Transfusion medicine
Transfusion therapy
Pathogen inactivation

Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Samantha Phou, M.D.
Patricia Kopko, M.D.

Minor changes: 23 November 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Pathogen inactivation[TI] transfusion[TIAB]

Samantha Phou, M.D.
Patricia Kopko, M.D.
Page views in 2019: 13
Page views in 2020 to date: 65
Cite this page: Phou S, Kopko P. Pathogen inactivation. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/transfusionmedpathogeninactivation.html. Accessed November 23rd, 2020.
Definition / general
  • Treatment of blood products that inactivate or reduce the communicability of infectious agents to reduce the risk of transfusion transmitted infections
  • Different technologies are currently used for plasma and platelets with varying usage and approval in different countries
  • Pathogen reduction of platelets on the rise in the U.S.
Essential features
  • Treatment of blood products that inactivate or reduce the communicability of infectious agents
  • Effective against a broad range of pathogens, including bacteria, viruses and parasites but not completely effective against all pathogens, based on factors such as pathogen concentration, species and spore formation
  • Inactivates leukocytes
  • Currently, used only on platelets and plasma products
  • Pathogen reduction technologies currently approved in the U.S.:
    • INTERCEPT for platelets and plasma
    • Solvent / detergent treated pooled plasma
Terminology
  • Leukoreduction is also known as leukofiltration
  • Pathogen inactivation is used synonymously with pathogen reduction
  • No current technology is able to completely eliminate the risk of pathogen contamination
  • Effectiveness of pathogen reduction depends on factors such as pathogen concentration and species / strain (Transfus Apher Sci 2018;57:683)
Pathophysiology
  • Leukoreduction
    • Removal of leukocytes from blood products
    • Filtration based method
    • Filters remove leukocytes by pore size and charge exclusion
    • Filtration can be performed either in line as part of a blood collection kit or after collection with gravity based filters
    • Leukoreduction can be performed prestorage, in the transfusion service or at the beside of the transfusion recipient (poststorage)
      • Prestorage leukoreduction preferred as this prevents donor leukocytes from releasing cytokines during storage (Oncotarget 2017;9:4385)
    • Most apheresis collection devices have built in leukoreduction mechanisms
    • Red blood cells, whole blood and apheresis derived platelets must contain < 5 x 106 leukocytes to be considered leukoreduced per FDA requirements
    • Whole blood derived platelets must contain < 8.3 x 105 leukocytes to be considered leukoreduced
    • Red blood cell loss from filtration must not exceed 15% (at least 85% recovery of original red blood cells)
    • Platelet loss in whole blood derived platelets must not exceed 15% and 75% of units must have a minimum of 5.5 x 1010 platelets
    • Leukoreduction reduces the risk of transmission of leukocyte associated viruses
    • Leukoreduced products are considered cytomegalovirus safe, which is considered equivalent to cytomegalovirus seronegative (Transfusion 2016;56:1581)
    • Sickle cell trait (hemoglobin AS) can cause leukoreduction failure due to filter obstruction (Transfus Med Rev 2004;18:168)
    • Granulocytes should never be leukoreduced
  • Solvent / detergent plasma
    • Pooled plasma is treated with solvent / detergent that disrupts lipid bilayers of cell membranes and lipid envelopes
    • Plasma is filtered both before and after solvent / detergent treatment to remove cells, cell fragments, bacteria and debris
    • Effective against bacteria, protozoa and enveloped viruses (including hepatitis B virus, hepatitis C virus and HIV) (Vox Sang 1998;74:207)
    • Not used in cellular products including platelets since solvent / detergent directly damages cell membranes
    • Likely reduces the risk of transfusion related acute lung injury (TRALI) as the use of pooled plasma dilutes antibodies implicated in TRALI pathogenesis compared to a single donor derived unit of plasma (Transfusion 2005;45:1628)
    • Octoplas, a commercially available frozen solution of solvent / detergent treated pooled plasma, is FDA approved in the U.S.
  • INTERCEPT Blood System
    • Amotosalen, a synthetic psoralen compound, is added to the blood component followed by illumination with UVA light
    • Photoactivated amotosalen forms covalent bonds with nucleic acids and intercalates between nucleotide bases, preventing nucleic acid replication
    • Residual amotosalen and photoproducts are then absorbed and removed
    • Effective against a broad spectrum of bacteria, viruses, protozoa and leukocytes
    • Varying levels of effectiveness on nonenveloped viruses with no inactivation of hepatitis A virus or parvovirus
    • Not effective against bacterial spores
    • Licensed in the U.S. and Canada for use with plasma and platelets
  • Mirasol Pathogen Reduction Technology
    • Riboflavin (vitamin B2) is added to the blood component and exposed to UVA and UVB light
    • Riboflavin associates with nucleic acids and generates reactive oxygen intermediates, leading to irreversible modification and damage of nucleic acids
    • No need for removal of riboflavin after illumination
    • Effective against both enveloped and nonenveloped viruses, protozoa, a broad range of bacteria and leukocytes (Transfus Med Hemother 2011;38:8)
    • Has shown reduced efficacy against certain bacterial species such as Staphylococcus aureus (Vox Sang 2014;107:254)
    • Has not been evaluated for inactivation of bacterial spores
    • Licensed in Europe for use with plasma and platelets
  • Theraflex methylene blue (Theraflex MB)
    • Methylene blue, a phenothiazine dye, is added to plasma
    • Methylene blue directly binds to nucleic acids
    • Subsequent illumination with visible light leads to oxidative damage of nucleic acids, preventing nucleic acid replication
    • After treatment, methylene blue and photoproducts are removed via filtration
    • Effective against a broad range of viruses; however, no effect on hepatitis A virus (Transfus Med Hemother 2011;38:55)
    • Primarily used to inactivate viruses but has shown some efficacy against bacteria, including spore forming bacteria (Vox Sang 2015;109:129)
    • Licensed in Europe for use with plasma
Clinical features
  • Benefits of pathogen inactivation
    • Reduces risk of transfusion transmitted infections
      • Potential to decrease transmission of emerging infectious agents
    • Leukoreduction also decreases the risk of
    • INTERCEPT can replace cytomegalovirus testing or irradiation for transfusion associated graft versus host disease prevention
    • Mirasol can replace irradiation for transfusion associated graft versus host disease prevention
    • Currently, technologies are used for platelets and plasma with more rapid implementation for platelets in the U.S. given the increased risk of sepsis with platelets due to room temperature storage
  • Cons of pathogen inactivation
    • Possible decreased effectiveness of blood product
      • Leukoreduction can lead to red blood cell and platelet loss, which may not exceed 15% per FDA requirements
      • Low to moderate loss of platelet function in vitro (Vox Sang 2015;108:328)
    • Not effective against spore forming bacteria
    • Variable effectiveness against nonenveloped viruses, depending on the virus strain and technology, with only Mirasol showing effectiveness against hepatitis A virus (Transfus Med Hemother 2011;38:8)
    • Not effective against prions
    • No current technologies approved for use on red blood cells or whole blood, with various clinical trials underway
      • Issues with UV light penetration of red blood cells
    • Leads to increased costs of blood products with lack of well established reimbursement policies (Transfusion 2019;59:3002)
Case reports
  • 74 year old woman with parvovirus B19 detected in her plasma after transfusion with INTERCEPT treated platelets (Transfus Med Hemother 2016;43:198)
  • 81 year old woman who developed disseminated intravascular coagulation and multiorgan failure after transfusion of a leukoreduced red blood cell unit contaminated with Anaplasma phagocytophilum (Am J Clin Pathol 2012;137:562)
  • Adult man who developed sepsis from an INTERCEPT treated platelet contaminated with Acinetobacter calcoaceticus / baumannii complex and Staphylococcus saprophyticus (Transfusion 2020 Aug 1 [Epub ahead of print])
Board review style question #1
A 26 year old African American woman presents to a blood donor center and attempts to donate a unit of whole blood; however, the leukoreduction filter clogs and the filtration attempt fails. What is the most likely cause of the leukoreduction failure?

  1. Bacterial sepsis
  2. Congenital immunodeficiency syndrome
  3. Low red blood cell count / low hematocrit
  4. Sickle cell trait
  5. Thrombocytopenia
Board review answer #1
D. Sickle cell trait

Comment Here

Reference: Pathogen inactivation
Board review style question #2
Which of the following is true regarding pathogen inactivation of blood products?

  1. Can inactivate all strains of bacteria
  2. Currently approved for use in the U.S. for plasma, platelets and red blood cells
  3. Is able to inactivate prions
  4. Reduces but does not eliminate the risk of transfusion transmitted infections
  5. Uses filtration as the principal method to eliminate pathogens
Board review answer #2
D. Reduces but does not eliminate the risk of transfusion transmitted infections

Comment Here

Reference: Pathogen inactivation
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