell lineages with normal cellular morphology and should be reviewed to exclude other causes of acute onset pancytopenia, such as a thrombotic microangiopathy (red cell schistocytes), acute hematologic malignancy (blasts), Evan syndrome (red cell spherocytes, with or without larger platelets)
    • Skin or liver biopsy will show characteristic histological findings of GVHD:
    • Molecular studies showing leukocyte chimerism (dual populations of donor and recipient lymphocytes) establish imputability of the diagnosis based on NHSN criteria (Transfus Med 2013;23:416, CDC: National Healthcare Safety Network Biovigilance Component Hemovigilance Module Surveillance Protocol [Accessed 18 January 2021])
    • Bone marrow biopsy is not required for diagnosis but will show severe hypoplasia or aplasia; the presence of increased blasts, increased fibrosis or dysplasia may suggest alternative etiologies of the pancytopenia
  • Blood bank / transfusion services considerations
    • Sources of radiation include gamma rays from either a cesium-137 or cobalt-60 source or Xrays
    • In the U.S., the requirements for the minimum radiation dose are
    • A radiation sensitive label is applied to the blood product prior to irradiation, with the words NOT IRRADIATED visible (see Clinical images)
    • After an appropriate dose has been administered to the container, only the word IRRADIATED remains visible (see Clinical images)
    • Irradiators are regulated by the FDA as part of their oversight of biological products, including blood and blood components
    • In the U.S., increased security measures are required around gamma irradiators to protect against unauthorized access to radioactive materials; this does not apply to Xray irradiators (U.S. NRC: Radioactive Material Security [Accessed 18 January 2021])
    • FDA has released recommendations regarding the gamma irradiation of blood products available through their website, including recommendations regarding maintenance of standard operating procedures, dosage delivery validation and labeling (FDA: Gamma Irradiation of Blood Products [Accessed 25 May 2021])
    • Verification of dose delivery to a fully loaded canister should be performed annually for cesium-137 as a radiation source and semiannually for cobalt-60 as a radiation source; the frequency of dose delivery verification for alternate radiation sources is per the manufacturer
    • National Nuclear Security Administration has incentivized voluntary replacement of cesium irradiators with FDA approved nonradioactive Xray irradiators through the Cesium Irradiator Replacement Project (National Nuclear Security Administration: Office of Radiological Security [Accessed 25 May 2021])
Case reports
  • 13 day old boy with familial hemophagocytic lymphohistiocytosis and development of TA-GVHD, with supportive skin biopsy after receiving a nonirradiated red cell unit (J Pediatr Hematol Oncol 2017;39:e309)
  • 7 month old boy developed pneumococcal sepsis and subsequent TA-GVHD, manifested by skin rash and supported by chimerism studies and was later found to have combined immunodeficiency (Transfusion 2010;50:2484)
  • 42 year old woman with refractory lupus nephritis who developed TA-GVHD from treatment with fludarabine and cyclophosphamide, resulting in profound myelosuppression (Transfusion 2003;43:1667)
  • 59 year old man who received multiple units of nonirradiated red blood cells for a gastrointestinal bleed, then subsequently developed TA-GVHD in the setting of multifactorial immune suppression, with chimerism showing shared HLA haplotype with a blood donor (Transfusion 2013;53:174)
Treatment
  • Treatment for TA-GVHD is largely palliative; prevention is essential
  • A systematic review that included 348 cases of TA-GVHD showed a marginal survival benefit with hematopoietic stem cell transplant (HSCT) and immunosuppression (Blood 2015;126:406):
    • HSCT is usually not considered a viable option, due to time limitations in identifying a potential donor
    • Immunosuppressive agents that have been considered as therapeutic options include corticosteroids, cyclosporine, intravenous immune globulin (IVIG) and antithymocyte globulin (ATG) and antilymphocyte globulin (ALG)
Clinical images

Images hosted on other servers:
Gamma irradiation indicator (before and after)

Gamma irradiation
indicator (before
and after)

Xray irradiation indicator (before and after)

Xray irradiation indicator (before and after)

Sample assessment & plan
  • Assessment: A 75 year old man presented to a local emergency department in an obtunded state after sustaining major bleeding in a motor vehicle accident. He received 5 units of emergency released, uncrossmatched packed red cells. It was subsequently discovered that the patient had received a kidney transplant at another institution, which was complicated by acute rejection requiring antithymocyte globulin (ATG) treatment. 14 days into his hospitalization for the motor vehicle accident, he developed a fever and a diffuse, erythematous, bullous skin rash. Complete blood count (CBC) revealed pancytopenia, including an absolute neutrophil count less than 100 cells/mm³ and a review of prior records showed that his CBCs had previously been normal. Bone marrow biopsy revealed a severely hypocellular marrow (10% cellularity). The patient then developed septic shock with multiorgan failure and blood cultures were positive for Candida albicans.
  • Plan: This patient's presentation is concerning for transfusion associated graft versus host disease (TA-GVHD). His treatment with antithymocyte globulin as well as his advanced age put him at risk for impaired cellular immunity. To cement the diagnosis, the patient's skin rash should be biopsied. In addition, chimerism studies of the patient's CD3+ cells can be performed. If his CD3+ cells are homozygous for a certain HLA haplotype and the patient is heterozygous for that haplotype, this supports a one way HLA match that would further increase his risk for TA-GVHD.
Differential diagnosis
  • Acute infection:
    • Can lead to transient myelosuppression with rash, especially in the case of a viral infection; however, severe neutropenia is generally not observed
  • Drug reaction:
    • Fever, rash and other systemic symptoms may be seen in drug reaction with eosinophilia and systemic symptoms (DRESS)
    • Most patients recover in weeks to months after drug withdrawal
  • Aplastic anemia:
    • Presentation tends to be subacute / chronic and review of prior CBCs shows progressive worsening of cytopenias
    • Hypocellularity of bone marrow, which may show features of dysplasia in MDS-AA overlap
    • Peripheral blood flow cytometry may show a paroxysmal nocturnal hemoglobinuria (PNH) clone
  • Acute leukemia:
    • Can lead to pancytopenia, although skin involvement is rare (localized skin eruptions can be seen in leukemia cutis)
    • Bone marrow biopsy shows infiltration by malignant blasts
Board review style question #1
What is the best way to mitigate the risk of transfusion associated graft versus host disease (TA-GVHD) in a 12 year old boy receiving granulocytes for a disseminated fungal infection during induction therapy for acute leukemia?

  1. Leukoreduction
  2. Freeze thaw
  3. Gamma irradiation with no more than 20 gray (Gy) delivered to the midline of the blood container
  4. Gamma irradiation with at least 25 gray (Gy) and no more than 50 Gy delivered to the midline of the blood container
  5. Risk mitigation is not required since this patient is not at risk for TA-GVHD
Board review style answer #1
D. Gamma irradiation with at least 25 gray (Gy) and no more than 50 Gy delivered to the midline of the blood container

Comment Here

Reference: Irradiation
Board review style question #2
A 1 day old baby born at 36 weeks gestation requires a red cell exchange for hyperbilirubinemia due to hemolytic disease of the fetus and newborn. To maximize safety, which of the following packed red blood cell products will be ideal for this patient?

  1. Leukoreduced pRBC with a negative screen for sickle cells
  2. Leukoreduced pRBC with a negative screen for sickle cells that was irradiated 15 days ago
  3. Leukoreduced pRBC with a negative screen for sickle cells that is irradiated just prior to issuing from the blood bank
  4. No special processing is needed since this patient is not at risk for TA-GVHD
Board review style answer #2
C. Leukoreduced pRBC with a negative screen for sickle cells that is irradiated just prior to issuing from the blood bank

Comment Here

Reference: Irradiation
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