Correspondence

Aortic Stenosis, von Willebrand Factor, and Bleeding

N Engl J Med 2003; 349:1773-1774October 30, 2003

Article

To the Editor:

We have a concern regarding the report by Vincentelli et al. (July 24 issue)1 on acquired von Willebrand syndrome in aortic stenosis. What is the true clinical relevance of the documented laboratory findings? In their study, 9 of 42 patients (21 percent) had bleeding symptoms, whereas 67 to 92 percent had hemostatic abnormalities that were consistent with the presence of acquired von Willebrand syndrome. We studied 10 patients (mean age, 73 years) with severe aortic stenosis (mean transvalvular gradient greater than 51 mm Hg) before aortic-valve replacement. One of them had mild mucocutaneous bleeding and a type 2A von Willebrand pattern, whereas eight had hemostatic abnormalities without any hemorrhage. Thus, our observation confirms the discrepancy between the low frequency of bleeding symptoms and the high prevalence of hemostatic abnormalities in this setting. Although aortic stenosis is a relevant in vivo model of shear stress–induced cleavage of von Willebrand factor with resultant loss of its largest multimers, the diagnosis of von Willebrand syndrome should be restricted to patients who have bleeding.

Christoph Sucker, M.D.
Peter Feindt, M.D.
Ruediger E. Scharf, M.D.
University Medical Center, 40225 Duesseldorf, Germany
sekretariat-ihtm@med.uni-duesseldorf.de

1 References

1. 1

   Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003;349:343-349
   Full Text | Web of Science | Medline

To the Editor:

Vincentelli et al. report the occurrence of bleeding and acquired von Willebrand syndrome in patients with severe aortic-valve stenosis (Heyde's syndrome). Proteolysis of von Willebrand factor is increased by high shear stress, and patients with hypertrophic obstructive cardiomyopathy may therefore be susceptible to a similar bleeding abnormality. Indeed, we recently reported a case of hypertrophic obstructive cardiomyopathy and occult bleeding in which the bleeding was eliminated by percutaneous alcohol septal ablation.1 Our patient, a 57-year-old man with hypertrophic obstructive cardiomyopathy (left ventricular outflow gradients of up to 200 mm Hg), presented with severe iron-deficiency anemia. An extensive search for the source of bleeding yielded no results, and attempts at discontinuation of iron supplementation were promptly followed by recurrent anemia. Subsequently, alcohol septal ablation was performed, with reduction of the left ventricular outflow gradient and elimination of the symptoms of hypertrophic obstructive cardiomyopathy. Iron supplementation was discontinued, and the anemia has not recurred. Although von Willebrand factor was not examined in this case, the disorder appears to be similar to Heyde's syndrome. We suggest that acquired von Willebrand syndrome may contribute to bleeding in patients with hypertrophic obstructive cardiomyopathy.

Peter R. Hansen, M.D., D.M.Sc.
Christian Hassager, M.D., D.M.Sc.
Gentofte University Hospital, DK-2900 Hellerup, Denmark
prh@dadlnet.dk

1 References

1. 1

   Riis Hansen P, Hassager C. Septal alcohol ablation and Heyde's syndrome revisited. J Intern Med 2003;253:490-491
   CrossRef | Web of Science | Medline

To the Editor:

I was pleased to read the article by Vincentelli et al. on acquired Von Willebrand syndrome in aortic stenosis. The authors' data clearly support the idea that von Willebrand factor abnormalities are directly related to the severity of aortic stenosis and are improved by valve replacement. Along with Heyde1 and Schwartz,2 I called attention to this association, in an article published in 1961.3 For some time after my article appeared, colleagues began to call the association Williams's syndrome. Later, when direct upper and lower endoscopies became common practice, the association between gastrointestinal bleeding and aortic stenosis was ascribed to arteriovenous ectasias and similar vascular abnormalities presumably associated with aging, in the same vein as aortic stenosis.

The observation by Vincentelli and coworkers only proves to me that if a physician lives long enough, a few things he or she has reported will turn out to be true.

Ralph C. Williams, Jr., M.D.
University of New Mexico, Albuquerque, NM 87131
rcwilliams@salud.unm.edu

3 References

1. 1

   Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl J Med 1958;259:196-196
   Web of Science

2. 2

   Schwartz BM. Additional note on bleeding in aortic stenosis. N Engl J Med 1958;259:456-456
   Web of Science

3. 3

   Williams RC Jr. Aortic stenosis and unexplained gastrointestinal bleeding. Arch Intern Med 1961;108:859-863
   Web of Science | Medline

Author/Editor Response

Dr. Sucker and colleagues confirm the high frequency of hemostatic abnormalities in severe aortic stenosis but point out that the frequency of bleeding symptoms is low. Such a discrepancy was also found in our series and is usual in the von Willebrand syndrome as well as in other hemostatic diseases, since bleeding symptoms depend on the presence of bleeding-prone lesions (such as angiodysplasias or traumatic or surgical lesions). It is well known that the clinical expression of acquired von Willebrand syndrome is highly variable.1 However, the diagnosis of this syndrome relies on biologic data.2 We believe that in circumstances involving trauma, such as noncardiac surgery, the risk of bleeding is present in patients with severe aortic stenosis, even if they do not have any spontaneous bleeding. Moreover, this risk could be especially high in patients who are not eligible for surgical valve replacement: in a prospective survey of 123 patients with asymptomatic aortic stenosis, 8 of the patients who did not undergo surgery died, 4 of them from cardiac causes and 2 from gastrointestinal bleeding, suggesting that the risk of bleeding is not negligible as compared with classic cardiac causes of death.3 In our opinion, the high probability of von Willebrand factor abnormalities should be taken into account in the management of severe aortic stenosis, even in the absence of bleeding symptoms.

Drs. Hansen and Hassager observed the association between bleeding symptoms and hypertrophic obstructive cardiomyopathy and suspect that similar proteolysis of high-molecular-weight multimers can occur in this disease, which is associated with high shear stress. Such a hypothesis is in good accordance with our findings and also with previously reported data and should be confirmed by specific exploration of von Willebrand factor in such cases.4

Finally, we would like to thank Dr. Williams for his perspicacity and for his continued interest in this issue, from 1958 to this day.

Sophie Susen, M.D.
André Vincentelli, M.D.
Brigitte Jude, M.D., Ph.D.
University Hospital, 59037 Lille, France

4 References

1. 1

   Veyradier A, Jenkins CSP, Fressinaud E, Meyer D. Acquired von Willebrand syndrome: from pathophysiology to management. Thromb Haemost 2000;84:175-182
   Web of Science | Medline

2. 2

   Federici AB, Rand JH, Bucciarelli P, et al. Scientific report of the registry on acquired von Willebrand syndrome: recommendations for diagnosis and management. (Accessed October 9, 2003, at http://www.med.unc.edu/isth/ssccomm.htm.)
   

3. 3

   Otto CM, Burwash IG, Legget ME, et al. Prospective study of asymptomatic valvular aortic stenosis: clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262-2270
   Web of Science | Medline

4. 4

   Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR. Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. Blood 1986;67:758-761
   Web of Science | Medline

Citing Articles (8)

Citing Articles

1. 1

   Manuel Méndez Balión, Nuria Muñoz Rivas. (2011) Insuficiencia cardiaca, anemia y angiodisplasia: ¿qué más puede hacerse?. Medicina Clínica 136:2, 85-86
   CrossRef

2. 2

   A. Casonato, S. Sponga, E. Pontara, M. G. Cattini, C. Basso, G. Thiene, G. Cella, V. Daidone, G. Gerosa, A. Pagnan. (2011) von Willebrand factor abnormalities in aortic valve stenosis: Pathophysiology and impact on bleeding. Thrombosis and Haemostasis 106:1, 58-66
   CrossRef

3. 3

   Mark S. Slaughter. (2010) Hematologic Effects of Continuous Flow Left Ventricular Assist Devices. Journal of Cardiovascular Translational Research 3:6, 618-624
   CrossRef

4. 4

   Helen M. Hayes, Lawrence G. Dembo, Robert Larbalestier, Gerry O'Driscoll. (2010) Management Options to Treat Gastrointestinal Bleeding in Patients Supported on Rotary Left Ventricular Assist Devices: A Single-Center Experience. Artificial Organs 34:9, 703-706
   CrossRef

5. 5

   Vijay Singh, Jeffrey A. Alexander. (2009) The evaluation and management of obscure and occult gastrointestinal bleeding. Abdominal Imaging 34:3, 311-319
   CrossRef

6. 6

   Gottumukkala S. Raju, Lauren Gerson, Ananya Das, Blair Lewis. (2007) American Gastroenterological Association (AGA) Institute Technical Review on Obscure Gastrointestinal Bleeding. Gastroenterology 133:5, 1697-1717
   CrossRef

7. 7

   Christoph Sucker. (2007) The Heyde syndrome: Proposal for a unifying concept explaining the association of aortic valve stenosis, gastrointestinal angiodysplasia and bleeding. International Journal of Cardiology 115:1, 77-78
   CrossRef

8. 8

   Kazunori Yoshida, Satoshi Tobe, Masahito Kawata, Masahiro Yamaguchi. (2006) Acquired and Reversible von Willebrand Disease With High Shear Stress Aortic Valve Stenosis. The Annals of Thoracic Surgery 81:2, 490-494
   CrossRef