The n e w e ng l a n d j o u r na l of m e dic i n e

clinical implications of basic research

The Clinical Implications of Basic Research series has focused on highlighting laboratory research that could lead
to advances in clinical therapeutics. However, the path between the laboratory and the bedside runs both ways:
clinical observations often pose new questions for laboratory investigations that then lead back to the clinic.
One of a series of occasional articles drawing attention to the bedside-to-bench flow of information is presented here,
under the Basic Implications of Clinical Observations rubric. We hope our readers will enjoy these stories of discovery,
and we invite them to submit their own examples of clinical findings that have led to insights in basic science.

basic implications of clinical observations

From Clinical Observation to Mechanism — Heyde’s Syndrome
Joseph Loscalzo, M.D., Ph.D.
In 1958, E.C. Heyde, a general practitioner from
Vancouver, Washington, sent to the Journal the
following letter to the editor, in which he report-
ed an association between calcific aortic-valve
stenosis and gastrointestinal bleeding:
To the Editor: In the past ten years, I have seen
at least 10 patients with calcific aortic steno-
sis who had massive gastrointestinal bleed-
ing for which we could discover no cause.
They were nearly all elderly people, ranging
from sixty to eighty, and most of them had
classic signs of calcific aortic stenosis, with
harsh systolic murmurs transmitted widely
into neck or back and palpable systolic
thrills. I have not found any reference to
this association in the literature, and thought
that a letter to a prominent journal might
elicit some response about the matter. I sup-
pose these people bleed from sclerotic ves-
sels, but I would certainly be interested in
hearing from some of your readers con-
cerning their observations. It seems to me
that people with this disease have gastro­
intestinal hemorrhage considerably more
often than comparable age groups without
it. I would appreciate your printing this
letter and hope it may stimulate some re-
plies or statistical studies.1
Twenty-eight years later, submucosal angio-
dysplasia was identified as the source of gastro-
intestinal bleeding in these patients.2 Over the
next 10 years, the association between aortic-
valve stenosis and angiodysplastic bleeding, al-
though interesting, was viewed as controversial,
since clinical studies were inconsistent in terms
of the statistical strength of the association be-
tween these two disorders, let alone inadequate
in offering a potential mechanism to account
for such an association.3
A key study in the evolution of this concept
was conducted by King et al., who reported the
cessation of gastrointestinal bleeding in 14 pa-
tients with aortic stenosis after aortic-valve re-
placement.4 One year earlier, two groups had
reported a loss of high-molecular-weight multi-
mers of von Willebrand factor in patients with
congenital and acquired aortic stenosis.5,6 Taken
together, these studies led Warkentin et al. to
hypothesize that Heyde’s syndrome is a form of
type IIA von Willebrand’s syndrome, an acquired
deficiency of high-molecular-weight von Wille-
brand factor multimers.7 Von Willebrand factor
is a 2050-amino-acid protein monomer that di-
merizes to form a 250-kD basic subunit. This
subunit is then multimerized in plasma to sizes
that range from 20 to 40 mers, with some very
large polymers exceeding 100 mers. These high-
molecular-weight multimers are particularly im-
portant for maintaining hemostasis during high
shear stress — flow conditions that are preva-
lent in patients with angiodysplastic lesions and
that facilitate identification of these lesions on
Doppler ultrasonography.8,9
Acquired deficiency of von Willebrand factor
is a rare disorder that has been described in pa-
tients with myeloma or monoclonal gammopa-
thy of undetermined significance10,11 and has
been associated with gastrointestinal angiodys-
plasia and bleeding.12 A case of lambda light-
chain monoclonal gammopathy with a deficiency
of high-molecular-weight multimers of von Wille­
brand factor has also been reported.11

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The New England Journal of Medicine

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 clinical implications of basic research

Von Willebrand multimer

Shear Von Willebrand multimer

stress
Coiled
von Willebrand
multimer in
circulation
Uncoiling
A2 domain

Aortic stenosis
ADAMTS13

ADAMTS13
cleaves multimer
at A2 domain

Figure 1. Conformational Change and Proteolytic Cleavage of von Willebrand Factor in Aortic-Valve Stenosis.
Blood flow through a stenotic aortic valve alters the conformation of high-molecular-weight von Willebrand factor and
exposes sites on A2 domains that can be cleaved by the plasma protease ADAMTS13. Consequently, high-molecular-
weight von Willebrand factor multimers are reduced in size and are hemostatically less competent than the intact
large multimers.

Among patients with aortic-valve stenosis,
loss of these high-molecular-weight multimers
was detected in the majority of 47 patients with
severe stenosis, and this abnormality was accom-
panied by abnormalities in platelet adhesion and
aggregation in vitro.13 These abnormalities re-
solved considerably after aortic-valve replacement.
Bleeding angiodysplasias of the gastrointestinal
tract,14 as well as epistaxis,15 have been reported
in patients with critical aortic-valve stenosis.
Vincentelli et al. studied 42 patients with criti-
cal aortic stenosis who underwent aortic-valve
replacement.16 Of these patients, 21% had a his-
tory of dermal or mucosal bleeding; platelet-
function abnormalities were noted under condi-
tions of high shear stress, with loss of the
largest multimers in up to 92% of patients, and
this deficiency correlated inversely with the trans-
valvular aortic gradient. That this relationship is
not specific to aortic-valve disease per se was
noted by Shimizu et al., who reported acquired
von Willebrand factor deficiency in a patient
with hypertrophic obstructive cardiomyopathy.17
The cause of the deficiency of high-molecular-
weight von Willebrand factor multimers in Heyde’s
syndrome was initially believed to be a conse-
quence of shear stress–induced binding of von
Willebrand factor to platelets, with consequent
enhanced clearance.18 With the identification of
shear stress–dependent cleavage of von Willebrand
factor in plasma,19 and with the recognition that
a plasma protease, ADAMTS13 (a disintegrin and
metalloproteinase with a thrombospondin type 1
motif, member 13), is responsible for that cleavage,

n engl j med 367;20 nejm.org november 15, 2012 1955

The New England Journal of Medicine
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Copyright © 2012 Massachusetts Medical Society. All rights reserved.
 clinical implications of basic research
the pathophysiology of the syndrome became ap-
parent (Fig. 1; see animation, available with the
An animation full text of this article at NEJM.org). There are no
showing the patho- natural inhibitors of ADAMTS13; rather, the con-
physiology of Heyde’s
formation of the von Willebrand factor substrate
syndrome is available
at NEJM.org regulates its proteolysis. Elevated shear stress con-
verts the globular von Willebrand polymer into an
elongated, highly asymmetric protein, unfolding
the A2 domain in the process. The conformation-
al change in this domain exposes cryptic exosites
to which ADAMTS13 binds, as well as the scissile
peptide bond (Y1605–M1606) that the protease
cleaves.20 As a result, high-molecular-weight mul-
timers are reduced in size and become less hemo-
statically competent than their parent polymers.
One last piece in the mechanistic puzzle of
Heyde’s syndrome concerns the basis for the an-
giodysplasia. Most authors have argued that an-
giodysplasia is a common accompaniment to
vascular aging and that bleeding from angiodys-
plastic lesions in patients with von Willebrand
factor deficiency states therefore reflects the
consequences of a rare hemostatic defect on the
backdrop of a common vascular disease. By
contrast, however, evidence exists for an intrin-
sic vascular diathesis in young patients with von
Willebrand’s disease, in which capillary dilata-
tion, tortuosity, and blood extravasation are ob-
served on nail-bed capillaroscopy.21 Taken to-
gether, these observations suggest that von
Willebrand factor is essential for the well-
known role of platelets in maintaining vascular
integrity independent of their essential function
in hemostasis.22
More than 50 years have passed since Heyde’s
original letter to the editor appeared in the Jour-
nal. His straightforward clinical report of an
association between aortic-valve stenosis and
gastrointestinal bleeding helped us understand
a fundamental biologic mechanism underlying a
complex aspect of hemostasis. Clearly, thought-
ful clinical observation is an essential element
of the scientific enterprise in biomedicine. Heyde’s
syndrome is, therefore, a fine illustration of the
principle that translational medicine is bidirec-
tional — not only can basic observations lead to
clinical application, but clinical observations can
lead to basic discovery.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston.
1. Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl
J Med 1958;259:196.
1956 n engl j med 367;20  nejm.org  november 15, 2012
The New England Journal of Medicine
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Copyright © 2012 Massachusetts Medical Society. All rights reserved.
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DOI: 10.1056/NEJMcibr1205363
Copyright © 2012 Massachusetts Medical Society.