Risk of transmission of amyloid β pathology via transfused blood products
Author links open overlay panel Gargi Banerjee PhD a , Gustaf Edgren PhD b , Jingcheng Zhao MD b , Prof Neil M Ferguson DPhil c , Prof Heli Harvala PhD d , James Hope PhD e , Graham S Jackson PhD a , Prof Philip J Lowry DSc f , Prof Simon Mead PhD a , Silvia A Purro PhD a , Prof Jonathan M Schott FMedSci g h , Prof Marc L Turner PhD i , Prof David J Werring FMedSci j , Prof Henrik Zetterberg PhD g h k l m n o , Prof John Collinge FRS a
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Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt–Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted via blood components and products, as was the case in rare instances for variant CJD. Recent epidemiological data showing the apparent transmission of haemorrhage risk between blood donors and recipients raise the possibility of blood-based CAA transmission. In this Viewpoint, we review the evidence for amyloid β transmission, provide an overview of relevant prion biology, and consider the circumstances under which bloodborne prion transmission has previously occurred. We discuss the implications for blood transfusion services, particularly in light of the UK Infected Blood Inquiry, and the key questions that need to be addressed to better quantify transfusion-related risk. Introduction
Blood transfusion is key to medical and surgical practice.1 Transfused products include blood components (eg, red cells, platelets, and clinical plasma) and plasma-derived medicinal products (eg, coagulation factors, immunoglobulins, and albumin).2Transfusion-transmitted infections are rare but potentially catastrophic,3 and even low risks of infection can undermine public confidence. In some cases, concerns that are relevant to blood transfusion can also extend to other allogeneic substances of human origin (eg, transplanted tissues, cells, and organs). In this Viewpoint, we discuss the bloodborne transmission of protein-only pathogens, or prions, given the recent recognition of iatrogenic forms of Alzheimer's disease4, 5 and iatrogenic amyloid β cerebral amyloid angiopathy (CAA).6 Section snippets
Prions and human disease
Prions are protein-only infectious agents composed of assemblies of misfolded host-encoded cellular prion protein (PrPC), which form amyloid fibrils.7 Prions propagate via a process of seeded amyloidosis, where the host PrPC is recruited by an elongating fibril that undergoes fission, producing more seeds in an autocatalytic process.7 As protein-only agents, prions are highly durable, resistant to inactivation via conventional sterilisation methods,8 and have a high binding affinity for steel Acquired amyloid β diseases: iatrogenic Alzheimer's disease and cerebral amyloid angiopathy
The amyloid β protein is traditionally associated with two diseases. The first is Alzheimer's disease, a dementia that is histopathologically characterised by parenchymal and vascular amyloid β deposition alongside aggregates of tau protein. The second is CAA, which causes intracranial haemorrhage—particularly lobar intracerebral haemorrhages—and in which amyloid β deposits are predominantly vascular.18Intracerebral haemorrhage due to CAA has a high risk of recurrence compared with Prion transmission via infected blood products
Variant CJD is a human prion disease first reported in the UK in 1996.42 Unlike other forms of CJD, there is prominent involvement of lymphoreticular tissues, raising early concerns that bloodborne prion transmission might occur via recirculating lymphocytes.43 These fears were realised, with three symptomatic cases of transfusion-associated (secondary) variant CJD following red cell transfusions; two additional people who died of other causes had variant CJD infection confirmed at autopsy in Evidence for bloodborne transmission of amyloid β
Amyloid β is detectable in blood, which plays a role in brain amyloid β clearance,51, 52 is produced by platelets,53 adheres to the surface of red blood cells,54, 55 and is a biomarker for Alzheimer's disease.56 Amyloid β has been detected in human cervical lymph nodes,57 which is an important destination for the meningeal lymphatics, glymphatic system, and other perivascular drainage pathways.58 This finding is particularly relevant, as the presence of variant CJD prions in lymphoreticular Determining amyloid β infectivity
There are no established methods for quantifying amyloid β seed titre in body fluids. Prion research has traditionally used rodent bioassays to measure infectivity, with endpoint titrations used to compare test material with serial dilutions of material with known titre. Through this method, researchers have been able to establish detection thresholds and dynamic range.69 However, unlike models of prion transmission, rodent amyloid β models do not have a clinical endpoint, and histopathological Implications for blood transfusion services
The maintenance of adequate stocks of blood components to meet highly dynamic clinical demand is essential for patient care, and anything that disrupts the balance of supply and demand has the potential to cause more harm than good. Donor numbers have fallen in the UK and internationally and their average age has increased, with blood component shortages becoming more common. The 2024 UK Infected Blood Inquiry83 investigated what has been called “the worst treatment disaster in the history of Conclusion
The transmission of amyloid β pathology via transfused blood and blood products is a justifiable concern. We need to acknowledge that we do not have sufficient information to quantify the extent of the problem or the technologies that are needed to address key questions. Further research is essential for informing both this and future discussions and, therefore, is of strategic national and global importance. Immediate priorities should include an epidemiological replication of the Scandinavian
Declaration of interests
GB has received honoraria for teaching at Universität Bern; has received travel support from the National Institute for Health and Care Research (NIHR), UK Stroke Forum, International Cerebral Amyloid Angiopathy Association, European Stroke Organisation, and European Academy of Neurology; is an unpaid Board Member of the International Cerebral Amyloid Angiopathy Association; is funded by an MRC Clinician Scientist Fellowship; held a previous position as an NIHR Clinical Lecturer; and has
Acknowledgments
In April, 2024, the MRC Prion Unit at UCL convened a workshop to address the question of bloodborne amyloid β transmission, bringing together expert clinicians, scientists, epidemiologists, government officials, and other stakeholders to review and discuss the evidence to date and its implications. This Viewpoint is derived from presented data and roundtable discussions from this workshop. We thank all attendees for their contributions to the workshop and its discussions. The MRC Prion Unit is…
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kind regards, terry
Author links open overlay panel Gargi Banerjee PhD a , Gustaf Edgren PhD b , Jingcheng Zhao MD b , Prof Neil M Ferguson DPhil c , Prof Heli Harvala PhD d , James Hope PhD e , Graham S Jackson PhD a , Prof Philip J Lowry DSc f , Prof Simon Mead PhD a , Silvia A Purro PhD a , Prof Jonathan M Schott FMedSci g h , Prof Marc L Turner PhD i , Prof David J Werring FMedSci j , Prof Henrik Zetterberg PhD g h k l m n o , Prof John Collinge FRS a
Show more
Share
Cite Only registered and activated users can see links., Click Here To Register... rights and content Summary
Seeded protein misfolding and aggregation are relevant to many neurodegenerative diseases. The archetype are prions: protein-only infectious agents that cause fatal neurodegenerative diseases including Creutzfeldt–Jakob disease (CJD). The recent recognition of iatrogenic amyloid β cerebral amyloid angiopathy (CAA) and Alzheimer's disease, caused by inadvertent seeding of amyloid β pathology following historical medical procedures, raises concerns that these conditions might also be transmitted via blood components and products, as was the case in rare instances for variant CJD. Recent epidemiological data showing the apparent transmission of haemorrhage risk between blood donors and recipients raise the possibility of blood-based CAA transmission. In this Viewpoint, we review the evidence for amyloid β transmission, provide an overview of relevant prion biology, and consider the circumstances under which bloodborne prion transmission has previously occurred. We discuss the implications for blood transfusion services, particularly in light of the UK Infected Blood Inquiry, and the key questions that need to be addressed to better quantify transfusion-related risk. Introduction
Blood transfusion is key to medical and surgical practice.1 Transfused products include blood components (eg, red cells, platelets, and clinical plasma) and plasma-derived medicinal products (eg, coagulation factors, immunoglobulins, and albumin).2Transfusion-transmitted infections are rare but potentially catastrophic,3 and even low risks of infection can undermine public confidence. In some cases, concerns that are relevant to blood transfusion can also extend to other allogeneic substances of human origin (eg, transplanted tissues, cells, and organs). In this Viewpoint, we discuss the bloodborne transmission of protein-only pathogens, or prions, given the recent recognition of iatrogenic forms of Alzheimer's disease4, 5 and iatrogenic amyloid β cerebral amyloid angiopathy (CAA).6 Section snippets
Prions and human disease
Prions are protein-only infectious agents composed of assemblies of misfolded host-encoded cellular prion protein (PrPC), which form amyloid fibrils.7 Prions propagate via a process of seeded amyloidosis, where the host PrPC is recruited by an elongating fibril that undergoes fission, producing more seeds in an autocatalytic process.7 As protein-only agents, prions are highly durable, resistant to inactivation via conventional sterilisation methods,8 and have a high binding affinity for steel Acquired amyloid β diseases: iatrogenic Alzheimer's disease and cerebral amyloid angiopathy
The amyloid β protein is traditionally associated with two diseases. The first is Alzheimer's disease, a dementia that is histopathologically characterised by parenchymal and vascular amyloid β deposition alongside aggregates of tau protein. The second is CAA, which causes intracranial haemorrhage—particularly lobar intracerebral haemorrhages—and in which amyloid β deposits are predominantly vascular.18Intracerebral haemorrhage due to CAA has a high risk of recurrence compared with Prion transmission via infected blood products
Variant CJD is a human prion disease first reported in the UK in 1996.42 Unlike other forms of CJD, there is prominent involvement of lymphoreticular tissues, raising early concerns that bloodborne prion transmission might occur via recirculating lymphocytes.43 These fears were realised, with three symptomatic cases of transfusion-associated (secondary) variant CJD following red cell transfusions; two additional people who died of other causes had variant CJD infection confirmed at autopsy in Evidence for bloodborne transmission of amyloid β
Amyloid β is detectable in blood, which plays a role in brain amyloid β clearance,51, 52 is produced by platelets,53 adheres to the surface of red blood cells,54, 55 and is a biomarker for Alzheimer's disease.56 Amyloid β has been detected in human cervical lymph nodes,57 which is an important destination for the meningeal lymphatics, glymphatic system, and other perivascular drainage pathways.58 This finding is particularly relevant, as the presence of variant CJD prions in lymphoreticular Determining amyloid β infectivity
There are no established methods for quantifying amyloid β seed titre in body fluids. Prion research has traditionally used rodent bioassays to measure infectivity, with endpoint titrations used to compare test material with serial dilutions of material with known titre. Through this method, researchers have been able to establish detection thresholds and dynamic range.69 However, unlike models of prion transmission, rodent amyloid β models do not have a clinical endpoint, and histopathological Implications for blood transfusion services
The maintenance of adequate stocks of blood components to meet highly dynamic clinical demand is essential for patient care, and anything that disrupts the balance of supply and demand has the potential to cause more harm than good. Donor numbers have fallen in the UK and internationally and their average age has increased, with blood component shortages becoming more common. The 2024 UK Infected Blood Inquiry83 investigated what has been called “the worst treatment disaster in the history of Conclusion
The transmission of amyloid β pathology via transfused blood and blood products is a justifiable concern. We need to acknowledge that we do not have sufficient information to quantify the extent of the problem or the technologies that are needed to address key questions. Further research is essential for informing both this and future discussions and, therefore, is of strategic national and global importance. Immediate priorities should include an epidemiological replication of the Scandinavian
Declaration of interests
GB has received honoraria for teaching at Universität Bern; has received travel support from the National Institute for Health and Care Research (NIHR), UK Stroke Forum, International Cerebral Amyloid Angiopathy Association, European Stroke Organisation, and European Academy of Neurology; is an unpaid Board Member of the International Cerebral Amyloid Angiopathy Association; is funded by an MRC Clinician Scientist Fellowship; held a previous position as an NIHR Clinical Lecturer; and has
Acknowledgments
In April, 2024, the MRC Prion Unit at UCL convened a workshop to address the question of bloodborne amyloid β transmission, bringing together expert clinicians, scientists, epidemiologists, government officials, and other stakeholders to review and discuss the evidence to date and its implications. This Viewpoint is derived from presented data and roundtable discussions from this workshop. We thank all attendees for their contributions to the workshop and its discussions. The MRC Prion Unit is…
Only registered and activated users can see links., Click Here To Register...
kind regards, terry
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