International Journal of Academic Medicine

CASE REPORT
Year
: 2016  |  Volume : 2  |  Issue : 2  |  Page : 243--248

Heyde/Heyde-Warkentin syndrome: A case report and literature review


Rodrigo Duarte-Chavez1, Mark William Fegley2, Lauren E Stone3, Amitoj Singh1, Sahil Agrawal1, Sudip Nanda1,  
1 Department of Internal Medicine, St. Luke's University Hospital Network, Bethlehem, Pennsylvania 18015, USA
2 Department of Family Medicine, St. Luke's University Hospital Network, Bethlehem, Pennsylvania 18015, USA
3 Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA

Correspondence Address:
Sudip Nanda
Department of Internal Medicine, St. Luke's University Hospital Network, 801 Ostrum Street, Bethlehem, Pennsylvania 18015
USA

Abstract

We present a case of a 77-year-old man admitted for chronic anemia secondary to recurrent gastrointestinal (GI) bleeding due to angiodysplasia with aortic stenosis (AS). Our patient was diagnosed with Heyde's syndrome. We review Heyde's syndrome, a combination of an acquired deficiency of the largest multimers of von Willebrand's factor (vWF) (Type 2A deficiency), bleeding angiodysplasia, and AS. AS causes high shearing forces on vWF, provoking changes in its shape that promote its cleavage, which further impairs the clotting ability of platelets. These patients are prone to clinically significant GI bleeds. Medical therapy offers little long-term benefit. Aortic valve replacement (AVR) frequently provides resolution of recurrent bleeds in up to 93% of patients. Recurrent bleeding in Heyde's syndrome is not an indication for AVR in the absence of symptomatic AS. AVR should be seriously considered in all cases of Heyde's syndrome. The following core competencies are addressed in this article: Patient care and medical knowledge.



How to cite this article:
Duarte-Chavez R, Fegley MW, Stone LE, Singh A, Agrawal S, Nanda S. Heyde/Heyde-Warkentin syndrome: A case report and literature review.Int J Acad Med 2016;2:243-248


How to cite this URL:
Duarte-Chavez R, Fegley MW, Stone LE, Singh A, Agrawal S, Nanda S. Heyde/Heyde-Warkentin syndrome: A case report and literature review. Int J Acad Med [serial online] 2016 [cited 2022 Dec 2 ];2:243-248
Available from: https://www.ijam-web.org/text.asp?2016/2/2/243/196868


Full Text



 Introduction



Heyde's syndrome is defined as a combination of an acquired deficiency of the largest multimers of von Willebrand's factor (vWF) (Type 2A deficiency) and aortic stenosis (AS), presenting as gastrointestinal (GI) bleeding from angiodysplasia lesions.[1] Heyde, in 1958, described 10 patients with calcific AS and massive GI bleeding without a cause. He asked for journal's readers help in identifying a possible cause for the connection.[2] In 1971, Boss and Rosenbaum reported multiple vascular lesions in the right colon seen at autopsy in patients with GI bleeding and AS, suggesting this was the source of bleeding.[3] Love, in 1980, demonstrated that aortic valve replacement (AVR) in two patients relieved the associated GI bleeding. In addition, he demonstrated that platelets of these patients failed to aggregate to thrombin, in the absence of anticoagulant or antiplatelet therapy.[4] In 1992, Warkentin reported that Heyde's syndrome was caused by an acquired deficiency of the largest multimers of vWF (Type 2A deficiency) and that bleeding in these patients was almost always secondary to angiodysplasia, finally finding a connection between all the factors involved in the syndrome.[5],[6],[7] His theory was later corroborated in a large epidemiological study.[8]

 Case Report



A 77-year-old man was admitted to the hospital for the evaluation of exertional dyspnea, chronic anemia, and tarry stools. His past medical history was significant for peptic ulcer disease, status postpartial gastrectomy with gastro-jejunostomy 5 years ago. There was no history of alcohol abuse, hepatitis, or liver cirrhosis. Two years prior to the admission, the patient suffered repetitive episodes of tarry stools and anemia, needing to be hospitalized several times. He was being treated for anemia with transfusions on a weekly basis. Previous work up for GI bleeding included multiple upper endoscopies and colonoscopies as well as capsule enteroscopy, being unable to find the cause of the anemia and GI bleeding. Multiple nonbleeding polyps were found in the colon on previous colonoscopies. A single gastric polyp was found oozing during a gastroscopy and coagulated with argon beam diathermy in the previous year.

On this admission, blood pressure was 110/80 mmHg, heart rate was 82 and regular, respiratory rate was 12 with oxygen saturation of 95% on room air. On physical examination, he appeared pale but in no acute distress, cardiac auscultation revealed a 3/6 systolic ejection murmur over the 2nd right intercostal space. Both lungs were clear and the abdominal exam was benign. On rectal examination, tarry stool was noted, positive for fecal occult blood test. Pertinent laboratory data revealed hemoglobin of 6.1 g/dL, microcytic and hypochromic, with normal differential and platelet count of 194,000. Further tests demonstrated low iron levels. Prothrombin time/international normalized ratio and partial thromboplastin time, blood urea nitrogen, creatinine, and liver function test were within normal limits. Electrocardiogram showed normal sinus rhythm. Chest x-ray indicated mild cardiomegaly. Echocardiogram revealed moderate AS with and aortic valve area between 1 and 1.5 cm 2, with aortic jet velocity >3 m/s and a mean gradient >25 mmHg [Figure 1].{Figure 1}

Because previous endoscopic studies were negative, a double balloon enteroscopy was performed at this time, finding multiple angiodysplasia in the jejunum. The lesions were coagulated with argon beam diathermy and the patient was transfused 1 unit of packed red blood cells and discharged after being stable. Additional endoscopies performed during other massive bleeding episodes showed recurrent angiodysplasia in different portions of the jejunum [Figure 2] and [Figure 3]. Repeated treatment with argon beam diathermy was performed. The presence of recurrent GI bleeds with angiodysplasia and underlying AS narrowed our diagnosis to Heyde's syndrome. vWF multimers were measured on a follow up visit and were normal. However, it has been reported that 11% of the cases can present with normal multimers, given its an acquired condition and the abnormalities on the large multimers of vWF can be transient.[7],[9] The patient was offered AVR, hoping the repair of the aortic valve could improve the episodes of GI bleeding, however, he declined. The patient is being followed closely and continues having hemoglobin levels measured on a weekly basis, being transfused as needed.{Figure 2}{Figure 3}

 Discussion



Von Willebrand factor

The deficiency in platelets is hypothesized to be caused by chronic activation/deficiency of large multimers of vWF, due to shearing of the platelets in the stenotic aortic valve.[5] Normally, vWF is secreted as a very large polymer to provide maximal adhesive activity at the site of bleeding. It circulates in a globular form and recognizes exposed collagen at damaged vessels. It then undergoes structural transition to an elongated conformation, exposing platelet binding sites, and slowing platelet motion by interacting with glycoprotein 1b on the platelet surface.[10],[11],[12] vWF is normally down-regulated to prevent unwanted thrombosis by its cleavage, which is mediated by ADAMTS 13.[11],[13] These shearing forces provoke structural changes on vWF shape, from coiled coil to elongated filament, exposing a single peptide bond between amino acids Tyr1605-Met1606 located within the central vWF A2 domain.[12],[14] This makes vWF more sensitive to proteolysis [Figure 4]. Experimental studies have demonstrated that the activity of the vWF-cleaving metalloproteinase increases during shear and elongation. vWF levels can be normal, and the abnormality can be diagnosed exclusively by electrophoresis of vWF multimers, considered the gold standard.[6],[15],[16],[17] However, even multimers can be normal during routine screening.[7],[9]{Figure 4}

A high pressure gradient on aortic valve has been related to increased vWF abnormalities; hence, the severity of platelet dysfunction and bleeding positively correlates with the severity of underlying AS.[18],[19],[20],[21] AS-induced shearing stress provokes an abnormal and counterproductive cleavage of vWF, rendering the patient prone to bleeding due to deficient activity of vWF. The abnormality in vWF is not specific to AS and has been described in other conditions with increased shearing forces: hypertrophic obstructive cardiomyopathy, supravalvular AS, ventricular septal defect, pulmonary hypertension, mitral regurgitation, and patent ductus arteriosus.[1],[7],[19],[22],[23],[24] When multiple records of patients with AS were reviewed, it was found that 2.6% of the patients had unidentifiable GI bleeding. Most patients had multiple hospital admissions due to acute blood loss anemia, with age ranging from 59 to 90-year-old but being more common in people older than 70.[25]

Two hundred and eighty-eight consecutive patients with AS were screened for occult blood in stools, GI bleeding was significantly more common in patients with AS when compared to a matched control group, those patients with AS who were positive for occult blood in the stools had prolonged bleeding time and had higher maximal gradient when pressure gradient over aortic valve was compared to the AS patients with no prolonged bleeding time. Within 5 months of AVR, most patients with prolonged bleeding time had normalization of their bleeding time.[15],[26]

Angiodysplasia

Vascular ectasia or angiodysplasia are acquired small lesions (generally <5 mm) and occurs commonly in patients older than 60 years. The lesions are more common in the cecum and ascending colon, but have been reported in the stomach, small bowel, colon, and rectum, and are not associated with angiomatous lesions in other organs or the skin. In the small bowel are the most common cause of obscure GI bleeding.[27] These tiny vessels sometimes are impossible to detect despite upper and lower endoscopies, and the etiology of obscure GI bleeding remains unexplained in as much as 10% of the patients. Selective mesenterogram has been advocated as the gold standard for diagnosis, but in order to be reliable, needs to be performed during an acute episode of bleeding.

A hypothesis is that angiodysplasia are secondary to low perfusion due to AS, which may cause ischemia in the endothelium between ecstatic vessels and GI tract lumen. However, other valve disorders with a low cardiac output should produce the same changes on intestinal mucosa. GI bleeding has a higher prevalence in AS when compared to mitral stenosis (MS), likely due to the higher shear forces of AS compared to MS.[28] A new in vitro study in a mouse model has shown that inhibition of vWF increased angiogenesis, suggesting the deficiency of vWF could contribute to the genesis of angiodysplasia.[21] Other authors suggest that angiodysplasia may be secondary to age-related degeneration of connective tissue, predisposing vessels to abnormal transformation.

Long-term obstruction at the submucosal mesenteric venous system would produce a loss of precapillary sphincters, leading to an arteriovenous communication.[7],[29] Angiodysplasia by itself does not explain the increased risk of bleeding. Comparing patients with bleeding angiodysplasia versus nonbleeding angiodysplasia, abnormal high molecular weight multimers of vWF were found in most patients with bleeding, meanwhile, nonbleeding patients had normal vWF.[6],[9] On the other hand, for bleeding to occur, the patient to have a lesion prone to bleeding and angiodysplasia are at high risk of bleeding since hemostasis in this lesions needs high molecular weight multimers of vWF.[18],[30]

Another interesting observation in patients with Heyde's syndrome is the presence of polyps and tumors of the colon. This could be a common finding correlated to the age of the patients with this condition, but the frequency was high when compared to age matched controls. A hypothesis is that an inflammatory process could be the cause of AS and the same inflammatory process would stimulate cell proliferation in the intestinal mucosa.[26],[31]

Treatment

Radiation, beta blockers, thalidomide, octreotide, and combined estrogen and progesterone have been used historically in the treatment of angiodysplasia with only transitory or poor results.[7],[27],[28],[29],[32],[33] Replacing the deficient vWF with factor VIII/vWF and desmopressin also did not work in the long-term, but could be an option in the perioperative period.[31],[34],[35],[36]

Surgical resection has been advocated as a therapeutic option once angiodysplasia have been identified, especially in patients who are the poor candidates for valve replacement.[37] However, angiodysplasia at different sites, irrespective of previous treatment, only stop bleeding after aortic valve has been replaced. Therefore, surgical resection of the involved segment should be considered only in cases of life threatening bleeding.[19],[38]

Super selective embolization is also an option during massive hemorrhage, but is associated with bowel infarction in up to 10% of the cases.[37],[39] Historically, most cases of bleeding were treated with upper and lower endoscopy with coagulation, with limited access to the small bowel. In 2001, the double balloon enteroscopy was introduced and the small bowel was no longer “unreachable” by endoscopic techniques. Single balloon enteroscopy is another option available. Capsule endoscopy is helpful in the diagnosis, although does not offer therapeutic options.[40],[41]

AVR is the definitive treatment: 93% of the patients stop having GI bleeding post-AVR, versus 5% resolution in patients treated with laparotomy. Angiodysplasia may remain detectable on endoscopy after AVR, but only 3.3% of cases have recurrent bleeding.[42] There have been reports of persistence 14 years after AVR with recurrent bleeding needing transfusion. Interestingly, those cases that had rebleeding after AVR occurred in presence of valve dysfunction.[10],[18],[30],[31]

 Conclusion



Heyde's syndrome comprises serious GI bleeding in the presence of AS. AVR in cases of Heyde's syndrome provides curative results. Although severe AS causes a more serious syndrome, even moderate AS can produce significant debility, as seen in our patient. In patients with AS and recurrent GI bleeding, Heyde's syndrome needs to be seriously considered, and confirmed by vWF multimers, especially during the bleeding event, because the deficit could be transient, and results can be normal in up to 11% of the cases during routine testing.[7],[9] If Heyde's syndrome is confirmed, AVR is highly recommended, irrespective of severity of stenosis, to prevent recurrent episodes of serious GI bleeding. Trans AVR is a good option in high risk patients, especially those with previous balloon valvuloplasty.[43],[44],[45] More studies are needed to consider the presence of Heyde's syndrome as an absolute indication for valve replacement without symptoms of “classic” AS.[10],[30],[46]

Acknowledgment

We acknowledge the role of Theodore Warkentin proposing the etiology of Heyde's syndrome and review its pathophysiology and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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