Heyde Syndrome

Etiology

Researchers believe that the collection of findings that constitute the diagnosis of Heyde syndrome is the direct result of increased circulatory shear forces and its effect on the physiologic confirmation and subsequent cleavage of large von Willebrand (VWF) multimers. In Heyde syndrome, increased shear forces are caused by stenosis at the aortic valve, although reports exist of similar pathophysiologic changes from other cardiac etiologies that result in increased circulatory turbulence, such as hypertrophic cardiomyopathy, complications of left ventricular assist device (LVAD) placement, and severe mitral regurgitation.[3]

Epidemiology

Heyde syndrome is typically a disease of the elderly population, diagnosed most often in patients greater than 65 years of age. At present, there is little data available on the actual prevalence of the syndrome, although the most prominent findings of Heyde syndrome (gastrointestinal bleeding in the setting of aortic valve stenosis) commonly present in the general population, and the prevalence of these conditions increases with age. Because of this, Heyde syndrome is likely underdiagnosed and underreported.

Aortic stenosis is prevalent in approximately 7.5% of persons 75 years of age or older.[3] Furthermore, approximately 1.8% of persons over the age of 75 classify as having moderate or severe aortic stenosis.[4] In a study of patients of this age group with moderate-to-severe AS, researchers observed clinically significant gastrointestinal bleeding in approximately 1% to 3% of cases.[5] Additionally, a study conducted by Vincentelli et al. (2003) found that anywhere from 20% to 70% of patients with AS also had a clinically significant reduction in high-molecular-weight multimers of VWF.[6] Further studies noted that the reduction in VWF multimers correlated inversely with the degree of AS severity. These findings support the notion that Heyde syndrome is likely more common than what current literature reflects.

Pathophysiology

It has taken several decades of study to elucidate the precise pathophysiologic basis of Heyde syndrome. The development of the syndrome involves insult at the level of the cardiovascular, gastrointestinal, and hematologic systems. In 1986, Gill et al. discovered that patients with congenital cardiac defects who had developed AVWS had abnormal blood clotting times, which suggested a causal relationship between cardiac dysfunction, changes to von Willebrand factor (VWF) and disorders of hemostasis.[7] Shortly afterward, a retrospective cohort study conducted by King et al. (1987) reported the cessation of recurrent bleeding in 93% of patients with recurrent gastrointestinal bleeding and aortic stenosis who had undergone aortic valve replacement, compared with a success rate of only 5% in those who had undergone surgical abdominal repair or resection.[8] T.E. Warkentin first introduced the hypothesis in 1992 that aortic valve stenosis may lead to AVWD and subsequent development of gastrointestinal angiodysplasias that predispose to recurrent gastrointestinal bleeding.[9] Currently, the most accepted mechanism of AVWS proposes that increased shear stress forces, particularly across a stenotic aortic valve, induce conformational changes in large VWF multimers that result in the exposure of the A2 domain. Exposure of this domain allows the enzyme ADAMSTS13 to cleave large VWF multimers into smaller fragments, which interferes with native inhibition of angiogenesis and the delivery of clotting factor VIII throughout the body.[10]

History and Physical

A thorough history and physical examination are essential for patients suspected of having Heyde syndrome. A comprehensive review of systems should be obtained, in addition to a careful review of the patient’s past medical history to search for a history of recurrent gastrointestinal hemorrhage, particularly if the bleeding is from an undiscovered source. The healthcare professional should also review the past medical records for a diagnosis of AS or evidence of the disease based on symptoms and prior procedural studies, such as imaging or echocardiographic findings. Moderate-to-severe AS increases the likelihood that AVWS is also present.[6] A complete family history should be obtained, with the specific inquiry on the presence of any hereditary coagulopathies, disorders of hemostasis, or malignancy. Careful assessment of the cardiovascular, gastrointestinal, and hematologic systems should also take place.

History of Present Illness

Notable symptoms that may suggest a diagnosis of Heyde syndrome fall into categories according to their respective body systems:

• Evidence of aortic stenosis – chest pain, syncope, exertional dyspnea, fatigue.
• Evidence of gastrointestinal bleeding – hematochezia, melena, hematemesis, fatigue
• Evidence of impaired hemostasis (AVWS) – fatigue, easy bruisability

Physical Examination Findings

Notable exam findings that may suggest a diagnosis of Heyde syndrome appear in the following outline:

• Evidence of aortic stenosis – early systolic ejection murmur, pulsus parvus et tardus, laterally displaced point of maximal impulse.
• Evidence of gastrointestinal bleeding – abdominal pain with palpation, blood on digital rectal examination, hemodynamic instability, or hypotension
• Evidence of impaired hemostasis (AVWS) – bruising, hemarthrosis, gastrointestinal bleeding

Of note, occult or intermittent gastrointestinal bleeding can be difficult for both the physician and the patient to appreciate if bleeding is not severe or obvious. Physical examination may be entirely unremarkable in such cases; therefore, the physician should pay careful attention to the patient's history and ask additional questions for clarification when necessary. A patient history that includes fatigue or worsening exhaustion, paleness of the skin, cravings for non-nutritive substances (as seen in pica syndrome), or darkening of the stool could suggest the presence of occult bleeding and subsequent anemia.

Evaluation

The clinician should suspect Heyde syndrome in an elderly patient who displays any combination of aortic valve stenosis, gastrointestinal bleeding, or evidence suggestive of AVWS. Evaluation and workup should first focus on ruling out the presence of life-threatening conditions before moving on to confirmatory studies.

Initial laboratory evaluation should at a minimum include the following:

• Complete blood count (CBC)
• Coagulation panel
• Metabolic panel
• Fecal occult blood testing

An electrocardiogram and echocardiogram should also merit consideration to assess the rhythm and structure of the heart if a recent study is not available for review. Imaging studies should follow at the healthcare professional's discretion in accordance with clinical exam findings and clinician gestalt. Examples include endoscopic referral or CT angiography for gastrointestinal bleeding and chest X-ray or CT studies of the thoracic cavity when suspicious cardiorespiratory findings are present.

Assessment of VWF

Studies to assess the function or fractional percentage of VWF multimers should be considered when AS and gastrointestinal bleeding are confirmed, especially in cases of gastrointestinal angiodysplasia refractory to endoscopic intervention. A few available laboratory studies are as follows:

• Platelet Function Assay (PFA) – PFA analyzes the ability of platelets to generate primary hemostasis.[11] Clinically significant dependent variables include platelet function, VWF level, platelet number, and hematocrit level.
• VWF Multimer Assay – the VWF multimer assay uses gel electrophoresis to sort different sized VWF multimers based on size. Quantitative analysis is then the means to determine the level of high molecular weight multimers (HMWM), which are necessary for normal hemostasis.[12]

Compared to a VWF multimer assay, the time it takes for a result is much faster (hours to complete a PFA versus 7 to 10 days to complete the multimer analysis). For this reason, PFA is often the preferred laboratory modality to screen for AVWD and is a useful screening modality in the initial workup of Heyde syndrome.[3][13] If PFA is abnormal, the clinician should then perform VWF multimer analysis as a confirmatory test to definitively demonstrate a reduction in HMWM.

Treatment / Management

There are currently no recommended guidelines or unifying protocols available regarding the management of Heyde syndrome. Therefore, the direction of the management of this condition should be according to guidelines related to aortic stenosis, gastrointestinal bleeding, and AVWS.

The Role of Aortic Valve Replacement

Recommendation by expert consensus advises that aortic valve replacement be considered the first-line treatment in the management of Heyde syndrome.[14] Aortic valve replacement has demonstrated high rates of cessation of recurrent gastrointestinal bleeding compared to other therapies.[8][15] Transcatheter aortic valve replacement (TAVR) is preferred over surgical aortic valve replacement (SAVR), as TAVR is a safer modality that offers a lower postoperative risk and eliminates the chance of HMWM VWF reduction as a result of cardiovascular bypass that would be required in SAVR.[16] There is currently insufficient data regarding the use of post-procedural anticoagulation after aortic valve replacement in Heyde syndrome; rendering this decision should be on a case-by-case basis, which considers input from a cardiologist, gastroenterologist, and sometimes a cardiothoracic surgeon. Currently, most patients with Heyde syndrome who undergo aortic valve replacement are given a several-month course of dual antiplatelet therapy, in accordance with standard valve replacement guidelines. (B2)

Management of Gastrointestinal Bleeding

The workup and management of suspected gastrointestinal hemorrhage are the same for patients with Heyde syndrome as in other gastrointestinal conditions. Initial evaluation and assessment should seek to rule out the presence of immediate, life-threatening bleeding, which may include hemodynamic instability or evidence of shock. If evidence of life-threatening bleeding is present, resuscitative measures should occur first before proceeding to any procedural interventions. Once the patient is hemodynamically stable, the clinician should consider endoscopic intervention to search for a bleeding source. In Heyde syndrome, most sources of gastrointestinal bleeding arise from angiodysplasias in the small bowel; as such, upper and lower endoscopic evaluations may not locate a bleeding source. Advanced image acquisition methods such as push enteroscopy or video capsule endoscopy may be necessary in such cases. Identification of a bleeding source should be a priority, as it helps to rule out other significant causes of bleeding and contributes to the triad of disorders when classifying Heyde syndrome. 

The Role of VWF Replacement Therapies

Therapeutic options typically employed for the treatment of hereditary von Willebrand disease – such as VWF or factor VIII replacement, octreotide, and desmopressin – are of little benefit or often altogether ineffective in the management of Heyde syndrome.[17][18] Any clinical or laboratory improvement that presents is often only temporary and does not address the primary pathophysiologic mechanism. For this reason, VWF replacement therapies are not a recommendation in the treatment of Heyde syndrome.

Recommended Approach

In patients who present with suspected or confirmed Heyde syndrome, consultation with a gastroenterologist and cardiologist for consideration of aortic valve replacement is the recommended therapeutic course. In hemodynamically unstable patients, normal resuscitative measures should take place before any intervention, including endoscopy or aortic valve replacement. In addition, anemia should be corrected with blood transfusion, as indicated by current guidelines.

Differential Diagnosis

Clinicians should suspect Heyde syndrome in any patient who presents with the triad of aortic stenosis, gastrointestinal bleeding, and evidence that supports the presence of AVWS. The differential diagnosis is broad and includes any number of etiologies that can manifest as one or several of the symptoms without meeting the complete triad required for the diagnosis of Heyde syndrome. Notable examples include:

• Gastrointestinal hemorrhage in the absence of aortic valve diseases, such as peptic ulcer disease, diverticular disease, or gastrointestinal malignancy.
• Aortic valve disease in the absence of gastrointestinal bleeding, such as isolated aortic stenosis/sclerosis, aortic calcification
• Disorders of hemostasis, such as hemophilia, VWF deficiency, thrombocytopenia, or clotting factor disorders. Both acquired and inherited disorders should be considered.

Aortic stenosis and gastrointestinal angiodysplasia are common findings, especially in older patient populations. As such, these conditions may coexist incidentally without causing any VWF-related disorders of hemostasis. Therefore, clinicians should perform a further assessment in patients who present with these findings.

Prognosis

Prognosis is excellent in patients who undergo aortic valve replacement, which is both effective and often curative.[8] In patients with Heyde syndrome who do not receive aortic valve replacement (AVR), the prognosis is negatively affected by recurrent gastrointestinal bleeding, and outcomes are poor.

Complications

The most important complication of Heyde syndrome is recurrent gastrointestinal bleeding, which can be life-threatening. Bleeding from other sources has also been documented, though it is much less frequent.