An Uncommon Presentation of Heyde Syndrome: Absence of Visible Endoscopic Angiodysplasia With Resolution After Transcatheter Aortic Valve Replacement

Introduction

Heyde syndrome (HS) is a pathology characterized by acquired von Willebrand syndrome that occurs secondary to severe aortic stenosis, which eventually causes recurrent gastrointestinal bleeding [1–3]. Diagnosis of Heyde syndrome has traditionally relied strictly on recognizing the concurrence of these 3 features; however, overlap of these symptoms with other common geriatric conditions can delay or obscure diagnosis, especially in cases where angiodysplasia is not observed [1,2,4,5]. This case report emphasizes a gap in the diagnostic algorithm for HS, discusses relevant endoscopic techniques and atypical findings, and reviews integrated management strategies to improve recognition and treatment of HS.

Case Report

A 73-year-old woman with a history of coronary artery disease (CAD), AS, hypertension, hyperlipidemia, type 2 diabetes, and hypothyroidism presented with a 2-week history of melena and 1 week of fatigue. She reported recent evaluation and treatment at another hospital for similar symptoms and was scheduled for cardiac catheterization for AV replacement. Vital signs showed a temperature of 37.2°C, heart rate of 71 bpm, respiratory rate of 18 bpm, blood pressure of 100/52 mmHg, mean blood pressure of 68 mmHg, and SatO2 of 96% on room air. Physical exam revealed pale mucous membranes and a loud harsh late-peaking systolic aortic murmur radiating to the carotids. She was hemodynamically stable, with normal sinus rhythm and no ischemic changes on EKG. Laboratory test results demonstrated hypokalemia (3.3 mmol/L[normal 3.5–5.0]), low hemoglobin (Hb) level (7.7 g/dL [normal 12–16 g/dL for females]), borderline low MCV (80.3 [normal 80–100 fL]), decreased mean corpuscular hemoglobin concentration (31.1 [normal 32–36 g/dL]), elevated red cell distribution width (16 [normal ~11.5–14.5%]), and fibrinogen of 335 mg/dL [normal 200–400 mg/dL]. After transfusion of 1 pRBC unit, Hb improved to 9.8 g/dl and MCV decreased to 77.1, consistent with microcytic hypochromic anemia from gastrointestinal bleeding. Elevated troponin levels (1.300 ng/mL [normal <0.04 ng/mL]) indicated possible type II myocardial infarction secondary to demand ischemia from severe anemia. Cardiac troponins were trended to peak and echocardiography was performed. During a hospitalization 5 years prior, the patient’s point-of-care activated clotting time was prolonged at 378 s [normal ~70–120 s]. Forty-five days after admission, her coagulation profile revealed a prothrombin time (PT) of 11.3 s (normal ~11–13.5 s), international normalized ratio (INR) of 1.0 (normal 0.8–1.2), and activated partial thromboplastin time (aPTT) of 34 s (normal 25–35 s).

Patient records documented 9-month intermittent melena, requiring esophagogastroduodenoscopies (EGDs), video capsule endoscopies (VCE), and colonoscopies from outside facilities, without bleeding source. VCE revealed melena in the proximal jejunum. Endoscopy 2 months prior revealed perianal hemorrhoids and hematin throughout the colon, including the cecum, preventing intubation of the terminal ileum; no specimens were collected (Figure 1A–1C).

Upper endoscopy noted normal esophagus and erosive gastropathy without bleeding stigmata; no specimens were collected. Transthoracic echocardiography showed normal systolic left ventricular function, EF 55% visually, mild left ventricular hypertrophy, and severe calcific AS (Figure 2A–2C) with aortic valve area (AVA) of 0.7 cm2, aortic valve max velocity (AV V max) of 4.23 m/s, mean pressure gradient of 47.11 mmHg, and Doppler velocity index (DVI) of 0.24 (Figure 2A).

Cardiac catheterization demonstrated severe AS (AVA 0.4 cm2), and severe CAD in the left circumflex artery/obtuse marginal branch disease, very small vessel not amenable for percutaneous coronary intervention (PCI), as well as a right coronary artery with complete total occlusion (RCA CTO) (Figure 3) with left to right collaterals and patent distal left anterior descending artery with stent. Given the chronic total occlusion of the RCA with robust collateral perfusion and absence of ischemic symptoms attributable to the right coronary territory, the risks of potential PCI outweighed its potential benefits, and it was therefore not indicated in this patient.

A plan was made for outpatient follow-up for TAVR after catheterization. Given numerous risk factors, including age, comorbidities, recurrent anemia with ongoing gastrointestinal blood loss, 2-vessel coronary artery disease requiring no immediate revascularization, and demand-mediated myocardial injury, the heart team advised transcatheter aortic valve replacement (TAVR) as the appropriate intervention, and the patient elected to proceed with their recommendation. Aspirin and high-intensity statin were continued for CAD. Proton pump inhibitor (PPI) was started at 40 mg twice daily for acute chronic blood loss anemia. Interventional cardiology implanted a SAPIEN 3 bioprosthetic valve via TAVR (Figure 4).

Double-balloon enteroscopy (DBE) was recommended if bleeding recurred. Six months after TAVR, the patient was asymptomatic, denying fatigue, melena, or bleeding, with resolved blood loss anemia and Hb 14.0. The patient had a documented positive fecal occult blood test (FOBT) 2 days after admissions, followed by a negative FOBT after TAVR.

This patient had presented with anemia at multiple facilities and the cause of her anemia remained undiagnosed. To the best of our knowledge, she was not evaluated for avWF deficiency at any of the previous facilities, for unknown reasons. No specialized testing to characterize acquired von Willebrand syndrome such as von Willebrand factor antigen, ristocetin cofactor activity, collagen binding activity, or multimer analysis was performed or available in the transferred medical records. No von Willebrand factor-specific studies or platelet function assays were available in the transferred records; however, basic serum protein evaluation revealed a total protein of 7.1 g/dL and albumin of 3.9 g/dL, with no findings suggestive of a paraproteinemia-associated disorder or monoclonal gammopathy. AV replacement was recommended after colonoscopy and upper endoscopy failed to find bleeding sources. Despite the absence of angiodysplasia, HS was diagnosed, as the bleeding was attributed to small-intestine angioectasias secondary to AS. The presence of severe AS and resolution of bleeding after TAVR strongly supported the diagnosis of HS, despite an atypical presentation. The timeline of diagnostic assessments, interventions, and final diagnosis is summarized in Table 1.

Discussion

PROCEDURAL STEPS:

Diagnostic algorithm:

TAVR procedure [8]:

POTENTIAL PITFALLS:

Drawbacks in this diagnostic algorithm include under-recognizing and inadequate screening of avWS, delayed AS diagnosis, misinterpreting gastrointestinal bleeding, and diminished interdisciplinary teamwork. Patients with unexplained bleeding should undergo thorough evaluation for the triad of HS, especially in elderly patients. Although TAVR is a generally safe and effective procedure for severe AS, potential complications include vascular injury, bleeding, valve issues (migration, malposition, embolization), new arrhythmias, stroke, kidney injury, and infection. Adhering carefully to diagnostic and procedural steps helps reduce risks.

Conclusions

Although commonly linked to gastrointestinal bleeding, a recent study of 91 cases found that 20.5% did not exhibit angiodysplasia, challenging the traditional diagnostic criteria [9].

Therefore, the absence of angiodysplasia should not preclude a diagnosis of Heyde syndrome.