Demystifying the Lab
ASH Clinical News takes a look at the complex scientific techniques that
hematologists/oncologists hear about every day, with practical information
for the practicing clinician.
DEMYSTIFYING
Genetic Testing for
Bleeding Disorders
When hemophilia and von Willebrand disease
(vWD) were first recognized, doctors didn’t
diagnose a patient until he (or, much more
infrequently, she) experienced a bleeding event
that lasted a dangerously long time. But the
consequences of the disease had been recog-
nized for centuries: According to the National
Hemophilia Foundation, in the second century,
the Talmud stated that Jewish baby boys were
exempted from circumcision if two of their
brothers had already died from excessive
bleeding after the process. 1
The genetic basis for uncontrolled bleed-
ing episodes was not identified until the early
20th century, when researchers discovered that
a hereditary lack of coagulation factors was to
blame for abnormal and excessive bleeding.
These discoveries led to the development of
treatments and prophylaxis that are still used
today.
The field made a giant leap forward in the
1980s, when researchers first characterized
the genes that encode coagulation factors,
opening the doors for genetic testing to aid in
the diagnosis and prognosis of patients with
hemophilia or vWD.
“Genetic testing results can be very reveal-
ing, but we know that genetic testing is still
an imperfect and rapidly evolving science,”
Stefanie Dugan, MS, CGC, a certified genetic
counselor at the Versiti Blood Center of Wis-
consin, told ASH Clinical News. “The advances
in technology have revolutionized the field,
and the clinically available options for genetic
testing – not just for hematology, but across
different disease areas – have exploded.”
More recently, scientists have set their sights
on a more ambitious goal: developing gene
therapies to replace defective gene sequences
with correct ones, which promises to eliminate
disease for a patient’s lifetime.
ASH Clinical News spoke with Ms. Dugan
and other geneticists and hematologists about
the advances in genetic testing for inherited
bleeding disorders, the challenges in the results’
interpretation, and prospects for gene therapies
for these conditions.
The Genetic History of Bleeding Disorders
In 1803, a Philadelphia physician, John Conrad
Otto, was the first to suggest that bleeding
disorders were inherited diseases that primar-
ily affected men and ran in certain families.
Twenty-five years later, Friedrich Hopff, a
student at the University of Zurich, and his
professor Johann Lukas Schönlein, coined the
term “haemophilia” to refer to patients who
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experienced uncontrolled bleeding episodes.
Researchers also determined that hemo-
philia is more common among males because
the genetic mutations responsible for hemo-
philia are located on the X chromosome; males
have only one X chromosome, so one altered
copy of the gene in each cell is enough to cause
the condition. However, females have two X
chromosomes, so women may carry the muta-
tion without displaying symptoms because
their other X chromosome holds a functional
gene. Fathers cannot pass X-linked traits to
their sons, but a woman who is a carrier has a
50-percent chance of passing the disorder on
to a son.
Factor I deficiency was first described in
1920, followed next by the discoveries of factors
II and V deficiency in the 1940s. During the
1950s there was an explosion of work on rare
factor deficiencies, with scientists describing
the role of deficiencies in factors VII, XI, XII,
and XIII. This allowed an Argentinian physi-
cian, Alfredo Pavlovsky, MD, to identify two
types of the disease, hemophilia A (caused by
deficient factor VIII [FVIII]) and hemophilia B
(caused by deficient factor IX [FIX]).
During the same era, in 1926, Finnish phy-
sician Erik von Willebrand described what he
called “pseudohemophilia,” a bleeding disorder
that affected men and women equally; years
later, in 1957, the disease became known as von
Willebrand disease, after Inga Marie Nilsson,
PhD, and researchers at the Malmo University
Hospital in Sweden determined that “pseudo-
hemophilia” was caused by a deficiency of a
protein in blood plasma that enables hemo-
stasis, later identified as von Willebrand factor
(vWF).
Why Use Genetic Testing?
In patients with hemophilia or vWD, a defi-
ciency in one of the coagulation factors due
to genetic mutations prevents the body from
synthesizing enough functional copies of the
necessary clotting proteins. Mutations in FVIII,
FIX, or vWF will cause slower clot formation,
which can lead to excessive bleeding after cuts
and surgeries or bleeding within joints that can
cause pain and loss of function.
Genetic testing is the next step after a
blood test, like a prothrombin time or partial
thromboplastin time test to measure the levels
of different clotting factors in the blood. 2
“You would never take somebody who is
suspected of having, say, hemophilia A and
sequence them first,” explained Laura Swystun,
PhD, a senior clinical scientist at the Canadian
National Inherited Bleeding Disorder Geno-
typing Laboratory at Queen’s University in
Ontario. “You would always first assess their
factor activity.”
After conducting a factor assay, a doctor
may use a genetic test to confirm the diagnosis
and gain more information to guide treatment
decisions. Genetic testing “can be a powerful
tool to help confirm a diagnosis in someone
whose symptoms or laboratory phenotype
might be borderline,” said Ms. Dugan.
Also, because hemophilia is inherited in
an X-linked recessive pattern, the results of
May 2019