Researchers
from the Medical College of
Wisconsin (MCW) in Milwaukee and
several other institutions published
a study in the July issue of
Blood, the journal of the
American Society of Hematology,
suggesting a DNA-based explanation
for discrepancies found in certain
lab tests that help diagnose von
Willebrand disease (VWD) in African
Americans.
The lead author of the study was
Veronica Flood, MD, pediatric
hematologist/oncologist and
assistant professor, Division of
Hematology/Oncology, Department of
Pediatrics, MCW. Flood’s research
was funded, in part, through a
Career Development Award from the
National Hemophilia Foundation.
VWD and its subtypes are
characterized by either quantitative
defects (decreased amount) or
qualitative defects (abnormal
structure or function) in von
Willebrand factor (VWF). Bleeding
symptoms can be mild, moderate or
severe, depending on the type. Types
I and III result from quantitative
defects--either partial VWF
production or a lack of it—while
type II and its subtypes result from
dysfunctional VWF. A patient history
of bleeding symptoms, plus the
presence of other affected family
members are part of the diagnosis
criteria. In addition, a battery of
lab tests measuring VWF quantity and
function can confirm the diagnosis.
VWF ristocetin cofactor activity (VWF:RCo)
is a relatively simple lab test in
which blood cells are separated from
a patient’s plasma (liquid component
of blood). Ristocetin, an antibiotic
that prompts the binding of VWF and
platelets, is then added to the
plasma. Blood with viable VWF will
clot, blood without it will not.
Researchers have found in this and
prior studies that African Americans
often exhibit a poorer ristocetin-induced
platelet aggregation, while showing
higher levels of VWF, measure by the
VWF antigen (VWF:Ag) test, which
indicates the quantity of VWF in the
blood.
Investigators used data from the TS
Zimmerman Program for the Molecular
and Clinical Biology of VWD (ZPMCB-VWD),
a large multicenter study on
patients with VWD. Citing the
ZPMCB-VWD data, the authors explain
that this discrepancy in the VWF:RCo/VWF:Ag
ratio, which is much more common
among African Americans, is the
result of a single variation in the
DNA sequence known as single
nucleotide polymorphisms (SNP). The
SNP in this instance is triggered by
an amino acid substitution in the
“D1472H” location in the DNA
sequence.
These contradictory results could
cause problems for patients.
“Reliance on the ristocetin cofactor
activity assay, however, may be a
source of diagnostic error in
certain patients, especially those
possessing SNPs that directly affect
ristocetin’s interactions with VWF.
In addition, the presence of D1472H
may affect ristocetin-induced
platelet aggregation and could be a
source of diagnostic error in
platelet function testing. It is
important to consider each patient’s
bleeding history, taking into
account historical challenges and
family history, as indiscriminate
VWF testing may result in erroneous
diagnosis and treatment,” concluded
the authors.
The study, “Common VWF Exon 28
Polymorphisms in African Americans
Affecting the VWF Activity Assay by
Ristocetin Cofactor,” was published
in the July 2010 issue of Blood.
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