Age and Ageing 2009; 38: 267–270

C The Author 2009. Published by Oxford University Press on behalf of the British Geriatrics Society.
doi: 10.1093/ageing/afp019 All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Published electronically 10 March 2009

Heyde syndrome: a common diagnosis in older

patients with severe aortic stenosis
M. W. MASSYN1 , S. A. KHAN2
1
Specialist Registrar, Department of Elderly Care, Lister Hospital, Corey’s Mill Lane, Stevenage, Herts SG1 4AB, UK
2
Consultant Physician & Deputy Clinical Director, Department of Elderly Care, Lister Hospital, Corey’s Mill Lane,
Stevenage, Herts SG1 4AB, UK
Address correspondence to: S. A. Khan. Tel: (+44) 1438 314333, Ext: 4197/5049; Fax: (+44) 1438 781449.
Email: shahidak@aol.com

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Abstract
Heyde syndrome is a triad of aortic stenosis, an acquired coagulopathy and anaemia due to bleeding from intestinal angiodys-
plasia. The evidence that aortic stenosis is the root cause of this coagulopathy is compelling. Resolution of anaemia usually
follows aortic valve replacement. This article discusses studies linking aortic stenosis with other conditions in the triad as well
as diagnosis and management of this complex pathology.

Keywords: aortic stenosis, iron deficiency anaemia, angiodysplasia, gastrointestinal bleeding, elderly

Introduction Aortic stenosis

In 1958, EC Heyde published 10 cases of calcific aortic steno-
sis and severe gastrointestinal bleeding. The combination of
calcific aortic stenosis and iron deficiency anaemia due to
gastrointestinal bleeding was described as Heyde syndrome
[1]. That same year Goldman reviewed 37,423 case notes
and found a 3-fold higher than predicted incidence of gas-
trointestinal bleeding in cases of aortic stenosis [2]. In 1965,
Cattell suggested that patients with aortic stenosis could
bleed from a lesion in the ascending colon which had not
been demonstrated by pathologists, and recommended blind
right haemicolectomy in such patients as a cure for recurrent
anaemia [3].
The association between aortic stenosis and intestinal
angiodysplasia has been controversial as retrospective studies
and cohort studies have reached opposing conclusions [3, 4].
The evidence that aortic stenosis is the root cause of the
coagulopathy is much stronger than the evidence for a casual
association with angiodysplasia.
Heyde syndrome now refers to a triad of aortic steno-
sis, acquired coagulopathy (von Willebrand syndrome type
2A, abbreviated here vWS-2A) and anaemia due to bleeding
from intestinal angiodysplasia or from an idiopathic site. This
article examines these conditions, the diagnosis and treatment
of Heyde syndrome.
Dystrophic calcification of heart valves was first described
by Mönckeberg in 1904 [5]. Aortic stenosis is now the most
common acquired valvular lesion in the elderly. The preva-
lence of critical aortic stenosis is 1–2% at age 75, rising to 6%
at 85 years. The precipitating cause is unknown, but chronic
inflammation of the valves causing thickening and fusion of
the aortic valve cusps and calcification seems plausible [6].
Risk factors for aortic stenosis are similar to those for arterial
atherosclerosis [6]. Critical aortic stenosis may present with
syncope, angina and dyspnoea.
Intestinal angiodysplasia
Angiodysplasia may occur anywhere in the gastrointestinal
tract, but is most common in the ascending colon, partic-
ularly the caecum. In a prospective study of colonoscopies
of 1,938 patients, typical angiodysplasia was found in 3%
of cases, but 80% were asymptomatic. The sites of highest
prevalence of the lesions were the caecum (37%) and sigmoid
colon (18%) [7]. A total of 1–6% of in-patient gastrointesti-
nal bleeds are caused by angiodysplasia, while 30–40% of
gastrointestinal bleeds of an obscure source are found to be
linked to angiodysplasia and it is possibly the most common

267
M. W. Massyn and S. A. Khan
cause of lower gastrointestinal bleeding in the elderly [6].
Angiodysplasia are found incidentally in 3% of non-bleeding
patients over age 65. They are present in 2.6–6.2% of patients
being investigated for gastrointestinal bleeding [8].
Association between aortic stenosis and
angiodysplasia
There are methodological difficulties in proving statistical
or causal links, partly because aortic stenosis and intesti-
nal angiodysplasia are common conditions in the elderly.
Aortic stenosis may only be detected in later symptomatic
stages, while intestinal angiodysplasia will not always result in
anaemia, and routine investigations may not reveal that they
are the cause of a patient’s anaemia. Thus, the prevalence of
Heyde syndrome is not clear, and it is likely that many mild
cases remain undiagnosed.
Some early studies on Heyde syndrome showed a correla-
tion of a typical murmur of aortic stenosis with idiopathic gas-
trointestinal bleeding, while later studies have used echocar-
diographic and endoscopic diagnoses. Sigmoidoscopy is the
most common investigation used to visualise the colon, but
colonoscopic diagnoses are usually used in retrospective stud-
ies. Many studies have not distinguished bleeding from non-
bleeding angiodysplasia; prosthetic valves may encroach on
valvular orifices causing mild stenosis (patient-prosthesis mis-
match) [8, 9].
According to one study, severe aortic stenosis is found
in up to 15–25% of patients with repeated bleeding [10].
Mehta et al. investigated 29 patients with gastrointestinal
angiodysplasia detected on endoscopy with echocardiogra-
phy, but found no cases of aortic stenosis [11]. Similarly,
Oneglia et al. investigated 59 patients and found that only
one had aortic stenosis [12]. In a prospective, case-matched
study of 40 patients who were found to have angiodyspla-
sia, Bhutani and colleagues found no increased prevalence of
aortic stenosis [3].
Pate and colleagues studied 3.8 million discharge sum-
maries retrospectively, and found a significant association
(P < 0.0001) between aortic stenosis and gastrointestinal
bleeding presumed to be due to angiodysplasia. Age was
statistically significant as a confounding factor, as patients
who had been diagnosed with both conditions were older
than patients with only one or neither (P < 0.0001) [6, 13]. In
another retrospective case-note study of 3,623 patients with
either aortic or mitral stenosis, gastrointestinal bleeding was
found to be significantly more common in the aortic stenosis
group (P < 0.001) [4].
In a study of patients diagnosed with angiodysplasia of
the gastrointestinal tract over a 10-year period, echocardio-
graphy significantly correlated with aortic stenosis but not
with mitral stenosis. Significant aortic stenosis was 2.6 times
more common than in controls, and severe aortic stenosis
was 4.1 times more common than in the general population.
The study included patients diagnosed by angiography as well
as endoscopy in contrast to the study of Bhutani et al. [9].
268
Aetiological theories
In 1971, Boss and Rosenbaum described distension of ves-
sels in the intestinal mucosa in post-mortem cases of aortic
stenosis and attributed the blood loss to this [14]. Low-grade
chronic hypoxia may stimulate reflex sympathetic vasodila-
tion and smooth muscle relaxation, progressing to true ectasia
of vessel walls [9, 15].
Another theory is that colonic mucosal hypoxia might
be caused by cholesterol emboli from the aortic valve or by
the altered pulse waveform in aortic stenosis. Angiodyspla-
sia have been described in hypertrophic cardiomyopathy, in
which alteration of the pulse waveform is also found [6].
Several studies comparing cases of aortic and mitral valve
stenosis have shown a higher prevalence of gastrointestinal
bleeding in the former [4, 16]. Other valvular lesions might
cause chronic hypoxia in the intestinal mucosa, but do not
induce altered pulse waveforms [4]. Some found no asso-
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ciation of aortic stenosis with angiodysplasia but found a
high frequency of colonic polyps and tumours whereas oth-
ers have suggested that Heyde syndrome is the end result of
senile degeneration of both aortic valvular and gastrointesti-
nal mucosal tissue [16, 17].
Coagulopathy
Aortic stenosis has been shown to cause acquired vWS-2A.
First described in 1968, approximately 270 cases of acquired
vWS had been published by 2000. In 12% of cases, it was
caused by a cardiovascular disorder [18]. Von Willebrand fac-
tor (vWF) synthesised by endothelial cells is stored in ultra-
large multimers and mediates platelet adhesion at sites of vas-
cular damage [19, 20]. It circulates as large multimers, one of
which exceeds the size of platelets [21, 22]. The high veloc-
ity of blood flow within telangiectasia requires the largest
multimers of vWF to maintain haemostasis [6].
Acquired vWS-2A in aortic stenosis arises from degra-
dation of vWF multimers by the shear stress across the
diseased valve. An aortic pressure gradient of 50 mmHg
may cause coagulopathy [23]. vWF multimers unfold from a
coiled structure to an elongated filament [24, 25] and are
then cleaved [24–27]. Degradation of the heaviest multi-
mers of vWF, which are most effective in platelet-mediated
haemostasis, is the basis for coagulopathy in Heyde syndrome
[25].
In a study of 50 consecutive patients with aortic steno-
sis, 84% of whom were treated with aortic valve replace-
ment (AVR), 21% of patients with severe aortic steno-
sis suffered from cutaneous or mucosal bleeding, and
67–92% had haematological abnormalities which correlated
with the severity. Haematological investigations were per-
formed 1 day, 7 days and 6 months postoperatively. The
abnormalities corrected on the first day, but tended to recur
at 6 months, especially when there was a mismatch between
patient and prosthesis [25].
Yoshida and colleagues showed electrophoretic deficits
of large multimers of vWF in patients with aortic stenosis

which resolved postoperatively, but no differences in pre-
and postoperative vWF were found in patients with severe
mitral regurgitation [10].
In a study of patients with aortic stenosis, a higher
incidence of prolonged bleeding time was found which
corrected following surgery [16]. Others have reported
loss of large multimer vWF preoperatively but bleeding
time normalised 2 days after surgery and vWF multimers
normalised after 7 days [26]. Yet others demonstrated a
causal relationship between aortic stenosis and vWS-2A
[27, 28].
By 1987, 30 cases of upper and lower gastrointestinal
angiodysplasia had been cured by AVR. Angiodysplasia might
remain visible at endoscopy even after AVR, but only 1
of the 30 cases ever developed recurrent gastrointestinal
bleeding [2].
Diagnosis
In an elderly patient with established aortic stenosis, devel-
opment of iron deficiency anaemia should raise the possibil-
ity of Heyde syndrome. Initial investigations should explore
other possibilities such as underlying gastrointestinal malig-
nancy, coeliac disease or nutritional deficiency. The presence
of angiodysplasia on sigmoidoscopy or colonoscopy or a
failure of the investigations to find any clear site of gas-
trointestinal bleeding, should raise the possibility of Heyde
syndrome. For patients in whom initial investigations show
no abnormality, angiodysplasia may be diagnosed by capsule
endoscopy.
Patients presenting with gastrointestinal bleeding should
be examined carefully for aortic stenosis and there should
be a low threshold for arranging echocardiogram in patients
with normal colonoscopies or proven arteriovenous malfor-
mations. It is important to consider the possible presence
of Heyde syndrome if metallic AVR is being considered, as
there is a need for lifelong anticoagulation subsequently.
In vWS-2A, routine screening tests for vWS are usually
normal. The gold standard is gel electrophoresis of vWF [6].
vWS-2A is characterised by absence of large vWF multimers
seen on SDS-agarose electrophoresis [21]. The sensitivity
of various tests for vWS-2A has been ranked as follows:
gel electrophoresis (most sensitive), PFA-100 closure time,
skin bleeding time, vWF ristocetin cofactor activity and vWF
antigen level (least sensitive) [2].
Treatment
Patients with Heyde syndrome who are treated by intesti-
nal resection generally continue to bleed from other sites,
while AVR usually cures the clotting disorder and anaemia.
A retrospective study of 91 patients with aortic stenosis and
chronic unexplained gastrointestinal bleeding revealed that
bleeding ceased in 93% of patients treated by valve replace-
ment, compared with 5% of those managed surgically, with
or without bowel resection. The figure of 5% represents one
Heyde syndrome
patient though, who had recurrent bleeding due to warfarin
toxicity [6, 29].
Treatments of vWS-2A itself include factor VIII/vWF
concentrates and desmopressin [6], but acquired vWS does
not respond well to these [22]. Patients with acquired vWS-
2A may be more prone to bleeding under cardiopulmonary
bypass, and there is a case for investigating and treating it
prophylactically, even if it is not symptomatic. It has been
proposed that guidelines for the management of aortic steno-
sis should have bleeding from intestinal angiodysplasia with
demonstrable acquired vWS added as an indication for valve
replacement, and that monitoring of the severity of acquired
vWS-2A should be considered as one of the factors determin-
ing the timing of surgery [6, 20]. The PFA-100 system may
provide a commercially available screening tool for vWS-2A
[2].
Episodes of severe bleeding may necessitate blood trans-
fusions and emergency bowel resection. The resolution of
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gastrointestinal bleeding following AVR has strengthened
the recommendation for AVR in Heyde syndrome [6, 13, 15,
30, 31]. Some authors have supported AVR in the presence
of iron deficiency anaemia, even if the aortic valve stenosis is
clinically insignificant.
Many elderly patients may be unfit for AVR or may refuse
surgery. Conservative management includes oral iron supple-
ments but regular blood transfusions may be necessary. Com-
bined oestrogen and progesterone have been used to reduce
bleeding from angiodysplasia, although the mechanism of
action is not understood [2]. In serious cases this could halve
transfusion requirements [32]. In patients with severe
recurrent bleeding, endoscopy with laser therapy may be an
option. In these circumstances treatment with octreotide
may be considered [33]. Many elderly patients have
co-morbidities requiring anticoagulants or antiplatelet agents,
but they should be avoided, particularly in severe cases.
Conclusion
Iron deficiency anaemia and aortic stenosis are common in
the elderly, but their association with angiodysplasia and
bleeding is not generally recognised. Heyde syndrome is a
complex disorder, resulting from interactions between aor-
tic stenosis, intestinal angiodysplasia and acquired vWS-2A.
AVR rather than bowel resection leads to long-term resolu-
tion of anaemia and should be considered in severe cases.
Early diagnosis and appropriate treatment of Heyde syn-
drome is essential but requires teamwork and liaison between
different specialities.
Key points
r There is an association between severe aortic stenosis and
bleeding from intestinal angiodysplasia.
r Aortic stenosis leads to acquired vWS-2A.
r Valve replacement offer long-term resolution of bleeding.
269
M. W. Massyn and S. A. Khan
r All patients with aortic stenosis should be screened for
iron deficiency anaemia.
r Antiplatelet and anticoagulants should be used with cau-
tion in these patients to reduce the risk of bleeding.
Conflicts of interest
None.
Supplementary data
Supplementary data are available at Age and Ageing online.
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Received 17 September 2008; accepted in revised form
11 January 2009