Early Resolution of Heyde's Syndrome following Transcatheter Aortic Valve Replacement

Recurrent gastrointestinal bleeding is the main manifestation of Heyde's syndrome (HS), comprising aortic valve stenosis (AVS), acquired von Willebrand's syndrome (AVWS), and intestinal angiodysplasia.[1] Von Willebrand factor (VWF) is a key molecule in promoting platelet adhesion, stabilization of factor VIII (FVIII), and suppression of angiogenesis. When AVS is severe, the blood flow through the orifice is characterized by high shear stress, which triggers an accelerated proteolysis of the high-molecular-weight (HMW) VWF multimers. A hemorrhagic diathesis develops due to reduced VWF plasma levels, especially HMW forms.[2] Indeed, the AVWS in HS mimics a type 2A (qualitative) disorder. Both angiodysplasia and AVS prevalence increase with aging, favoring the coexistence of the two anatomical substrates of HS. Conversely, a causal relationship between the pathogenesis of angiodysplasia, namely a thin-walled ectatic vessel prone to bleeding, and AVS is more controversial. A deficiency of VWF, given its ability to suppress angiogenesis or preserve vascular and endothelial function, might be hypothetically implicated.[3]

An 82-year-old woman with permanent atrial fibrillation (AF), severe AVS, and worsening dyspnea was admitted to our hospital. She suffered from iatrogenic hypoadrenalism requiring replacement therapy. In the past, she had undergone chronic anticoagulant therapy with warfarin as thromboembolic prophylaxis for AF, right nephrectomy for kidney cancer, and left adrenalectomy due to cortical adenoma without bleeding complications. Her family history was negative for bleeding. The recent medical history included two admissions for digestive hemorrhage and severe anemia requiring blood transfusions, treatment of duodenal and jejunal angiodysplasia by argon plasma coagulation, infiltration of adrenaline, and deployment of metal clips ([Fig. 1]). Thus, long-term oral anticoagulation was interrupted. Previous anticoagulation therapy, major surgery, and family history without bleeding prompted the suspicion of an acquired disorder. The echocardiography showed a hypertrophic left ventricle with normal volume and systolic function, mild mitral regurgitation, severe AVS (mean gradient of 50 mm Hg, valve area of 0.55 cm²) with mild insufficiency, and a pulmonary artery pressure of 40 mm Hg. Angiography demonstrated subcritical coronary atherosclerosis and a porcelain aorta. After analysis of anatomical feasibility by computed tomography (CT), the hospital's heart team recommended transfemoral transcatheter aortic valve replacement (TAVR; [Fig. 2A]). The patient was referred to the blood transfusion center due to hemoglobin values oscillating down to a minimum of 6.6 g/dL (reference interval: 12.0–15.5) and requiring repeated transfusions. Platelet count, activated partial thromboplastin time, and prothrombin time were normal. Further laboratory investigations performed on Sysmex CS-5100 analyzer (Siemens) showed a low FVIII activity (Siemens Chromogenic FVIII assay) of 48.6% (normal range: 60–152) together with decreased VWF antigen (VWF:Ag; Siemens) and a platelet glycoprotein Ib binding activity assay (VWF:GPIbM; Siemens Innovance VWF Ac) of 36.9% (63–166) and 17.5% (51–175), respectively, with significant VWF activity/antigen ratio (0.47) reduction (normal range > 0.6).[4] These findings were consistent with a type 2A AVWS.

Fig. 1 (A) Contrast dye (arrow) in a duodenal loop close to the ligament of Treitz, persistent in the different acquisition phases, and compatible with ongoing bleeding. (B) Linear angiodysplasia in the third duodenal portion (dotted arrow).

Fig. 2 (A) Vascular access and valve root analysis at the virtual basal ring level to prepare for TAVR. (B) Angiography post-TAVR with a SAPIEN-3 Ultra 23 mm (Edwards Lifesciences). (C) Absence of aortic regurgitation after TAVR in the parasternal color Doppler view. TAVR, transcatheter aortic valve replacement.

We considered the scheduled transfemoral TAVR a relatively low-risk intervention for bleeding, especially due to the use of dedicated vascular hemostasis systems and techniques (e.g., iliac bifurcation crossover, preclosure); thus, we decided not to pretreat the patient with an intravenous administration of FVIII–VWF concentrate. Within 6 weeks of HS diagnosis, the patient underwent successful transfemoral TAVR without major bleeding complications. The echocardiography displayed a mean transprosthesis gradient of 10 mm Hg and no paravalvular leak ([Fig. 2B, C]). Due to new-onset, persistent, and complete atrioventricular block post-TAVR, there was an indication for a permanent pacemaker implantation. In consideration of a higher procedure-related bleeding risk, 48 hours after TAVR we repeated blood tests, which showed full normalization of hemostasis parameters: FVIII activity of 172%, VWF:Ag of 127%, VWF:GPIbM activity of 144%, with an activity/antigen ratio of 1.13. These results excluded the need for FVIII–VWF replacement therapy before pacemaker implantation, which was performed without complications. No further blood loss occurred, and hemoglobin stabilized at a level of 9.5 g/dL (reference interval: 12.0–15.5). Considering the potential bleeding risk, the patient received a single antiplatelet therapy with clopidogrel at discharge, planning to initiate oral long-term anticoagulation with warfarin at 6 months after the completion of the recommended antiplatelet treatment period and in the absence of bleeding events. At 3 months, she was asymptomatic, and the hemoglobin level increased to 11.5 g/dL.

The role of VWF deficiency, as caused by AVWS, has steadily emerged since the initial descriptions of HS. As a proof of concept, bleeding cessation after aortic valve replacement has previously been described, with long-term clinical benefit.[5] [6] [7] An improvement in laboratory test findings have been demonstrated early after surgery[5] but rarely after TAVR. In a few reports, VWF multimers return to normal within minutes to days.[8] [9] In our case, the assays we employed—VWF:Ag, VWF:GPIbM, and FVIII—may be considered first-line assays,[10] and these returned to normal within 48 hours after TAVR. Similarly, the report by Caspar et al[11] including 48 TAVR patients identified that VWF-specific tests improved 1 week after TAVR in the whole population but more significantly in those patients (n = 11) with evident baseline AVWS. However, only one patient had a definitive diagnosis of HS. Another study comprising more than 74 patients treated by TAVR included two cases with clinical features of HS, but none fulfilled the criteria for AVWS. The analysis of the VWF:Ag and binding to platelet GPIb by ristocetin cofactor activity (VWF:RCo) at day 1 and 7 after the procedure demonstrated an increase in plasma levels of VWF in the whole population.[12]

It is worth mentioning that the decrease of VWF levels correlates inversely with the transaortic gradient both before and after valve replacement. Notably, more recent data suggest a correlation between paravalvular leaks after TAVR and the AVWS. This suggests that severe AVS and regurgitation, both characterized by turbulent flow through a restricted orifice, may share the same pathophysiological mechanism based on VWF multimers disruption.[8] [9] [11] Therefore, in a TAVR strategy, optimal prosthesis choice and deployment to achieve the lowest transprosthesis gradient and avoid paravalvular leaks are of paramount importance to correct the AVWS and foster long-term bleeding-free survival, particularly when patients need antiplatelet or anticoagulant therapy.

Publication History

Article published online:
23 December 2020

• References

• 1 Warkentin TE, Moore JC, Morgan DG. Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's disease the link?. Lancet 1992; 340 (8810): 35-37
• 2 Pareti FI, Lattuada A, Bressi C. et al. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation 2000; 102 (11) 1290-1295
• 3 Franchini M, Mannucci PM. Von Willebrand disease-associated angiodysplasia: a few answers, still many questions. Br J Haematol 2013; 161 (02) 177-182
• 4 Laffan MA, Lester W, O'Donnell JS. et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
• 5 Vincentelli A, Susen S, Le Tourneau T. et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349 (04) 343-349
• 6 Godino C, Lauretta L, Pavon AG. et al. Heyde's syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol 2013; 61 (06) 687-689
• 7 Ramachandran R, Uqdah H, Jani N. A case of recurrent obscure gastrointestinal bleeding: Heyde's syndrome - case report and review. J Community Hosp Intern Med Perspect 2018; 8 (03) 127-129
• 8 Van Belle E, Rauch A, Vincent F. et al. Von Willebrand factor multimers during transcatheter aortic-valve replacement. N Engl J Med 2016; 375 (04) 335-344
• 9 Spangenberg T, Budde U, Schewel D. et al. Treatment of acquired von Willebrand syndrome in aortic stenosis with transcatheter aortic valve replacement. JACC Cardiovasc Interv 2015; 8 (05) 692-700
• 10 Nichols WL, Hultin MB, James AH. et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
• 11 Caspar T, Jesel L, Desprez D. et al. Effects of transcutaneous aortic valve implantation on aortic valve disease-related hemostatic disorders involving von Willebrand factor. Can J Cardiol 2015; 31 (06) 738-743
• 12 Sedaghat A, Kulka H, Sinning JM. et al. Transcatheter aortic valve implantation leads to a restoration of von Willebrand factor (VWF) abnormalities in patients with severe aortic stenosis - incidence and relevance of clinical and subclinical VWF dysfunction in patients undergoing transfemoral TAVI. Thromb Res 2017; 151: 23-28