Early release, published at www.cmaj.ca on June 29, 2015. Subject to revision. CMAJ Practice CME

Cases Heyde syndrome: gastrointestinal bleeding and

Bartosz Hudzik MD PhD, Krzysztof Wilczek MD PhD, Mariusz Gasior MD PhD

n 82-year-old man presented with a two- time, diminished ristocetin cofactor activity and Competing interests: week history of increasing shortness of depletion of high-molecular-weight multimers of None declared. Abreath and exercise intolerance. His medi- von Willebrand factor on gel electrophoresis) This article has been peer cal history included chronic obstructive pulmonary confirmed type IIA acquired von Willebrand syn- reviewed. disease, hypertension and chronic kidney disease. drome (deficit of high-molecular-weight multi­ The authors have obtained He had undergone left nephrectomy and splenec- mers of von Willebrand factor). patient consent. tomy for abdominal trauma and had had three epi- Given the patient’s comorbidities and an Correspondence to: sodes of lower gastrointestinal bleeding for which extremely high risk of intraoperative death (logistic Bartosz Hudzik, blood transfusions had been required. Prior workup EuroSCORE­ 42.7% and Society of Thoracic Sur- [email protected] for gastrointestinal bleeding included geons adult cardiac surgery risk score 29.3%; CMAJ 2015. DOI:10.1503​ and argon plasma coagulation for . sources available in Appendix 1, at www.cmaj.ca/ /cmaj.150194 The patient’s vital signs were normal. On lookup/suppl/doi:10.1503/cmaj.150194/-/DC1), the chest examination, there were audible crackles at patient was not considered a suitable candidate for the bases of both lungs and a grade 4/6 systolic surgical aortic valve replacement and was referred murmur at the second right intercostal space for transcatheter aortic valve implantation. radiating toward the right carotid artery. The Following implantation of a CoreValve 31 findings of a rectal examination (including test- aortic valve, the valve area was 3.7 cm2. The ing for fecal occult blood) were normal. Oxygen patient did not experience gastrointestinal bleed- saturation was 94% on room air. ing in the periprocedural period. However, Laboratory tests showed hemoglobin 95 (nor- because of procedural blood loss (bleeding at the mal 130–170) g/L, hematocrit 30% (normal 40%– access site), two units of packed red blood cells 52%), platelets 201 (normal 150–400) × 109/L, were transfused. The patient was discharged creatinine 150 (normal 70–110) µmol/L, estimated seven days later with a six-month prescription for glomerular filtration rate 37 (normal > 90) mL/min a single antiplatelet agent (clopidogrel). The per 1.73 m2 and N-terminal pro-B-type natriuretic 12-month follow-up was unremarkable, with no peptide 5670 (normal < 125) pg/mL. Troponins further episodes of gastrointestinal bleeding were within the normal range. Electrocardiography reported. Left ventricular ejection fraction had on admission was suggestive of left ventricular increased to 37%, and the patient’s respiratory hypertrophy with no ischemic changes. Radio- symptoms had improved (New York Heart Asso- graphic signs of cardiac enlargement were present. ciation functional class II). A follow-up coagula- Transthoracic echocardiography showed severe tion study showed no deficit of high-molecular- depression of left ventricular systolic function with weight multimers of von Willebrand factor. an ejection fraction of 24%, along with severe aor- tic stenosis, a heavily calcified aortic valve with Key points aortic valve area of 0.7 cm2 and a mean aortic valve gradient of 37 mm Hg (Figure 1). • An association exists between severe aortic stenosis and recurrent The history of lower gastrointestinal bleeding bleeding from intestinal angiodysplasia. (angiodysplasia) and the presence of aortic steno- • For patients with recurrent gastrointestinal bleeding, the differential diagnosis should include Heyde syndrome. sis were consistent with Heyde syndrome. An enhanced coagulation study was requested, • Management of Heyde syndrome is challenging, with treatment options that include medical therapy, endoscopic interventions, colonic including platelet function and measurement of surgery and valve replacement. the function and concentration of von Willebrand • If valve replacement is performed, antiplatelet and anticoagulant complex:factor VIII. The results (prolonged agents should be used with caution, to minimize the risk of rebleeding. platelet function analyzer [PFA-100] closure

©2015 8872147 Canada Inc. or its licensors CMAJ 1 Practice

Discussion much lower prevalence (see references available in Appendix 1, www.cmaj.ca/lookup/suppl/ The association between chronic gastrointesti- doi:10.1503/cmaj.150194/-/DC1). In patients for nal bleeding due to angiodysplasia and calcific whom aortic stenosis is the index diagnosis, there aortic stenosis was first described in 1958 by is a 100-fold greater risk of gastrointestinal bleed- Edward Heyde and has since been termed Heyde ing, relative to those without aortic stenosis.3 Still, syndrome. Not until 1992 did Warkentin and col- angiodysplasia is the most common vascular leagues elucidate the role of acquired coagulo­ abnormality of the and the pathy (depletion of high-molecular-weight multi- second leading cause (after diverticulosis) of mers of von Willebrand factor) in the patho­genesis lower gastrointestinal bleeding in patients over of Heyde syndrome (historical sources listed the age of 60.7 in Appendix 1, available at www.cmaj.c​ a/lookup/ suppl/doi:10.1503/cmaj.150194/-/DC1). Although Pathophysiology there is no consensus definition, many authors There are several plausible explanations for Heyde affirm that Heyde syndrome refers to a triad of syndrome, but the most convincing link between aortic stenosis, acquired type IIA von Willebrand aortic stenosis and gastrointestinal bleeding from syndrome and recurrent bleeding from gastroin- angiodysplasia is a deficiency of high-molecular- testinal angiodysplasia (Figure 2).1–5 weight multimers of von Willebrand factor.3,4 Fig- ure 2 summarizes the pathophysiologic mechanisms Epidemiology underlying Heyde syndrome. Aortic stenosis or Degenerative aortic stenosis is the most common sclerosis is associated with high shear stress, which valvular heart disease in older patients and is one elevates von Willebrand factor–cleaving metallo- of the main causes of morbidity and mortality in protease activity, leading to proteolysis of von this age group. Its prevalence increases with age, Wille­brand factor, and increases interactions reaching 2%–7% after the age of 65 years.6 The between von Willebrand factor and platelets, lead- presence of symptoms from aortic stenosis heralds ing to degradation or clearance of von Willebrand poor prognosis and warrants surgery.6 However, factor.4 the role of aortic valve replacement in patients Von Willebrand factor, an adhesive glycopro- who are asymptomatic remains controversial.6 tein that is synthesized in endothelial cells and Angiodysplasia is another age-related degen- megakaryocytes, has two major functions in erative process, characterized by dilated, thin- hemostasis. It helps with platelet–subendothelium walled tortuous vessels in the mucosa and sub- adhesion and platelet–platelet interactions (i.e., mucosa of the gastrointestinal tract, including aggregation), and it carries factor VIII in plasma. arterioles, capillaries and venules. Angiodysplasia Von Willebrand factor also prolongs the half-life accounts for 1%–6% of hospital admissions for of factor VIII by protecting it from proteolytic gastrointestinal bleeding.2 It may occur through- degradation. It delivers factor VIII to the site of out the gastrointestinal tract, but most particularly vascular injury, thus enhancing the hemostatic in the right colon and cecum.2,3,7 process.8 Defects or deficiencies in von Wille- Proving an association between aortic stenosis brand factor underlie both inherited von Wille- and angiodysplasia is challenging, because both brand disease and acquired von Willebrand syn- entities are common in older patients. Some drome.8 Changes in the function of von Willebrand authors have suggested that the rate of aortic ste- factor are not specific to aortic valve disease. Con- nosis among patients with gastrointestinal bleed- ditions linked to von Willebrand syndrome are ing is as high as 30%–40%.3 Others have reported listed in Box 1.

Figure 1: Transthoracic echocardiography shows (A) severe aortic stenosis with heavily calcified aortic valve (AV); (B) aortic valve area (AVA) of 0.7 cm2; and (C) mean aortic valve gradient of 37 mm Hg. LA = left atrium, LV = left ventricle.

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Other possible factors implicated in the patho- electrophoresis (quantification of high-molecular- genesis of Heyde syndrome include mucosal weight multimers) > PFA-100 closure time > von ischemia, cholesterol embolization, acquired plate- Willebrand factor ristocetin cofactor > bleeding let dysfunction and inflammatory reactions.3 Bleed- time > von Willebrand factor antigen.4 ing from angiodysplasia may reflect an interac- tion between an uncommon coagulopathy (caused Treatment by a common valvular disease) and a common Management of Heyde syndrome often requires a vascular disease of the gastrointestinal tract. multidisciplinary approach, and treatment options include medical therapy, endoscopic interven- Diagnostic workup tions, colon surgery and aortic valve replacement.3 Initial investigations should explore other Treatment modalities used in von Willebrand sources of gastrointestinal bleeding, including disease (e.g., desmopressin, octreotide or supple- gastric or duodenal ulcer, diverticular disease, mentation of factor VIII or von Willebrand fac- gastrointestinal malignancy and inflammatory tor) are usually insufficient or ineffective for bowel disease. All patients with gastrointestinal acquired type IIA von Willebrand syndrome.2–4 bleeding should undergo colonoscopy. Capsule Administration of von Willebrand factor – factor or computed tomography may be VIII concentrate immediately before surgery useful when initial investigations show no abnor- should be considered for patients who have tran- mality. The presence of angiodysplasia should sient improvement in von Willebrand factor alert the physician to possible aortic valve dis- activity with a test dose (see references listed in ease, and Heyde syndrome should be included in Appendix 1). Some experts suggest the use of the differential diagnosis for gastrointestinal estrogen–progesterone preparations; however, the bleeding in which the cause is unclear.2,3,7 mechanism of action of such treatment is still Given the complexity of von Willebrand factor unknown.3,4 Thalidomide has been shown to pathophysiology, there is no single “robust” assay reduce the incidence of severe gastrointestinal that can be used in the diagnosis of a bleeding diath­ bleeding in several studies.3 Repeated blood esis. Several tests are warranted, which can be cate- transfusions may offer some, though transient, gorized as screening tests and discriminating assays symptomatic relief. (see Appendix 2, www.cmaj​.ca​/lookup/suppl/ Local endoscopic interventions for gastroin- doi:10.1503/cmaj.150194/-/DC1). A complete set testinal bleeding include heat probe and bipolar– of laboratory investigations is necessary to fully multipolar coagulation, neodymium-doped diagnose all variants of von Willebrand disease and yttrium aluminum garnet laser and argon plasma von Willebrand syndrome. Ranked in descending coagulation.3 Epinephrine and ethanolamine can order, the sensitivity of various tests for type IIA be injected independently or concomitantly. von Willebrand syndrome in patients with bleeding Medical or endoscopic interventions for the gastrointestinal angiodysplasia is as follows: gel bowel are often used as bridge therapies to valve

Age-related degenerative disease

Gastrointestinal mucosa Gastroinstestinal hypoxia, Aortic stenosis angiodysplasia altered pulse waveform, cholesterol emboli

High shear stress Loss of HMW vWFmultimers

Gastrointestinal Acquired type IIA bleeding von Willebrandsyndrome

Figure 2: Pathophysiologic mechanisms underlying Heyde syndrome, which link aortic stenosis, gastrointes- tinal angiodysplasia and acquired type 2A von Willebrand syndrome. Solid arrows = recognized mecha- nisms, dashed arrows = possible mechanisms. Adapted, with permission, from Gola and Lelonek5 (© 2010 Via Medica). HMW = high-molecular-weight, vWF = von Willebrand factor.

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replacement. In cases of severe bleeding, emer- (e.g., prior major bleed, comorbidities).6 Experts gent bowel resection may be needed; however, recommend lifelong oral anticoagulation for bleeding may continue from other sites.1–3 Recur- patients with a mechanical prosthesis.6 Low-dose rent severe gastrointestinal bleeding, particularly acetylsalicylic acid (ASA) should be considered when medical and endoscopic interventions have for the first three months after implantation of an failed, often necessitates aortic valve replacement, aortic bioprosthesis.6 Alternatively, oral anticoagu- which is usually employed in the treatment of lation may be considered for the first three months severe aortic stenosis.1–3 Valve replacement has after implantation of an aortic bioprosthesis.6 been shown to improve coagulation abnormalities More recently, transcatheter aortic valve im- in Heyde syndrome and may offer the possibility plantation has emerged as a feasible option for of long-term resolution of symptoms.1–3 patients with severe aortic stenosis whose risk is Oral anticoagulation following valve replace- deemed too high for surgical aortic valve re- ment increases the risk of rebleeding. Use of a bio- placement.9 Experts recommend dual-antiplate- prosthesis precludes long-term anticoagulation. let therapy (low-dose ASA + clopidogrel) for Generally, a bioprosthesis should be considered one to three months following the procedure.10 for patients older than 65 years and is also recom- However, the use of ASA could increase the risk mended when anticoagulation at therapeutic levels of recurrent gastrointestinal bleeding. A recent is contraindicated because of a high bleeding risk systematic review and meta-analysis11 showed that dual-antiplatelet therapy following trans- Box 1: Causes of acquired von Willebrand catheter aortic valve implantation had no benefit syndrome* over single-antiplatelet therapy in terms of re- Cardiovascular disease duction of ischemic events, with a trend toward • Aortic stenosis increased harm due to bleeding. The authors concluded that in future, consideration should be • Hypertrophic cardiomyopathy (with obstruction of left ventricular outflow tract) given to clopidogrel monotherapy. • Dysfunctional heart valve prosthesis • Ventricular septal defect References 1. Massyn MW, Khan SA. Heyde syndrome: a common diagnosis • Patent ductus arteriosus in older patients with severe aortic stenosis. Age Ageing 2009;​ • Left ventricular assist device 38:267-70, discussion 251. 2. Pate GE, Chandavimol M, Naiman SC, et al. Heyde’s syndrome: Autoimmune disorders a review. J Heart Valve Dis 2004;13:701-12. • Systemic lupus erythematosus 3. Islam S, Cevik C, Islam E, et al. Heyde’s syndrome: a critical review of the literature. J Heart Valve Dis 2011;20:366-75. • Scleroderma 4. Warkentin TE, Moore JC, Anand SS, et al. Gastrointestinal • Mixed connective tissue disease bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev 2003;17:272-86. Lymphoproliferative disorders 5. Gola W, Lelonek M. Clinical implication of gastrointestinal bleeding in degenerative aortic stenosis: an update. Cardiol J • Monoclonal gammopathy of undetermined 2010;17:330-4. significance 6. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the • Lymphoma management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451-96. • Multiple myeloma 7. Regula J, Wronska E, Pachlewski J. Vascular lesions of the Myeloproliferative disorders gastrointestinal tract. Best Pract Res Clin Gastroenterol 2008;​ 22:313-28. • Essential thrombocythemia 8. Flood VH. Perils, problems, and progress in laboratory diagnosis of von Willebrand disease. Semin Thromb Hemost 2014;​40:41-8. • Polycythemia vera 9. Godino C, Lauretta L, Pavon AG, et al. Heyde’s syndrome • Chronic myeloid leukemia incidence and outcome in patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61:687-9. Nonhematologic neoplasms 10. Webb J, Rodes-Cabau J, Fremes S, et al. Transcatheter aortic • Wilms tumour valve implantation: a Canadian Cardiovascular Society posi- tion statement. Can J Cardiol 2012;28:520-8. • Adenocarcinoma 11. Gandhi S, Schwalm JDR, Velianou JL, et al. Comparison of Drugs dual-antiplatelet therapy to mono-antiplatelet therapy after trans- catheter aortic valve implantation: systematic review and meta- • Ciprofloxacin analysis. Can J Cardiol 2015;31:775-84. • Griseofulvin • Valproic acid Affiliation: Third Department of Cardiology, Silesian Centre for Heart Disease, Medical University of Silesia, Zabrze, Poland • Hydroxyethyl starch • Recombinant factor VIII Contributors: All authors made substantial contributions to the conception of the manuscript and to drafting and revising Chronic kidney disease (uremia) the manuscript, gave final approval of the revised version to Cirrhosis of the liver be published and agree to act as guarantors for the work. 5 *Based on various sources, including Gola and Lelonek and Acknowledgement: The authors acknowledge Dr. Lukasz references listed in Appendix 1 (available at www.cmaj.ca/ lookup/suppl/doi:10.1503/cmaj.150194/-/DC1). Siedlecki for his contribution in the preparation of the manuscript.

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