Transcatheter aortic valve implantation in a patient with suspected hereditary von Willebrand disease and severe gastrointestinal bleeding – a case report

Introduction

Inherited von Willebrand disease (VWD) is a common autosomal inherited bleeding disorder with an estimated prevalence ranging from 1 in 10,000 to 1%. ¹ According to the current classification, three types of inherited VWD are distinguished: type 1 represents a partial quantitative deficiency of the von Willebrand factor (VWF), type 2 is characterised by qualitative abnormalities of VWF and type 3 represents a total quantitative deficiency of VWF, with very low levels of the VWF antigen (VWF:Ag) and VWF activity (VWF:RCo).^1,2 In contrast to inherited VWD, acquired von Willebrand syndrome (AVWS) comprises bleeding disorders secondary to malignant, cardiovascular or autoimmune processes that lead to functional or structural defects in VWF. Diagnosis of AVWS can be challenging, as no single test is usually sufficient to prove or exclude this condition. ³ In particular, hereditary type 2a VWD is characterised by a decreased quantity of large VWF multimers in multimer analysis and resembles the presentation of AVWS induced by aortic valve stenosis.

The acquired triad of calcific aortic valve stenosis, coagulopathy and anaemia due to gastrointestinal bleeding from angiodysplasia is known as Heyde Syndrome. ⁴ The coagulopathy is a result of the degradation of VWF multimers by the shear stress across the stenosed valve, resulting in an AVWS. ⁴ Since its first recognition in 1958, ⁵ various case reports have reported Heyde Syndrome in patients with aortic valve stenosis, but nevertheless, the prevalence of the syndrome remains elusive. In a recent trial by Tjahjadi et al., it was found that anaemia was present in 30.1% of patients undergoing aortic valve replacement (AVR), which may indicate that Heyde Syndrome is more prevalent than has been generally appreciated. ⁶

In our case, a patient with a previously diagnosed inherited VWD and concomitant severe aortic valve stenosis benefitted greatly from transcatheter aortic valve implantation (TAVI).

Case presentation

A 73-year-old patient presented to the emergency department of our hospital and stated that she had suffered from increasing fatigue for a few days when performing regular activities of daily living. Furthermore, she was concerned about her stool being dark and malodourous, which she had noticed the day before. The patient reported that she suffered from VWD, which was diagnosed in the US more than 25 years previously, and that she had experienced multiple bleeding episodes in the past. These episodes included spontaneous nasal and oral bleeding and post-operative haemorrhages after dental surgery. At the age of 39 years, the patient had required blood transfusions after a minor bicycle accident and subsequent haematoma. The patient had also required factor VIII replacement because of bleeding after colonoscopy with polypectomy. At the age of 71 years, the patient was hospitalised because of severe pyoderma gangrenosum of her right lower leg, which had to be amputated subsequently. Since then, the patient was bound to a wheelchair. Further evaluation revealed a positive family history for bleeding disorders, with her father having had severe episodes of bleeding with the need of blood transfusion after prostatectomy.

On examination, a grade 3 systolic murmur was discovered in the second intercostal space at the right sternal border, radiating to the area of the right carotid artery. Pulmonary rales or other clinical signs of acute decompensation were not found at the time of presentation. No abnormalities were noted on abdominal examination, but rectal examination revealed melaena.

The patient reported that she suffered from a heart valve stenosis, which turned out to be a moderate aortic valve stenosis that had been diagnosed a year earlier at the department of cardiology of our hospital. She had then undergone coronary angiography and had been diagnosed with coronary heart disease, with a 70% stenosis of the left main (LM), a moderate stenosis of the left anterior descending (LAD) artery and a severe stenosis of a diagonal branch of the LAD. Back then, coronary artery bypass graft surgery, combined with surgical replacement of the aortic valve, had been declined by the patient.

Since melaena was evident and her initial haemoglobin concentration was 6.5 g/dl, the patient was admitted to the department of surgery and immediately received two units of packed red blood cells. Emergency gastroscopy and colonoscopy were performed. Neither procedure showed any apparent source of the gastrointestinal bleeding. However, since melaena persisted, and the haemoglobin concentration was again decreasing, capsule endoscopy was performed and the patient was transferred to the department of cardiology for the evaluation of possible Heyde Syndrome based on a severe aortic valve stenosis.

Upon echocardiography, a progression of the aortic valve stenosis was found, which was now graded as severe (Vmax 4.9 m/s, Pmax/mean 98/53 mmHg, aortic valve area, AVA 0.8 cm², see Figure 2). Since the amputation of her right lower leg two years before, the patient was bound to a wheelchair and was therefore asymptomatic regarding the aortic valve stenosis and her pre-existent coronary artery disease – she reported that she had not experienced any chest pain or dyspnoea in the past.

Melaena persisted, requiring regular blood transfusion in order to stabilise the haemoglobin concentration. The department of haematology was consulted and analysis of the von Willebrand multimers and anti-VSF antibodies was conducted. The results of a von Willebrand multimer analysis performed four years earlier were also requested. Following this, the diagnosis of a VWS type 2 was made (discrimination between inherited VWD type 2a and AVWS would not be possible based on these results). Treatment with tranexamic acid and desmopressin, and later with tranexamic acid and VWF, remained unsuccessful and the bleeding could not be stopped by conservative treatment.

Approximately two weeks after the initial presentation, active bleeding in the terminal ileum was found upon capsule endoscopy (see Figure 3). Double balloon endoscopy was attempted twice, but the source of the bleeding could not be reached because a fixed kinking of the terminal ileum prevented insertion of the endoscope. Furthermore, CT-angiography scan showed no possibility for an interventional therapy such as coiling. The possibility of surgical enteric resection was dismissed because of the inability to determine the exact location of the bleeding and the possibility of multiple bleeding foci.

Subsequently, the patient developed influenza (B) and had to be transferred to the intensive care unit because of respiratory distress and worsening of her general condition.

Although the presence of AVWS could not be proven, the aortic valve stenosis was suspected to at least aggravate the bleeding in our patient. The option of giving recombinant factor VII or thalidomide, reportedly effective in refractory gastrointestinal bleeding due to AVWS,^7,8 was discussed but ruled out in view of the increased cardiovascular risk in our patient and the difficulty of close bleeding monitoring. Therefore, a replacement of the stenosed aortic valve was considered the only reasonable option to improve the current bleeding episode. The case was discussed in the interdisciplinary heart team conference where the patient was deemed unfit for open surgical AVR and coronary artery bypass grafting owing to her comorbidities and current physical status.

Given the lack of reasonable options to control the bleeding, TAVI (Medtronic CoreValve Evolut R, 29 mm) and the implantation of a drug eluting stent in the LM were performed. This was successful. In view of the active gastrointestinal bleeding, clopidogrel monotherapy was chosen over dual antiplatelet therapy post-interventionally.

After the procedures, the melaena stopped and haemoglobin concentration increased. The patient was transferred to the regular ward three days after the intervention. There was no recurrence of gastrointestinal bleeding and the patient was discharged home 10 days later.

In follow-up outpatient visits, the patient reported no further bleeding episodes. The haemoglobin concentration increased and remained stable at normal levels throughout subsequent follow-up visits (13.5 g/dl upon discharge, see Figure 1). An analysis of the von Willebrand multimers conducted three months later revealed a normal quantity of the multimers, as well as normal triplet-structures of all the oligomers. OPEN IN VIEWER

Discussion

VWF is a multimeric plasma glycoprotein that plays a paramount role in haemostasis by mediating platelet adhesion and acting as a plasma carrier for clotting factor VIII. ⁹ Besides its role in haemostasis, VWF has been found to interact with various cell surface proteins and extracellular proteins, thus regulating other physiological pathways in humans. It was recently discovered that VWF plays a role in angiogenesis through interaction with Ang-2 and integrin αvβ3, ¹⁰ and the lack or dysfunction of VWF results in enhanced VEGF signalling, which promotes angiogenesis and can result in gastrointestinal angiodysplasia. ¹⁰

The pathogenetic mechanism behind Heyde Syndrome is thought to be a mechanical disruption of the large VWF multimers by the high fluid shear stress of blood flow across the stenosed aortic valve. Exposure to shear stress results in conformational unfolding of the multimers, which renders them susceptible to degradation by a plasma zinc metalloprotease (ADAMTS13),^11,12 which ultimately leads to an ‘acquired’ VWD type 2a.^11,13

Treatment options include endoscopic interventions, interventional radiology or colectomy,^14–16 but nevertheless, the most effective treatment for Heyde Syndrome is the replacement of the calcified aortic valve. Notably, although it is effective in patients with VWD, the treatment with desmopressin or factor VIII is not effective in patients with Heyde Syndrome. ¹⁶ In our case, Heyde Syndrome resulted in severe gastrointestinal bleeding, that could be stopped by neither conservative nor endoscopic interventions. Although the administration of recombinant factor VII and thalidomide are valid options in controlling bleeding in some patients, we decided against both options owing to the increased cardiovascular risk in our patient.^17–19 Various trials have investigated the therapeutic benefit of AVR in patients with recurrent gastrointestinal bleeding^17,20–22 and, according to King et al., AVR results in a cessation of bleeding in 93% of the patients, ¹⁸ while Thompson et al. reported that AVR is curative in 80% of patients with known Heyde Syndrome. ¹⁹ Similarly, TAVI, which has become a valuable therapeutic alternative in patients suffering from severe aortic valve stenosis who are deemed unfit for conventional AVR,^23,24 was found to be feasible and effective in patients suffering from Heyde Syndrome.^25–27 However, whereas the effect of AVR is well examined in patients with AVWS, its effect in patients with inherited VWD and concomitant aortic valve stenosis is not known.

In our case, the diagnosis of VWD 25 years before, the long bleeding history and the positive family history, all suggested an inherited bleeding disorder that was aggravated by Heyde Syndrome. Whether this was truly the case remains uncertain. The initial hypothesis of a pre-existent inherited VWD is questionable in view of the quantitatively normal VWF antigen and the normal results of the von Willebrand multimer analysis post-interventionally. Nevertheless, we cannot exclude that the bleeding episodes in the history of our patient were a result of VWD type 1, since the plasma levels of VWF antigen can improve over time in mild VWD type 1. ²⁸ The rapid post-interventional increase in haemoglobin concentration, as well as the normal multimer analysis three months after the intervention, are, however, highly suggestive of AVWS being the main trigger of the current bleeding. With regard to the results of the multimer analysis four years previously, at which time the diagnosis of VWD type 2 was made, we retrospectively cannot exclude the aortic valve being at least to some extent stenotic when the assay was conducted, resulting in an incipient AVWS.

Conclusion

Retrospectively, this life-threatening gastrointestinal bleeding was a result of severe Heyde Syndrome, which could be alleviated by TAVI. Whether the patient had suffered from inherited VWD in the past, remains uncertain. AVWS should be considered in patients with suspected inherited VWD and concomitant severe aortic valve stenosis, since it constitutes a treatable cause of a potentially severe bleeding disorder. OPEN IN VIEWER

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Figure 3.

(a+b) Active bleeding in the terminal ileum upon capsule endoscopy.