Opinion
EDITORIAL
Precision in Transfusion Medicine
Matthew D. Neal, MD; Beverley J. Hunt, MD
Blood transfusion management has come a long way since the
introduction of blood banks in the 1930s, leading to the wide-
spread use of plasma and blood in the Second World War. The
gradual introduction of blood components, such as platelets
and c r yoprec ipitate, oc-
curred in the following de-
Related article
cades. However, the utility of
blood components in various settings was never assessed using
modern clinical trial methodology. Some would argue this has
led to the overuse of blood components in many clinical set-
tings, based solely on the assumption that using components
is better than not using them.
Today, increasing evidence is guiding how to use blood
components; however, much of the data, especially involv-
ing patients who are massively bleeding, come from blood loss
due to trauma. Severely injured trauma patients experience a
unique trauma-induced coagulopathy that is acutely man-
aged with either whole blood or a high ratio of plasma and
platelets to red blood cells; early use of tranexamic acid; and,
if bleeding continues, targeted therapies based on repeated
laboratory coagulation testing and/or viscoelastic hemostatic
assays.1 Even for traumatic bleeding, which has been the sub-
ject of numerous randomized clinical trials, the notion of one
strategy benefits all has been convincingly disproved. Recent
translational science using multiomic approaches has charac-
terized the differential response of various patient endotypes
to transfusion, which demonstrates that specific patient char-
acteristics may affect the response to transfusion therapy.2,3
Moreover, a present challenge in transfusion medicine is
that these data, which had been obtained from injured pa-
tients with unique coagulopathy, have been extrapolated to re-
suscitate bleeding in multiple different clinical settings. In the
treatment of infectious diseases, it would be rudimentary and
wrong to characterize all cases of pneumonia as similar and
accept that a particular antibiotic, as an example, would be ac-
ceptable to treat any infection, regardless of source (viral, bac-
terial, fungal), much less the specific organism and microbial
resistance pattern. This overly simplified example unfortu-
nately highlights the lack of precision medicine in transfusion—
presently a nonspecific, limited repertoire of blood products
are available to treat bleeding of all types. Attention to the
unique pathophysiology of the cause of bleeding and the likely
variation among individual products derived from different do-
nors almost certainly contributes to outcomes in resuscita-
tion in a manner that modern medicine has yet to recognize.
Precision diagnostics to accurately identify the specific com-
ponent requirements of the bleeding patient are lacking. Herein
lies the call for an increased focus on precision medicine for
blood transfusion.
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Design of Precision Transfusion Approaches
The call for precision in transfusion medicine can be applied
to both recipients of blood products and to the products them-
selves. A pertinent example is postpartum hemorrhage, which
unacceptably remains a leading global cause of death in women
in low- and middle-income countries. Although there are some
similarities between postpartum hemorrhage and trauma, in-
cluding the lifesaving application of tranexamic acid,4 under-
standing of the hemostatic pathophysiology of postpartum
hemorrhage is limited. Indeed, apart from the World Maternal
Antifibrinolytic (WOMAN)4 study, few clinical trials have ex-
amined transfusion and hemostatic management. The con-
trast between the lack of research attention given to a major
cause of death among young women compared with the global
efforts to improve clinical outcome in trauma, the major cause
of death of young men, is stark. Transfusion management in
postpartum hemorrhage is currently derived from the appli-
cation of trauma-derived massive transfusion protocols. These
may be of benefit, but this is largely unstudied, and it leaves
the clinician with only a blunt and unproven instrument in the
treatment of a life-threatening condition that could end tragi-
cally in a death with major social and financial implications
for the partner and the surviving children.5
In addition to conducting trials studying common bleeding
scenarios beyond trauma, modern and sophisticated clinical trial
design needs to be applied in transfusion medicine. The future
of transfusion clinical trials should achieve precision medicine,
ideally through adaptive platform trials that allow comparisons
among multiple interventions and account for patient-level char-
acteristics, including biomarker-driven studies to more rapidly
identify patient cohorts that benefit and save valuable blood prod-
uct resources by identifying promptly those who do not benefit.6
The next level of precision extends to the intervention, ie,
understanding the nuances and complexities of the actual
blood products themselves. Incompatibilities between donor
and recipient have been well recognized since 1818 when James
Blundell showed that blood from animals was not suitable for
humans: later shown to be due to preexisting xeno antibod-
ies in human recipients.7 The discovery of the ABO blood
groups by Karl Landsteiner in 1901 demonstrated that mis-
match in antigen expression existed between individual
humans and that the presence of preformed antibodies
against another human’s ABO antigens can also cause a life-
threatening reaction.8 Today, extended red blood cell pheno-
type matching is automatically performed for those with a need
for regular transfusions because the development of alloan-
tibodies between those with different antigens can hinder fur-
ther treatment. This means, however, that there can be short-
ages of donors who are well matched with a minority group
(Reprinted) JAMA Published online October 12, 2023 E1
 Opinion Editorial

requiring regular transfusions. This is highlighted in a UK cam-
paign to increase blood and organ donation from Asian and
Black individuals to support the 15 000 UK residents with sickle
cell disorders.9
Ideally, the precision of donor-recipient matching needs
to be increased. A recipient should receive blood from a fully
matched donor or a donor whose allogenic antigens have been
removed. It is therefore exciting to consider in the Recovery
and Survival of Stem Cell Originated Red Cell (RESTORE) trial10
that red blood cells were grown from stem cells from donors
and small amounts of red cells were transfused into recipi-
ents without adverse effects. Could this be scaled so that fully
compatible red blood cells are obtained from a biological sci-
ence facility? Similar studies to grow supplies of platelets from
stem cells are also in progress.11
Another consideration of donor blood is how it functions
within a recipient. Increasing attention has been directed to
the variation of function of blood constituents between do-
nors. A recent study12 has shown that platelet and cryopre-
cipitate from female donors improved coagulopathy in vitro
more than from male blood donors. It begs the question: Do
the hemostatic differences between male and female donors
affect clinical outcomes? Even more broadly, might we iden-
tify ideal donor characteristics (age, sex, and cellular and mo-
lecular profiles) that might be best matched to a particular
pathophysiology or cause of bleeding? A futuristic outlook in-
cludes the potential to design bioinspired products that over-
come barriers of blood product storage and can be optimized
for specific bleeding conditions.13
Implementation of Precision Medicine
Considerable variation in transfusion practice exists both be-
tween and within institutions. This has been well recognized
since the Safe and Good Use of Blood in Surgery (SANGUIS)14
study in 1993, which showed that the transfusion rate de-
pends more on the individual clinician than on the type of pro-
cedure, patient population, or hospital. This variation still ex-
ists today as evidenced by the International Point Prevalence
Study of Intensive Care Unit Transfusion Practices (InPUT)
study.15 Why does such variation persist? The reasons for the
large variability of transfusion practice remain elusive, and cli-
nicians’ attitudes appear slow to change. Patient blood man-
agement guidelines exist but are not well implemented.
Barriers include access to knowledge, beliefs about the inter-
vention, and tension for change.
In conclusion, blood transfusion practice has come a long
way, but further efforts toward precision medicine are re-
quired to ensure that patients receive the most effective com-
ponents. These products should be matched to patients as in-
dividuals who have unique antigens and a variable host
response, and how to use the appropriate blood components
in different clinical settings must be understood.

ARTICLE INFORMATION patterns align with outcomes and treatment information/why-black-asian-and-minority-ethnic-

Author Affiliations: Trauma and Transfusion
Medicine Research Center, Department of Surgery,
University of Pittsburgh, Pittsburgh, Pennsylvania
(Neal); Thrombosis and Haemophilia Centre, Guy’s
and St Thomas’ NHS Foundation Trust, London,
United Kingdom (Hunt).
Corresponding Author: Matthew D. Neal, MD,
Department of Surgery, University of Pittsburgh,
200 Lothrop St, F1271.2 PUH, Pittsburgh, PA 15213
(nealm2@upmc.edu).
Published Online: October 12, 2023.
doi:10.1001/jama.2023.16134
Conflict of Interest Disclosures: Dr Neal reported
serving as the chief medical officer of Haima
Therapeutics and on the advisory boards and
speaking bureaus of Haemonetics and Takeda;
receiving grants from the National Institutes of
Health, Instrumentation Laboratories, Alexion, and
the US Department of Defense; and having 2 US
patents. No other disclosures were reported.
REFERENCES
responses. Cell Rep Med. 2021;2(12):100478. doi:
10.1016/j.xcrm.2021.100478
4. WOMAN Trial Collaborators. Effect of early
tranexamic acid administration on mortality,
hysterectomy, and other morbidities in Women
With Post-Partum Haemorrhage (WOMAN): an
international, randomised, double-blind,
placebo-controlled trial. Lancet. 2017;389(10084):
2105-2116. doi:10.1016/S0140-6736(17)30638-4
5. AbouZahr C. Global burden of maternal death
and disability. Br Med Bull. 2003;67:1-11. doi:10.
1093/bmb/ldg015
6. Del Junco DJ, Neal MD, Shackelford SA, et al. An
adaptive platform trial for evaluating treatments in
patients with life-threatening hemorrhage from
traumatic injuries: planning and execution.
Transfusion. 2022;62(suppl 1):S242-S254. doi:10.1111/
trf.16982
7. Ellis H. James Blundell, pioneer of blood
transfusion. Br J Hosp Med (Lond). 2007;68(8):447.
doi:10.12968/hmed.2007.68.8.24500
8. Schwarz HP, Dorner F. Karl Landsteiner and his
donors-are-needed/
10. First ever clinical trial of laboratory grown red
blood cells being transfused into another person.
National Health Services. November 7, 2022.
Accessed August 22, 2023. https://www.nhsbt.nhs.
uk/news/first-ever-clinical-trial-of-laboratory-
grown-red-blood-cells-being-transfused-into-
another-person/
11. Sugimoto N, Kanda J, Nakamura S, et al. iPLAT1:
the first-in-human clinical trial of iPSC-derived
platelets as a phase 1 autologous transfusion study.
Blood. 2022;140(22):2398-2402. doi:10.1182/blood.
2022017296
12. DeBot M, Erickson C, Kelher M, et al. Platelet
and cryoprecipitate transfusions from female
donors improve coagulopathy in vitro. J Trauma
Acute Care Surg. 2023;94(4):497-503. doi:10.1097/
TA.0000000000003857
13. Luc NF, Rohner N, Girish A, Didar Singh Sekhon
U, Neal MD, Sen Gupta A. Bioinspired artificial
platelets: past, present and future. Platelets. 2022;
33(1):35-47. doi:10.1080/09537104.2021.1967916

1. Moore EE, Moore HB, Kornblith LZ, et al.
Trauma-induced coagulopathy. Nat Rev Dis Primers.
2021;7(1):30. doi:10.1038/s41572-021-00264-3
2. Thau MR, Liu T, Sathe NA, et al. Association of
trauma molecular endotypes with differential
response to transfusion resuscitation strategies.
JAMA Surg. 2023;158(7):728-736. doi:10.1001/
jamasurg.2023.0819
3. Wu J, Vodovotz Y, Abdelhamid S, et al; PAMPer
study group. Multi-omic analysis in injured humans:
major contributions to haematology. Br J Haematol.
2003;121(4):556-565. doi:10.1046/j.1365-2141.2003.
04295.x
9. Why Black and Asian donors are needed: the
increasing priority of finding people from all
backgrounds and communities to be blood and
organ donors. National Health Services. Accessed
August 22, 2023. https://www.nhsbt.nhs.uk/how-
you-can-help/get-involved/key-messages-and-
14. Baele PL, De Bruyère M, Deneys V, et al. The
SANGUIS Study in Belgium: an overview of
methods and results. Acta Chir Belg. 1994;94(2):
69-74.
15. Raasveld SJ, de Bruin S, Reuland MC, et al; the
InPUT Study Group. Red blood cell transfusion in
the intensive care unit. JAMA. Published online
October 12, 2023. doi:10.1001/jama.2023.20737

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