Recurrent gastrointestinal bleeding in a patient with Heyde syndrome with elevated factor VIII levels: A case report.

Heyde syndrome is the association between gastrointestinal (GI) bleeding from intestinal angiodysplasia (IA) and aortic stenosis (AS). Although the course of disease progression that links AS and GI bleeding has not been determined, overlaps among AS, intestinal dysplasia, and acquired von Willebrand's syndrome is thought to result in GI bleeding. Proper repair of the aortic valve can result in significant improvement of GI bleeding and its recurrence. Herein, we are reporting this rare case, in which a patient with moderate AS on echocardiogram presents with recurrent GI bleeding from multiple IA in the setting of elevated factor VIII levels, to propose a theory that angiodysplasia could potentially develop due to intermittent, recurrent low-grade obstruction of submucosal veins at the level of the muscularis propria secondary to venous thrombosis related to elevated factor VIII levels. Copyright:

INTRODUCTION

Heyde syndrome is a clinical syndrome described as gastrointestinal (GI) bleeding from previously latent intestinal angiodysplasia (IA) associated with aortic stenosis (AS).[1] A deficiency of high molecular weight (HMW) multimers of von Willebrand factor (vWF) (Type 2A von Willebrand disease) has been described in some of these cases.[1] The prevalence of Heyde syndrome is higher among elderly persons than among other age groups, suggesting that a degenerative process may be a significant factor in disease progression.[2] The main treatment approach for this syndrome is to replace the aortic valve with the goal of correcting the vWF abnormalities and a long-term resolution of GI bleeding.[3] The pathophysiology of angiodysplasia is not well understood. However, a proposed theory is that the condition develops due to intermittent, recurrent low-grade obstruction of submucosal veins at the level of the muscularis propria. We report this case of Heyde syndrome with elevated factor VIII levels to propose a theory that these patients develop a recurrent localized submucosal venous thrombosis related to elevated factor VIII levels and this, in turn, results in venous obstruction which subsequently results in dilatation and tortuosity of the draining areas (i.e., submucosal vessels, venules, and superficial capillaries).

CASE REPORT

An 85-year-old female with a medical history of hypertension, coronary artery disease, heart failure with preserved ejection fraction, and history of multiple vascular malformations in the colon on the previous endoscopic evaluations that were done 2 years before admission, presented to the hospital with lower GI bleeding and shortness of breath. She was on aspirin 81 mg daily for coronary artery disease. The patient described multiple episodes of maroon-colored rectal bleeding starting 1 day before her admission. Initially, vital signs were within the normal limits in the emergency department. On her physical examination, vital signs blood pressure 130/80 mmHg, heart rate 90/min, respiratory rate 18/min, SaO2 98% on room air, temperature 99.1 degrees F° and there was a systolic murmur with a grade of 4/6 at the second right intercostal space with clear lung fields. Her pulmonary, cardiac, and abdominal examinations were unremarkable. No purpura, petechiae, or bruises were evident on examination of her skin. No fresh blood was noted on the digital rectal examination. Laboratory tests showed hemoglobin of 7.6 (normal 12–15.5) g/L, hematocrit 24% (normal 39.4%–44.5%), platelets 170 (normal 150–400) × 109/L, serum electrolytes were normal, creatinine 1.7 and her baseline is 0.8 (normal 0.7–1.1) μmol/L, troponins were within the normal range and coagulation parameters (prothrombin time 11 s, partial thromboplastin time 27 s, and international normalized ratio 1.1). Moreover, as part of the workup of the shortness of breath, electrocardiography shows a ventricular premature complex with left axis deviation. A chest X-ray was done and it did not reveal any acute pathology. Transthoracic echocardiography revealed a normal left ventricular systolic function with an ejection fraction of 60%–65%, left atrium is mildly dilated, moderate AS with peak aortic valve gradient is 23 mmHg, calculated aortic valve area by the continuity equation is 1.1 cm2 and severe pulmonary hypertension [Figure 1a and b].

Figure 1

(a and b) 2Decho images showing moderate aortic stenosis with peak aortic valve gradient 23 mm Hg, aortic valve area 1.1cm2

The patient received two units of packed red blood cells, blood thinner (aspirin) was held, and she had a colonoscopy which revealed a few medium-sized localized angiodysplasia lesions that were actively bleeding in the cecum [Figure 2]. Hemostasis was achieved by successfully deploying clips on the bleeding vessel. In addition to that, multiple small-mouthed diverticula were found in the sigmoid and the descending colon with no evidence of bleeding. She did not require any anticoagulant reversal agents. A von Willebrand profile was ordered which revealed an elevated factor 8 activity 278% (Normal 56%–140%), elevated vWF Ag 286% (50%–200%), and normal VWF activity 193% (50%–200%). She remained hemodynamically stable for the next 2 days after the procedure and was discharged home with cardiology and gastroenterology follow-up.

Figure 2

Revealing Cecal angiodysplasias

DISCUSSION

We are reporting a rare case of a patient who presented with the clinical manifestations of Heyde syndrome, including GI bleeding associated with moderate AS and elevated factor VIII levels. This disease entity was first described in 1958 by Edward Heyde who was the first one to describe the association between chronic GI bleeding due to angiodysplasia and calcific AS.[4] In 1992, Warkentin et al. clarified the role of depletion of HMW multimers of vWF in the pathogenesis of Heyde syndrome.[5] Heyde syndrome is defined as a triad of AS, anemia due to bleeding from IA, and an acquired coagulopathy in a form of acquired Type IIA von Willebrand syndrome.[6] Refer to Table 1 for further characteristics of acquired VWD in comparison with hereditary VWD.

Table 1

Highlighting differences between acquired and inherited von Willebrand’s disease

	Acquired VWD	Inherited VWD
Onset of bleeding	Late in life	Early in life
Family history for VWD	Negative	Positive
Presence of an inhibitor or antibody for VWF	Presence	Absence
Remission of bleeding posttreatment	Yes	No
Response to immunoglobulin IV	Yes	No
Response to desmopressin	Short lived	Long lived

VWF: Von Willebrand factor; VWD: Von Willebrand’s disease

The acquired von Willebrand syndrome in patients with AS is explained by the mechanical disruption of von Willebrand multimers during turbulent passage through the narrowed valve and in addition to the interaction between the vWF with platelets that triggers platelet clearance. As it passes through the stenotic valve, vWF is subjected to high fluid shear stress that renders the multimers susceptible to cleavage by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13).[78] The severity of the vWF abnormality is related directly to the severity of the AS, which is measured by the mean transvalvular gradient.[9] One of the key features of Heyde syndrome is degenerative AS which represents the most prevalent valvular disease in Western countries.[10] It is more common in the elderly population and increases with age. While the prevalence is low in patients <60 years of age, it increases dramatically to approximately 10% in patients >80 years of age.[1112] Angiodysplasia is also considered an age-related degenerative process, it is the most common vascular anomaly encountered in the GI tract and it is most often detected in patients older than 60 years.[1314] It can occur anywhere in the GI tract but is most common in the ascending colon, particularly the cecum.[12] In a prospective study of colonoscopies of 1938 patients, typical angiodysplasia was found in 3% of cases, but 80% were asymptomatic. The sites of the highest prevalence of the lesions were the cecum (37%) and sigmoid colon (18%).[15]

The von Willebrand profile for our patient was not consistent with a diagnosis of acquired VWD. However, our patient did have elevated factor VIII levels. There are several studies reporting that high levels of factor VIII are associated with an increased risk of recurrences of thrombosis. Kraaijenhagen et al. found factor VIII levels ≥150 IU/dL in 57% of patients with recurrent venous thrombosis.[16] Kyrle et al. followed 360 patients with venous thromboembolism and found a recurrence in 27% of patients with factor VIII levels >234% and in 9% of patients without elevated factor VIII levels.[17] This led us to propose our theory that localized submucosal venous thrombosis secondary to elevated factor VIII levels may cause venous obstruction which subsequently results in dilatation and tortuosity of the draining areas (i.e., submucosal vessels, venules, and superficial capillaries). This would possibly explain why angiodysplasia often occurs in the right colon where wall tension is highest because this increased wall tension selectively compresses thin-walled veins compromised by the venous obstruction while allowing normal flow through the thicker-walled higher-pressure arterioles. Table 2 shows further characteristicsand differences between acquired VWD and Heyde syndrome.

Table 2

Differences between Heyde syndrome versus von Willebrand disease

	VWD	Heyde syndrome
Aortic stenosis	−	+
Angiodysplasia of the GI tract	−/+	+
Activated partial thromboplastin time	Normal/prolonged	Prolonged
PT	Normal	Normal
WBC	Normal	Normal
Platelet count	Normal/except type 2 B inherited VWD	Normal
IDA	−/+	−/+
PFA-100	Abnormal	Abnormal
VWF: Ag	Normal/low	Normal/low
VWF: RCo	Normal/low	Normal/low
Factor VIII: C	Normal/low	Normal/low/high
VWF: propeptide to VWF: Ag	High	High
VWF multimers	Normal/decreased	Decreased
VWF: collagen binding	Decreased	Decreased

VWD: Von Willebrand’s disease; GI: Gastrointestinal; PT: Prothrombin time; WBC: White blood cell; IDA: Iron deficiency anemia; PFA: Platelet function analyzer: VWF: Von Willebrand factor; VWF: Ag: VWF antigen; VWF: RCo: VWF ristocetin cofactor activity

The most effective treatment for Heyde syndrome is aortic valve replacement (AVR) which usually improves clotting disorder and anemia. In one study, 91 patients were evaluated for AS and suspected chronic small bowel bleeding secondary to angiodysplasia, 16 of the patients underwent AVR for AS, during follow-up of 8–12 years, 15 had cessation of chronic GI blood loss.[18] This fact supports the direct relationship between the severity of the angiodysplasia with the AS.[181920] Alternative treatment options include colectomy for the treatment of colic angiodysplasia and endoscopic intervention.[18]

Research quality and ethics statement

This case report did not require approval by the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the CARE guideline, during the conduct of this research project.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.