ASH News Daily 2017 - Issue 3 - A-3

ASH News Daily

Monday, December 11, 2017

Page A-3
®

P L E N A RY - R E D B L O O D C E L L S

Creating Bespoke Cells That Are "Prêt-à-Transfuser"
By Lynne Lederman, PhD

atients, including those with
sickle cell disease (SCD),
who receive repeated red
blood cell (RBC) transfusions develop alloantibodies, limiting the
availability of compatible units.
Identification of alloantibodies is
hampered by the inadequacy of
current serologic typing reagents.
In yesterday's Plenary Scientific Session (abstract #3) Dr. Stella
T. Chou said, "Despite providing
blood matched for Rh, we recently demonstrated that antibodies
to the Rh blood group system are
the most common, in part because
of RH genetic heterogeneity in individuals with SCD. More than
half of patients have RH (gene)
variants, which result in loss of
common parts of the protein and
increase risk of antibody formation." The antibodies formed
against Rh are often complex; it
can take hours to days for blood
banks to identify these antibodies
and obtain compatible blood for
transfusion.
In her presentation, Dr. Chou
discussed the use of induced pluripotent stem cells (iPSCs) to create
reagent RBCs that lack the highprevalence antigens and/or have

Dr. Stella T. Chou

RH variants. "Currently, these do
not exist or are only available in a
few reference laboratories, and are
in limited supply," she said.
Dr. Chou described engineering
customized iPSCs for a renewable
RBC source by reprogramming
O donor cells and using CRISPRCas9 genome editing techniques to
disrupt RHCE alleles. The resultant
cells express rare blood group antigen phenotypes or combinations
that are difficult or impossible to
find as donor RBCs, including cells
that are Rh null, are negative for
the high-prevalence Rh antigen
hrS, express a partial C antigen

that also lacks the high prevalence
Rh antigen hrB, or that express the
low prevalence Rh antigens V and
VS that also lack nrB. In theory, it is
possible to produce iPSCs expressing any combination of rare antigens. Dr. Chou discussed protocols
to improve hematopoietic differentiation of iPSCs from a primitive
phenotype to iRBCs suitable for
use in blood bank assays.
Dr. Chou said that customized
reagent iPSCs that express rare
blood group antigen phenotypes or
combinations would facilitate antibody identification, as they can be
designed to function with current

blood bank assays for antibody
screening and detection, making
them feasible for widespread use,
and would also decrease delays
in providing transfusions and improve transfusion safety for patients with SCD.
When asked how soon we can
expect these customized cells to be
available for use in the blood bank
or in the clinic, Dr. Chou replied,
"Researchers at The Children's
Hospital of Philadelphia and New
York Blood Center hope to develop the tool into a simple and
cost-effective screening test within
the next few years. These reagent
red cells would allow local blood
banks caring for patients with SCD
to quickly identify Rh antibodies
and guide their blood selection."
Abstract introducer Dr. Naomi
L.C. Luban predicted that "work
by Dr. Chou's group will undoubtedly result in additional diagnostic reagents that will improve the
identification of alloantibodies,
allow differentiation of alloantibodies versus true autoantibodies,
and, if fully scalable in the future,
allow production of specialized
iRBCs for transfusion."
Dr. Lederman indicated no relevant
conflicts of interest.

P L E N A RY - B L E E D I N G D I S O R D E R S

We All Bleed the Same (or Do We?)
By Saad Usmani, MD

ature has been very kind
to us when it comes to preventing unnecessary bleeding and clotting, by giving us more
platelets than we need and creating
several layers of redundant mechanisms set aside as fail-safes. Yet
bleeding remains a common occurrence in the general population -
one in four people will have bleeding symptoms during their lifetime.
From the Talmud and the New
Testament in the second century, to
the account of Arabian physician
Abu Qasim in the 10th century, human history is filled with accounts
of bleeding diatheses. Different art
forms have demonstrated fascination with "bleeding" across the centuries. This perhaps in part explains
why Leona Lewis "keeps bleeding"
and the real reason Pink Floyd did
not have the nerve to make the final
cut.
Genome sequencing has evolved
from being an expensive, time-consuming, and cumbersome technology reserved for highly specialized

Dr. Claire Lentaigne

research centers in the 1990s to a
more efficient, cheaper desktop tool
used in today's pathology laboratories. This tool is being utilized across
the spectrum of human pathology
in both the clinical and research
domains. Patients with a bleeding,
thrombotic, and platelet disorder
(BPD) are defined as having an abnormal platelet number, volume,

morphology, function, or tendency
to bleed abnormally. Given the spectrum of BPDs in the general population, employing a high-throughput
sequencing test would help identify these patients and channel them
toward appropriate management
strategies. To this end, Dr. Claire
Lentaigne of Imperial College London presented data on behalf of the
Thrombogenomics Consortium during the Plenary Scientific Session abstract on 3,449 patients with BPDs.
Dr. Jorge Di Paolo from the University of Colorado introduced the
abstract by elegantly summarizing
the complexity of normal hemostasis. He then described the genes
responsible for normal hemostasis
and the journey of genetic discovery
in this particular arena of research,
before paving the way for Dr. Lentaigne's presentation. The study investigators recruited patients in two
different groups and used a 96-gene
high-throughput sequencing panel
and whole-genome sequencing. The
first group of patients (n=1,321) was
suspected to have a defect in one of
the known BPD genes, and the sec-

ond group (n=1,916) included patients suspected of a BPD not attributable to one of the 96 known BPD
genes. Pathogenic variants were
identified in 54 percent and 13 percent of the cases, respectively. These
findings have led to 808 patients
being diagnosed with a mutationrelated BPD. Interestingly, for the
"non-syndromic" thrombocytopenic patients, pathogenic variants
were identified in about 30 percent,
compared to only 4 percent in cases
with significant bleeding disorder in
absence of other platelet or coagulation abnormality. There were 23
novel BPD genes identified in the
second group (including NBEAL2,
RBM8A, SRC, DIAPH1, TPM4,
ABCC4, and KDSR genes). Dr. Lentaigne concluded her talk by saying
that precision diagnosis has enabled
better diagnosis of rare BPDs, and
the future endeavors of the study
team will include epigenetic mechanisms and contributions to BPD
pathogenesis.
Dr. Usmani indicated no relevant
conflicts of interest.

Table of Contents for the Digital Edition of ASH News Daily 2017 - Issue 3