Heyde's syndrome is a syndrome of gastrointestinal bleeding from angiodysplasia in the presence of aortic stenosis. It is named after Edward C. Heyde, MD, who first noted the association in 1958. 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).
Pathophysiology
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 . 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. 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. As the quantity of von Willebrand factor in the blood decreases, the rate of bleeding dramatically increases. 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. 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. When people with aortic stenosis also have gastrointestinal bleeding, it is invariably from angiodysplasia. 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.
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. 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, 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. 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.
Management
The definitive treatment for Heyde's syndrome is surgical replacement of the aortic valve. Recently, it has been proposed that transcatheter aortic valve implantation (TAVI) can also be used for definitive management. Direct surgical treatment of the bleeding (e.g. surgical resection of the bleeding portion of the bowel) is only rarely effective. 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. 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, including people with valvular heart disease. 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.
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%. 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, 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. It is a disease mainly found in older adults but a rare case of Heyde's syndrome has been reported in children.
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