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RELATIONSHIP BETWEEN VON WILLEBRAND FACTOR
DEGRADATION AND HEYDE SYNDROME DIAGNOSIS
Marcelo Flavio Gomes Jardim Filho1
Abstract: Heyde’s Syndrome is a clinical condition characterized by the coexistence of aortic stenosis
and gastrointestinal bleeding, typically associated with angiodysplasia. This study reviews recent
literature, highlighting the relationship between aortic stenosis and the degradation of von Willebrand
factor (vWF), leading to the development of acquired von Willebrand disease (AVWD). The review
addresses the key biochemical parameters and diagnostic methods used for identifying the syndrome,
emphasizing the importance of echocardiography for detecting aortic stenosis and multimer analysis
of vWF for conrming AVWD. The analysis includes discussions on the diagnostic challenges and
clinical implications of the syndrome, proposing guidelines that could improve therapeutic management
and reduce associated morbidity. It concludes that an integrated, evidence-based diagnostic approach
is essential for the early detection and eective treatment of Heyde’s Syndrome.
Keywords: Diagnosis; von Willebrand Factor; Heyde’s Syndrome
1 Cardiologist, title of Specialist in Cardiology from SBC, Certicate of Specialist in Hyperten-
sion by the Brazilian Society of Hypertension, Major Medical of the Military Police of RJ, duty of the
Coronary Unit of the Salgado Municipal Hospital, Public Servant Municipal
Introduction
Diverticular Disease and angiodysplasia/arteriovenous malformations (AVMs) are the main
causes of lower gastrointestinal bleeding (LGIB) in the elderly population. In contrast, Heyde’s
syndrome, a rare condition more commonly seen in the elderly, is characterized by a unique
relationship between aortic stenosis and gastrointestinal bleeding, where the source of bleeding is
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typically angiodysplasia. The most widely accepted hypothesis to explain the pathophysiology of
Heyde syndrome is acquired von Willebrand syndrome (AVWS). Specically, there is evidence in
the literature demonstrating the destruction of high molecular weight von Willebrand factor (vWF)
multimers on gel electrophoresis, secondary to shear by a stenotic aortic valve, resulting in AVWS
and, consequently, gastrointestinal hemorrhage (Tsuchiya, S.; Matsumoto, Y.; Doman, T.; Fujiya, T.;
Sugisawa, J.; et al, 2020)
However, this hypothesis remains controversial, as there are cases reported in the literature
where no evidence of such destruction was found, raising doubts about the universality of this
explanation for all cases of Heyde’s syndrome. Since Dr. Heyde’s rst description in 1958, numerous
cases of this unique association have been reported, but to date, no comprehensive systematic review
of case reports has been conducted. This study presents a systematic review of this type, summarizing
the epidemiology, risk factors, clinical characteristics, diagnostic approach, including the prevalence
of AVWS, and the management of Heyde’s syndrome according to the cases reported in the literature
(Islam, S.; Cevik, C.; Islam, E.; Attaya, H.; Nugent, K, 2011).
In the literature, several parameters have been discussed to aid in the diagnosis of Heyde’s
syndrome. Among them, the analysis of von Willebrand factor, a glycoprotein crucial for primary
hemostasis, whose function is frequently compromised in patients with severe aortic stenosis, stands
out. The fragmentation of von Willebrand’s factor, induced by the mechanical stress generated by
aortic stenosis, is one of the most relevant biochemical markers for the diagnosis of this syndrome,
as pointed out by studies such as those by Venerito et al. (2021) and Tsuchiya et al. (2020). The
degradation of this factor results in a lower capacity for platelet adhesion, predisposing patients to
gastrointestinal hemorrhages.
Despite progress in understanding this syndrome, diagnosis still presents considerable
challenges, in part due to the absence of standardized diagnostic criteria and overlapping symptoms with
other conditions. Identication of aortic stenosis, often performed by transthoracic echocardiography,
is a critical step, but should be complemented by laboratory evaluation of von Willebrand factor and
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endoscopic imaging methods for the detection of angiodysplasias.
This study aims to review the recent scientic literature on Heyde’s Syndrome, focusing
on biochemical parameters and diagnostic approaches that can facilitate the early and accurate
identication of this condition. The consolidation of this information aims to contribute to the
development of clinical guidelines that improve therapeutic management and reduce the morbidity
associated with the syndrome.
This revised introduction provides a clearer and more articulate context on the relevance of
Heyde’s syndrome in clinical practice, highlighting the importance of diagnostic advances and the
need for well-established guidelines for the eective management of this condition.
PATHOPHYSIOLOGY
Aortic stenosis is widely recognized as the most common valvular heart disease and
represents the main indication for valve surgery in western regions. Specic risk factors, such as the
presence of bicuspid or tricuspid aortic valve, play a signicant role, accounting for 50% and 30-40%
of cases, respectively. However, degenerative aortic stenosis is best understood as a multifactorial
process similar to atherosclerosis, where the risk factors for its development coincide with those
already associated with atherosclerosis. Notably, coronary artery disease is present in 30% of patients
with mild to moderate aortic stenosis and in 50% of those with severe stenosis (Messika-Zeitoun;
Lloyd, 2018; Blackshear et al., 2013).
For valvular areas smaller than 1.5 cm², both the transvalvular gradient and maximum
velocity tend to increase, often resulting in turbulent or jet ows that increase the shear stress on the
aortic valve (Natorska et al., 2016). Under conditions of low shear stress, von Willebrand factor (vWF)
circulates in a globular and quiescent form, being activated only in situations of vascular injury. When
activated, vWF adopts a linear conformation that facilitates its interaction with platelets, promoting
their activation and adhesion. High molecular weight multimers (MEPM) in vWF are considered
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highly eective due to their ability to spontaneously bind to both platelets and collagen (Hilligass;
Limdi, 2016; Van Belle et al., 2015).
Under normal conditions, the enzyme ADAMTS13, a disintegrin and metalloprotease,
regulates the distribution of high molecular weight multimers to prevent thrombus formation. However,
in situations of high shear stress, such as aortic stenosis, MEPM undergo dynamic modulations that
result in the loss of their globular shape, exposing the sites of attachment to the ADAMTS13 and
facilitating their cleavage (Tiede et al., 2008). The decrease in multimers with higher molecular
weight, with percentages below 10.5%, is associated with an increased hemorrhagic risk (Hilligass;
Limdi, 2016).
The importance of shear stresses in hemostasis has been conrmed by studies using
ventricular assist devices. These studies have shown that a high-velocity and shear stress environment
results in the progressive loss of MEPM in all patients, with a signicant association with bleeding
complications, particularly in the gastrointestinal tract, observed in 20-40% of patients (Spangenberg
et al., 2015).
When studying 95 patients with moderate to severe aortic stenosis, Spangenberg et al. (2015)
observed a reduction in MEPM in 42% of cases. Similarly, Vincentelli et al. (2003) reported that 79% of
patients with severe aortic stenosis and 75% of those with moderate stenosis had a signicant decrease
in MEPM. However, in a study with a comparable sample size, only 20% of patients exhibited a
signicant reduction in MEPM, and these individuals showed a 34.8% higher maximum transvalvular
gradient compared to patients with normal percentages of MEPM (Natorska et al., 2016).
Although these ndings support the correlation between aortic stenosis and von Willebrand
factor decit, the disparity in reported rates (42% vs. 79-75% vs. 20%) indicates that this relationship
is complex and dependent on individual factors, including age, the presence of comorbidities such as
thyroid disease, and the severity of aortic stenosis (Franchini et al., 2004). In patients with thyroid
pathologies, for example, approximately 2.6% demonstrate coagulation alterations consistent with
acquired von Willebrand disease (Franchini et al., 2004).
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Bowen et al. (2003) demonstrated that blood group, especially group O, inuences
susceptibility to proteolysis and vWF clearance by ADAMTS13. VWF, synthesized in endothelial
cells, megakaryocytes and platelets, undergoes a series of modications until its glycosylation. The
study showed that the oligosaccharides present in the VWF structure protect the cleavage site by the
ADAMTS13. The presence of blood group O-specic oligosaccharides appears to prevent proteolysis,
resulting in lower baseline VWF levels in these individuals compared with those of other blood groups.
Regarding the role of age in Heyde’s syndrome, Balaoing et al. (2014) observed that vWF,
expressed and secreted by endothelial cells throughout life, tends to accumulate in the valvular
subendothelium, promoting the formation of nodules and subsequent calcication. This accumulation
of vWF in an older, dispersed, and disorganized extracellular matrix may aect the development
and progression of calcication aortic stenosis. In addition, the study indicated that ADAMTS13
expression is not aected by age, suggesting an increasing imbalance in the vWF/ADAMTS13 ratio
over time, which may explain the higher hemorrhagic risk in elderly patients (Balaoing et al., 2014).
Acquired von Willebrand factor (vWF) decit, when associated with episodes of hemorrhage
in individuals without a personal or family history of recurrent hemorrhage, is an indication for
the diagnosis of acquired von Willebrand disease (VWD). This condition, although rare, with an
estimated prevalence of 0.04%, is associated with signicant morbidity. It is characterized by a
qualitative decit in vWF, similar to that observed in hereditary von Willebrand disease type 2A
(Giannini et al., 2011). Although most patients do not have a history of hemorrhages, about 48%
manifest hemorrhagic diathesis, often evidenced by episodes of mucocutaneous bleeding, such as
epistaxis, gingival bleeding, and gastrointestinal hemorrhages (Giannini et al., 2011).
In the specic subgroup of individuals with VWD secondary to aortic stenosis, studies indicate
that, despite the vWF decit, only between 9% and 21% of patients have a history of hemorrhage or
anemia (Vincentelli et al., 2003). Natorska et al. (2016) suggest that mechanisms intrinsic to aortic
stenosis itself may explain why the incidence of hemorrhages or anemia in these patients is lower than
expected. In fact, in patients with moderate to severe aortic stenosis and with an elevated transvalvular
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gradient, the decit of high molecular weight multimers (MEPM) is accompanied by an increase in
thrombin production and platelet activation. This phenomenon alters the hemostatic balance towards
thrombosis, promoting the formation of brin-rich thrombi, regardless of the presence of vWF
(Natorska et al., 2011).
Thus, understanding the pathophysiology of Heyde’s syndrome requires an analysis of the
mechanisms that connect aortic stenosis with gastrointestinal bleeding, particularly in elderly patients.
This complex clinical picture is mediated by the loss of high molecular weight von Willebrand factor
(MEPM vWF) multimers, a condition that leads to acquired von Willebrand disease (VWAD) and is
closely related to hemostatic dysfunction.
Aging, a key factor that exacerbates this condition, as it is associated with hypoxia of
the gastrointestinal mucosa and progressive venular dilation, which in turn contributes to the
incompetence of the precapillary sphincters. These factors create an environment conducive to the
development of gastrointestinal (GI) angiodysplasia, one of the main causes of hemorrhage in this
population. Recent studies highlight that the interaction between vWF and angiopoietin-2 (Ang-2)
in endothelial cells modulates signaling through the VEGFR2 receptor, a process critical for cell
proliferation and migration. These interactions are essential in angiogenesis, and the dysregulation of
this process, exacerbated by aortic stenosis, results in an anomalous vascularization characteristic of
angiodysplasia (Randi, Laan, 2017; Gragnano et al., 2017).
Also, in vascular smooth muscle cells, vWF plays a signicant role in the maturation of
vessels, a process that is also aected by its deciency. This not only contributes to the predisposition
to bleeding, but also to the formation of anomalous vessels, which can bleed easily, further aggravating
the clinical condition of patients with Heyde’s Syndrome (Hudzik, Wilczek, & Gasior, 2016).
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DIAGNOSIS
Gastrointestinal Angioplasty
In individuals who experience anemia or gastrointestinal bleeding, it is essential to investigate
possible sources of gastrointestinal bleeding, including gastric or duodenal ulcers, diverticular
disease, neoplasms, and inammatory bowel diseases (Hudzik, Wilczek, Gasior, 2016). The rst
recommended approach is to perform upper GI endoscopy and colonoscopy, to comprehensively
evaluate the possible causes of bleeding.
Capsule endoscopy is a valuable method for visualizing the small intestine, and is considered
a safe and eective technique for identifying lesions that may go unnoticed in other endoscopic
examinations. However, this technique has limitations, such as the diculty in identifying all lesions,
especially those located in the distal small intestine, impaired visibility in cases of active hemorrhage,
and the impossibility of direct intervention (Thompson et al., 2012; Michot et al., 2012). To overcome
these limitations, balloon enteroscopy, either one or two balloons, can be employed. Although
enteroscopy oers better image quality, it also does not allow, in isolation, extensive therapeutic
maneuvers (Randi & Laan, 2017).
Endoscopically, angiodysplasia is characterized by small (usually smaller than 5 mm), at,
cherry-red lesions distributed along the gastrointestinal mucosa. These lesions are often seen in
the right colon and cecum, areas where intestinal wall thickness and tension seem to increase the
predisposition to the development of these anomalies (Michot et al., 2012). These lesions may also
have a paler surrounding mucosa, giving them a “clear halo” appearance, which is characteristic in
some cases of angiodysplasia (Hudzik, Wilczek, Gasior, 2016).
The success of any endoscopic procedure depends on several factors, including the operator’s
experience, visibility during the procedure, and the location and size of the lesion. Due to the possibility
of confusion with areas of inammation or trauma, repeat upper GI endoscopy or colonoscopy is
recommended in cases of high clinical suspicion or when the initial examination is of poor quality,
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before considering investigation of the small bowel with additional techniques (Blackshear et al.,
2013).
Radiographic techniques, such as angiography, are indicated for patients who have acute
gastrointestinal bleeding and whose endoscopies have not identied any lesion, or to conrm the
location of suspicious lesions previously visualized by endoscopy. Angiography is particularly useful
in the acute diagnosis of angiodysplasia, as it does not require previous bowel preparation, allows
precise localization of the hemorrhagic lesion, and enables therapeutic embolization of the lesion.
However, the associated risks, such as intestinal ischemia, should be considered, limiting their
indication to patients with severe hemorrhage and hemodynamic instability (Michot et al., 2012).
If relevant lesions are not identied, such as neoplasms or other gastrointestinal pathologies,
or if angiodysplasia is diagnosed, the possibility of valvular disease, such as aortic stenosis, should be
considered, suggesting the presence of Heyde’s Syndrome as a dierential diagnosis. In this context,
Blackshear et al. (2013) recommend performing an echocardiogram to evaluate aortic stenosis, along
with von Willebrand factor (vWF) testing, in order to exclude or conrm the presence of VWA.
Aortic Stenosis
Aortic stenosis, one of the main acquired valvular heart disease in elderly patients, is often
associated with gastrointestinal angiodysplasia and acquired von Willebrand disease (VWD), thus
characterizing Heyde’s Syndrome. The diagnosis of this syndrome often begins with the identication
of aortic stenosis, usually through a transthoracic echocardiogram.
The transthoracic echocardiogram is the test of choice to assess the presence and severity of
aortic stenosis. This examination allows a detailed visualization of the valve leaets, their movement,
the degree of calcication, and the function of the left ventricle. In patients with aortic stenosis,
signicant calcication of the valve cusps is often observed, which leads to a reduction in the valve
area and an increase in the pressure gradient across the valve. This pressure overload, in turn, can
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lead to decreased ventricular function over time, exacerbating clinical symptoms and increasing the
risk of complications such as gastrointestinal hemorrhages associated with angiodysplasia (Grimard,
Saord, & Burns, 2016).
The association between aortic stenosis and gastrointestinal hemorrhage due to angiodysplasia
is an important marker of Heyde’s syndrome. Calcication of the aortic valve and consequent alteration
of blood ow can lead to the degradation of high molecular weight von Willebrand factor (vWF)
multimers, resulting in VAWD. This condition predisposes patients to bleeding, especially in the
gastrointestinal tract. Early detection of aortic stenosis through echocardiography allows clinicians
to consider the possibility of Heyde syndrome in patients with a history of unexplained anemia or
episodes of gastrointestinal bleeding (Carità et al., 2016).
Conrmation of the diagnosis of Heyde’s syndrome requires not only the identication of
aortic stenosis, but also the investigation of laboratory parameters related to vWF. The decrease in
high molecular weight vWF multimers, often observed in patients with signicant aortic stenosis,
is indicative of VWD. This nding, combined with clinical symptoms and endoscopic evidence of
angiodysplasia, reinforces the diagnosis of Heyde’s Syndrome and guides therapeutic management,
which may include aortic valve replacement to resolve both stenosis and associated bleeding
complications (Van Belle et al., 2019).
Von Willebrand Acquired
The correct diagnostic approach to Heyde’s syndrome, with emphasis on the identication of
acquired von Willebrand disease (VWAD), requires the application of sensitive and specic laboratory
tests that can conrm changes in hemostasis. Given that VWD is a condition often associated with
severe aortic stenosis, it is essential that the initial evaluation includes a panel of coagulation tests.
The diagnostic protocol should begin with basic coagulation tests, including activated
partial thromboplastin time (APTT) and prothrombin time (PT). APTT, which measures the intrinsic
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and common coagulation pathway, may be normal or slightly increased in patients with VAWD.
Prothrombin time, in turn, usually does not show signicant changes. Along with these tests, it
is recommended to perform the PFA-100, a platelet function analyzer that has high sensitivity in
detecting defects in high molecular weight von Willebrand factor (MEPM) multimers, which are
often decreased in patients with aortic stenosis. Studies indicate that PFA-100 is prolonged in 92%
of patients with severe aortic stenosis and in 50% of those with moderate stenosis, although its use is
limited in specic conditions such as anemia (hemoglobin <10 mg/dL), hemolysis, thrombocytopenia,
or use of antiplatelet drugs (Hudzik, Wilczek, Gasior, 2016).
If VWD is suspected based on initial tests, it is imperative to order specic tests that allow a
denitive diagnosis. Landmark studies suggest that a sensitivity of 86% was achieved in patients with
VWD when reductions in at least one of the following parameters were observed (Tiede et al., 2008):
• VWF <50 IU/dL – This test quanties von Willebrand factor monomers regardless
of their polymerization. A signicant reduction in this value indicates a global factor
deciency, which is common in VAWD.
• VWF/Ag ratio <0.7 – This ratio reects the ratio between the activity of the ristocetin
cofactor and the vWF antigen, and its reduction may indicate the presence of inhibitory
antibodies or a selective loss of high molecular weight multimers.
• WF/Ag ratio <0.8 – This measure, which compares collagen binding with vWF antigen,
is a marker of loss or decrease in MEPM. Studies show that this ratio is decreased in 67%
of patients with severe aortic stenosis and in 25% of those with moderate stenosis.
Although the combination of tests such as PFA-100, APTT, and PT can provide a preliminary
diagnosis of acquired von Willebrand disease (VWA) in most cases, it is important to emphasize that
the exclusion of this condition should not be based on these results alone. In situations of high clinical
suspicion, it is recommended to perform electrophoresis of von Willebrand factor (vWF) multimers,
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which is considered the gold standard for the detection of structural anomalies in multimers. This test
allows the detailed identication of multimerized forms of vWF, highlighting reductions or absences
of high molecular weight multimers, which are indicative of VWD in patients with aortic stenosis
(Tiede et al., 2008).
The use of immunohistochemistry techniques, such as enzyme-linked immunosorbent assay
(ELISA), allows the detection of anti-vWF antibodies. Although the presence of these antibodies is
not considered a denitive diagnosis of VAWD, studies suggest that their presence may be associated
with a higher frequency of bleeding episodes, indicating cases of greater severity. These antibodies,
by interfering with normal vWF function, may exacerbate the predisposition to bleeding in patients
already vulnerable due to aortic stenosis, making the identication and monitoring of these markers
a useful tool for risk stratication and more personalized clinical management (Budde et al., 2008).
Final Thoughts
Heyde Syndrome is a complex and multifaceted condition that presents signicant challenges
in both diagnosis and clinical management. The association between aortic stenosis and gastrointestinal
bleeding, particularly due to angiodysplasia, highlights the importance of a diagnostic approach that
combines clinical, laboratory, and imaging methods. The literature reviewed throughout this study
underlines the relevance of integrating these tools for a more accurate and timely diagnosis.
The diagnosis of Heyde’s Syndrome should begin with the identication of aortic stenosis,
usually performed by means of transthoracic echocardiography, which allows a detailed evaluation of
valve function and the detection of associated hemodynamic changes. At the same time, laboratory
evaluation of von Willebrand factor (vWF), with emphasis on the analysis of high molecular weight
multimers, is crucial for the conrmation of acquired von Willebrand disease (VWAD), a hallmark
characteristic of this syndrome. The combination of these tests allows not only the conrmation of
the diagnosis, but also the stratication of patients according to the risk of bleeding complications.
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Although the understanding of the pathophysiology of Heyde syndrome has advanced
signicantly, there are still gaps in knowledge that require further investigation. Additional studies
are needed to explore the clinical variability observed among patients, as well as to develop new
therapeutic approaches that can improve clinical outcomes and quality of life for aected patients.
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