Heyde's syndrome

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Heyde's syndrome
Aortic stenosis rheumatic, gross pathology 20G0014 lores.jpg
A stenotic aortic valve
Specialty Cardiology, general surgery
Symptoms Aortic valve stenosis symptoms:

Chest pain (angina) or tightness Shortness of breath, especially during exertion or when lying down Fatigue or weakness Irregular heartbeat or heart palpitations Dizziness or fainting episodes Gastrointestinal bleeding symptoms: Occult (hidden) or overt (visible) blood in the stool Black, tarry stools (melena) Blood in vomit (hematemesis) Fatigue or weakness due to chronic blood loss

Anemia (low red blood cell count)

Contents

Complications Gastrointestinal bleeding, Iron-deficiency anemia, Cardiovascular complications, Thromboembolic events, and Endocarditis.
Usual onsetUncommon.
Duration23.8±39 months.
TypesAortic stenosis, gastrointestinal angiodysplasia, and acquired von Willebrand disorder.
CausesDeficiency of high-molecular-weight multimers of von Willebrand factor.
Risk factors Recurrent gastrointestinal bleeding and heart failure.
Diagnostic method CBC, coagulation studies, metabolic panel, and test for fecal occult blood.
Differential diagnosis Aortic stenosis, gastrointestinal bleeding, and evidence that supports the presence of AVWS.
PreventionUnknown.
TreatmentAortic valve replacement, medical therapy, endoscopic interventions, and colonic surgery.
Medication None.
Prognosis Excellent in patients who undergo aortic valve replacement, which is both effective and often curative.
Frequency7.5% of persons 75 years of age or older.
Deaths29.16% (from 48 to 62 per 100,000) and 22.7% (from 3.7 to 4.54 per 100,000) from 2007 to 2014.

Heyde's syndrome is a syndrome of gastrointestinal bleeding from angiodysplasia in the presence of aortic stenosis. [1] [2]

It is named after Edward C. Heyde, MD, who first noted the association in 1958. [3] It is caused by cleavage of Von Willebrand factor (vWF) due to high shear stress forces from aortic valvular stenosis. This results in Von Willebrand disease type IIA (acquired). [4] [5]

Signs and symptoms

Pathophysiology

Pathophysiology of Heyde's Syndrome a. von Willebrand Factor (vWF) passes through a normal aortic valve and remains in its coiled form. b. vWF passes through a stenotic aortic valve and uncoils. c. Coiled vWF is unaffected by the catabolic enzyme ADAMTS13. d. Uncoiled vWF is cleaved in two by ADAMTS13. e. In damaged arterioles vWF uncoils and becomes active. It binds collagen, platelets bind to vWF, and a clot forms. f. Inactive vWF cannot bind to the collagen, no clot forms. Heydes Syndrome Pathophysiology.svg
Pathophysiology of Heyde's Syndrome
a. von Willebrand Factor (vWF) passes through a normal aortic valve and remains in its coiled form.
b. vWF passes through a stenotic aortic valve and uncoils.
c. Coiled vWF is unaffected by the catabolic enzyme ADAMTS13.
d. Uncoiled vWF is cleaved in two by ADAMTS13.
e. In damaged arterioles vWF uncoils and becomes active. It binds collagen, platelets bind to vWF, and a clot forms.
f. Inactive vWF cannot bind to the collagen, no clot forms.

Von Willebrand factor is synthesized in the walls of the blood vessels and circulates freely in the blood in a folded form. When it encounters damage to the wall of a blood vessel, particularly in situations of high velocity blood flow, it binds to the collagen beneath the damaged endothelium and uncoils into its active form. Platelets are attracted to this activated form of von Willebrand factor and they accumulate and block the damaged area, preventing bleeding [ citation needed ].

In people with aortic valve stenosis, the stenotic aortic valve becomes increasingly narrowed resulting in an increase in speed of the blood through the valve in order to maintain cardiac output. This combination of a narrow opening and a higher flow rate results in an increased shear stress on the blood. This higher stress causes von Willebrand factor to unravel in the same way it would on encountering an injury site. [6] [7] [8] As part of the normal hemostasis of the blood, when von Willebrand factor changes conformation into its active state, it is degraded by its natural catabolic enzyme ADAMTS13, rendering it incapable of binding the collagen at an injury site. [4] [6] As the quantity of von Willebrand factor in the blood decreases, the rate of bleeding dramatically increases. [9]

The unraveling of high molecular weight von Willebrand factor in conditions of high shear stress is essential in the prevention of bleeding in the vasculature of the gastrointestinal system where small arterioles are common, as platelets cannot bind to damaged blood vessel walls well in such conditions. [7] This is particularly true in the presence of intestinal angiodysplasia, where arteriovenous malformations lead to very high blood flow, and so the loss of von Willebrand factor can lead to much more extensive bleeding from these lesions. [9] [10] When people with aortic stenosis also have gastrointestinal bleeding, it is invariably from angiodysplasia. [4] [7]

It has been hypothesized that defects in high molecular weight von Willebrand factor could actually be the cause of the arteriovenus malformations in intestinal angiodysplasia, rather than just making existing angiodysplasic lesions bleed. This hypothesis is complicated by the extremely high rates of intestinal angiodysplasia in older people (who also have the highest rate of aortic stenosis), and thus requires further research for confirmation. [4] [11]

Diagnosis

Heyde's syndrome is now known to be gastrointestinal bleeding from angiodysplasic lesions due to acquired vWD-2A deficiency secondary to aortic stenosis, and the diagnosis is made by confirming the presence of those three things. Gastrointestinal bleeding may present as bloody vomit, dark, tarry stool from metabolized blood, or fresh blood in the stool. In a person presenting with these symptoms, endoscopy, gastroscopy, and/or colonoscopy should be performed to confirm the presence of angiodysplasia. [12] [13] Aortic stenosis can be diagnosed by auscultation for characteristic heart sounds, particularly a crescendo-decrescendo (i.e., 'ejection') murmur, followed by echocardiography to measure aortic valve area (see diagnosis of aortic stenosis). While Heyde's syndrome may exist alone with no other symptoms of aortic stenosis, [2] the person could also present with evidence of heart failure, fainting, or chest pain. Finally, Heyde's syndrome can be confirmed using blood tests for vWD-2A, although traditional blood tests for von Willebrand factor may result in false negatives due to the subtlety of the abnormality. [13] The gold standard for diagnosis is gel electrophoresis; in people with vWD-2A, the large molecular weight von Willebrand factors will be absent from the SDS-agarose electrophoresis plate. [2]

Management

The definitive treatment for Heyde's syndrome is surgical replacement of the aortic valve. [10] [14] Recently, it has been proposed that transcatheter aortic valve implantation (TAVI) can also be used for definitive management. [15] Direct surgical treatment of the bleeding (e.g. surgical resection of the bleeding portion of the bowel) is only rarely effective. [14] [16]

Medical management of symptoms is possible also, although by necessity temporary, as definitive surgical management is required to bring levels of von Willebrand factor back to normal. [4] In severe bleeding, blood transfusions and IV fluid infusions can be used to maintain blood pressure. In addition, desmopressin (DDAVP) is known to be effective in people with von Willebrand's disease, [17] [18] including people with valvular heart disease. [19] [20] Desmopressin stimulates release of von Willebrand factor from blood vessel endothelial cells by acting on the V2 receptor, which leads to decreased breakdown of Factor VIII. Desmopressin is thus sometimes used directly to treat mild to moderate acquired von Willebrand's disease and is an effective prophylactic agent for the reduction of bleeding during heart valve replacement surgery. [19] [20]

Epidemiology

The exact prevalence of the syndrome is unknown, because both aortic stenosis and angiodysplasia are common diseases in the elderly. A retrospective chart review of 3.8 million people in Northern Ireland found that the incidence of gastrointestinal bleeding in people with any diagnosis of aortic stenosis (they did not subgroup people by severity) was just 0.9%. They also found that the reverse correlation—the incidence of aortic stenosis in people with gastrointestinal bleeding—was 1.5%. [21] However, in 2003 a study of 50 people with aortic stenosis severe enough to warrant immediate valve replacement found GI bleeding in 21% of people, [10] and another study done in the USA looking at angiodysplasia rather than GI bleeding found that the prevalence of aortic stenosis was 31% compared to 14% in the control group. [4] [22] It is a disease mainly found in older adults but a rare case of Heyde's syndrome has been reported in children. [23]

History

The American internist Edward C. Heyde originally described the syndrome in a 1958 letter to the New England Journal of Medicine , reporting on ten patients with the association. [3] Heyde graduated from Johns Hopkins School of Medicine in 1938, served three years in the Army Medical Corps in World War II and joined the Vancouver Clinic, Vancouver, Washington in 1948, practicing medicine there for 31 years. He died on October 13, 2004.[ citation needed ]

In the 45 years following its initial description, no plausible explanations could be found for the association between aortic valve stenosis and gastrointestinal bleeding. Indeed, the association itself was questioned by a number of researchers. [5] [24] Several studies demonstrated a statistically significant association between aortic stenosis and gastrointestinal bleeding, [25] [26] [27] and in 1987 King et al. even noted the successful resolution of bleeding symptoms with aortic valve replacement in 93% of people, compared to just 5% in people where the bleeding was treated surgically. [16] However, the potential causal association between the two conditions remained elusive and controversial.[ citation needed ]

Several hypotheses for the association were proposed, the most prominent being the idea that there is no causal relationship between aortic stenosis and gastrointestinal bleeding, they are both just common conditions in the elderly, and they sometimes overlap. Other hypotheses included hypoxia of the colonic mucosa and bowel ischemia due to low blood flow, both of which were discounted by later research. [4] [5] Another early hypothesis of note was proposed by Greenstein et al. in 1986. [27] They suggested that GI bleeding could be caused by thinning of the wall of the cecum due to abnormal pulse waves in the ileocolic artery (an artery that supplies blood to the cecum) causing dilation of that artery. Specifically, they note that the usual anacrotic and dicrotic notches were absent from the pulse waves of their people with aortic stenosis. There has been no further research investigating this hypothesis, however, as it has been eclipsed by newer research into acquired von Willebrand's disease.[ citation needed ]

The important role of depletion of von Willebrand factor in aortic stenosis was first proposed in 1992 by Warkentin et al. [7] They noted a known association between aortic stenosis (in addition to other cardiac diseases) and acquired von Willebrand's disease type IIA, [20] which is corrected by surgical replacement of the aortic valve. They also noted that von Willebrand's disease is known to cause bleeding from angiodysplasia. Based on these facts, they hypothesized that acquired von Willebrand's disease is the true culprit behind gastrointestinal bleeding in aortic stenosis. They also proposed a possible mechanism for the acquired von Willebrand's disease, noting that von Willebrand factor is most active in 'high shear' vessels (meaning small vessels in which blood flows rapidly). They used this fact to hypothesize that this may mean that von Willebrand factor is activated in the narrowed stenotic aortic valve and thus cleared from circulation at a much higher rate than in healthy individuals.[ citation needed ]

This hypothesis received strong support in 2003 by the publication of a report by Vincentelli et al. that demonstrated a strong association between von Willebrand factor defects and the severity of aortic valve stenosis. [10] They also showed these defects resolved within hours following aortic valve replacement surgery and remained resolved in most people, although in some people the von Willebrand factor defects had returned at six months. Following this observation the shear stress dependent depletion of von Willebrand factor was confirmed, and the protease responsible, ADAMTS13, was identified. [4]

Related Research Articles

<span class="mw-page-title-main">Aortic stenosis</span> Narrowing of the exit of the hearts left ventricle

Aortic stenosis is the narrowing of the exit of the left ventricle of the heart, such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse over time. Symptoms often come on gradually with a decreased ability to exercise often occurring first. If heart failure, loss of consciousness, or heart related chest pain occur due to AS the outcomes are worse. Loss of consciousness typically occurs with standing or exercising. Signs of heart failure include shortness of breath especially when lying down, at night, or with exercise, and swelling of the legs. Thickening of the valve without narrowing is known as aortic sclerosis.

von Willebrand disease Medical condition

Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition.

<span class="mw-page-title-main">Thrombotic thrombocytopenic purpura</span> Medical condition

Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur.

In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel. It is the first stage of wound healing. This involves coagulation, which changes blood from a liquid to a gel. Intact blood vessels are central to moderating blood's tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin, and prevent platelet aggregation with nitric oxide and prostacyclin. When endothelium of a blood vessel is damaged, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor, which initiate the maintenance of hemostasis after injury. Hemostasis involves three major steps:

<span class="mw-page-title-main">Hemolytic–uremic syndrome</span> Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney injury, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

<span class="mw-page-title-main">Vascular surgery</span> Medical specialty, operative procedures for the treatment of vascular disorders

Vascular surgery is a surgical subspecialty in which vascular diseases involving the arteries, veins, or lymphatic vessels, are managed by medical therapy, minimally-invasive catheter procedures and surgical reconstruction. The specialty evolved from general and cardiovascular surgery where it refined the management of just the vessels, no longer treating the heart or other organs. Modern vascular surgery includes open surgery techniques, endovascular techniques and medical management of vascular diseases - unlike the parent specialities. The vascular surgeon is trained in the diagnosis and management of diseases affecting all parts of the vascular system excluding the coronaries and intracranial vasculature. Vascular surgeons also are called to assist other physicians to carry out surgery near vessels, or to salvage vascular injuries that include hemorrhage control, dissection, occlusion or simply for safe exposure of vascular structures.

von Willebrand factor Mammalian protein involved in blood clotting

Von Willebrand factor (VWF) is a blood glycoprotein that promotes hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic–uremic syndrome. Increased plasma levels in many cardiovascular, neoplastic, metabolic, and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may predict an increased risk of thrombosis.

<span class="mw-page-title-main">Aortic regurgitation</span> Medical condition

Aortic regurgitation (AR), also known as aortic insufficiency (AI), is the leaking of the aortic valve of the heart that causes blood to flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle. As a consequence, the cardiac muscle is forced to work harder than normal.

<span class="mw-page-title-main">Angiodysplasia</span> Medical condition

In medicine (gastroenterology), angiodysplasia is a small vascular malformation of the gut. It is a common cause of otherwise unexplained gastrointestinal bleeding and anemia. Lesions are often multiple, and frequently involve the cecum or ascending colon, although they can occur at other places. Treatment may be with colonoscopic interventions, angiography and embolization, medication, or occasionally surgery.

<span class="mw-page-title-main">Bicuspid aortic valve</span> Medical condition

Bicuspid aortic valve (BAV) is a form of heart disease in which two of the leaflets of the aortic valve fuse during development in the womb resulting in a two-leaflet (bicuspid) valve instead of the normal three-leaflet (tricuspid) valve. BAV is the most common cause of heart disease present at birth and affects approximately 1.3% of adults. Normally, the mitral valve is the only bicuspid valve and this is situated between the heart's left atrium and left ventricle. Heart valves play a crucial role in ensuring the unidirectional flow of blood from the atrium to the ventricles, or from the ventricle to the aorta or pulmonary trunk. BAV is normally inherited.

<span class="mw-page-title-main">Desmopressin</span> Medication

Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should only be used for mild to moderate cases. It may be given in the nose, by injection into a vein, by mouth, or under the tongue.

<span class="mw-page-title-main">Congenital heart defect</span> Defect in the structure of the heart that is present at birth

A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular disease. Signs and symptoms depend on the specific type of defect. Symptoms can vary from none to life-threatening. When present, symptoms are variable and may include rapid breathing, bluish skin (cyanosis), poor weight gain, and feeling tired. CHD does not cause chest pain. Most congenital heart defects are not associated with other diseases. A complication of CHD is heart failure.

<span class="mw-page-title-main">Coarctation of the aorta</span> Medical condition

Coarctation of the aorta, also called aortic narrowing, is a congenital condition whereby the aorta is narrow, usually in the area where the ductus arteriosus inserts. The word coarctation means "pressing or drawing together; narrowing". Coarctations are most common in the aortic arch. The arch may be small in babies with coarctations. Other heart defects may also occur when coarctation is present, typically occurring on the left side of the heart. When a patient has a coarctation, the left ventricle has to work harder. Since the aorta is narrowed, the left ventricle must generate a much higher pressure than normal in order to force enough blood through the aorta to deliver blood to the lower part of the body. If the narrowing is severe enough, the left ventricle may not be strong enough to push blood through the coarctation, thus resulting in a lack of blood to the lower half of the body. Physiologically its complete form is manifested as interrupted aortic arch.

Aortic valve replacement is a procedure whereby the failing aortic valve of a patient's heart is replaced with an artificial heart valve. The aortic valve may need to be replaced because:

<span class="mw-page-title-main">ADAMTS13</span> Metalloprotease enzyme

ADAMTS13 —also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor (vWf), a large protein involved in blood clotting. It is secreted into the blood and degrades large vWf multimers, decreasing their activity, hence ADAMTS13 acts to reduces thrombus formation.

<span class="mw-page-title-main">Valvular heart disease</span> Disease in the valves of the heart

Valvular heart disease is any cardiovascular disease process involving one or more of the four valves of the heart. These conditions occur largely as a consequence of aging, but may also be the result of congenital (inborn) abnormalities or specific disease or physiologic processes including rheumatic heart disease and pregnancy.

<span class="mw-page-title-main">Aortic valvuloplasty</span>

Aortic valvuloplasty, also known as balloon aortic valvuloplasty (BAV), is a procedure used to improve blood flow through the aortic valve in conditions that cause aortic stenosis, or narrowing of the aortic valve. It can be performed in various patient populations including fetuses, newborns, children, adults, and pregnant women. The procedure involves using a balloon catheter to dilate the narrowed aortic valve by inflating the balloon.

<span class="mw-page-title-main">Ortner's syndrome</span> Medical condition

Ortner's syndrome is a rare cardiovocal syndrome and refers to recurrent laryngeal nerve palsy from cardiovascular disease. It was first described by Norbert Ortner (1865–1935), an Austrian physician, in 1897.

<span class="mw-page-title-main">Percutaneous aortic valve replacement</span> Technique for replacement of the aortic valve in a heart

Transcatheter aortic valve replacement (TAVR) is the replacement of the aortic valve of the heart through the blood vessels. The replacement valve is delivered via one of several access methods: transfemoral, transapical, subclavian, direct aortic, and transcaval, among others.

Vonicog alfa, sold under the brand names Vonvendi and Veyvondi, is a medication used to control bleeding in adults with von Willebrand disease. It is a recombinant von Willebrand factor.

References

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  18. ↑ Federici AB, Mazurier C, Berntorp E, Lee CA, Scharrer I, Goudemand J, Lethagen S, Nitu I, Ludwig G, Hilbert L, Mannucci PM (2004). "Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study". Blood . 103 (6): 2032–8. doi: 10.1182/blood-2003-06-2072 . ISSN   0006-4971. PMID   14630825.
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