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Invited Commentary
May 2016

Valvular Heart Disease and Acquired Type 2A von Willebrand SyndromeThe “Hemostatic” Waring Blender Syndrome

Author Affiliations
  • 1Heart South Cardiovascular Group, Department of Biostatistics, University of Alabama at Birmingham, Alabaster and Birmingham, Alabama
  • 2Hugh Kaul Personalized Medicine Institute, Departments of Neurology and Epidemiology, University of Alabama at Birmingham, Alabaster and Birmingham, Alabama
JAMA Cardiol. 2016;1(2):205-206. doi:10.1001/jamacardio.2016.0182

Few have witnessed the so-called Waring blender syndrome. This hemolysis of red blood cells, sometimes life-threatening, typically occurs in the setting of a dysfunctional prosthetic heart valve.1 Biomedical engineering and surgical advances have largely reduced this syndrome to textbooks. Unlike this exceedingly rare syndrome, acquired type 2A von Willebrand syndrome is a relatively common and typically unrecognized life-threatening condition with a similar etiology.2

Acquired type 2A von Willebrand syndrome also arises from blood flow exposed to abnormally increased shear stress. Blackshear and colleagues3 convincingly extend the recognition of acquired von Willebrand syndrome to dysfunctional prosthetic valves. They and others have previously described this phenomenon and confirmed its mechanism in native valve diseases, abnormal vascular structures, congenital heart lesions, and therapy with left ventricular assist devices. Advances in the last decade only now permit a detailed mechanistic understanding of this syndrome. While diagnostic and treatment criteria remain to be rigorously defined, pathophysiologic knowledge will help guide clinical recognition and management.

Gastrointestinal bleeding from angiodysplasia in the setting of aortic stenosis was described by Edward C. Heyde, MD, in a letter to the New England Journal of Medicine in 1958.4 Heyde syndrome is now known to be caused by the induction of acquired type 2A von Willebrand syndrome.5,6 Shear stress is crucial in the homeostasis of the plasma glycoprotein von Willebrand factor (vWF).7 Von Willebrand factor is an adhesive, multifunctional, large multimerized protein that has binding sites for collagen, platelet glycoprotein receptors, and coagulation factor VIII. It binds to the injured vessel wall, recruits platelets to adhere and aggregate at the site, and binds as well as protects factor VIII to activate the coagulation cascade. Normal hemostatic function in the arteries and during microcirculation critically depends on the proper percentage of vWF high molecular weight multimers (HMWMs): too few vWF HMWMs and bleeding ensues, too many HMWMs and abnormal clotting, such as thrombocytopenic purpura, may result.8 Regulation of the distribution of vWF multimers is crucial for the optimal interaction of platelets and coagulation to maintain the balance between bleeding and thrombosis in response to vessel injury and vascular lesions.

The concentration of vWF HMWMs is controlled by the plasma metalloprotease ADAMTS-13 (a disintegrin and zinc metalloprotease with a thrombospondin type 1 motif, member 13) (also known as von Willebrand factor–cleaving protease), which cleaves between a tyrosine at position 1605 and a methionine at 1606 in vWF, reducing the percentage of HMWMs.9 The increased shear stress in severe aortic stenosis (and the other conditions described by Blackshear et al3) causes a conformational change in HMWMs of vWF exposing this cleavage site. If the percentage of circulating vWF HMWMs falls below approximately 10.5%, the risk of bleeding increases. The percentage of HMWMs is inversely correlated with the transvalvular mean gradient in moderate to severe aortic stenosis: the higher the gradient, the lower the percentage of vWF HMWMs. The induced clotting dysfunction disrupts the hemostatic mechanism that prevents common underlying vascular lesions from bleeding. This is particularly true for vascular malformations that also have high local shear stress (eg, angiodysplasia). The Platelet Function Analyzer 100 (Siemens USA) adenosine diphosphate cartridge closure time, a measure of platelet function at high shear stress, can help one diagnose the hemostatic defect in acquired type 2A von Willebrand syndrome.

The theme of biomedical science building on the astute and foundational clinical observations of Erik Adolf von Willebrand in 1926 and Edward C. Heyde in 1958 should not be overlooked. In the dawning age of “big data” and “-omics,” the work of Blackshear et al3 is an elegant testimonial to the continued informative role of detailed, time-consuming, and difficult-to-fund bedside research embedded in clinical practice with a modest-sized patient cohort.

The study by Blackshear et al3 in JAMA Cardiology describes the frequency of the hemostatic defect and clinical Heyde syndrome in the setting of dysfunctional prosthetic valves, whether surgical or transcatheter implants. Recognition of the hemostatic defect of the acquired von Willebrand syndrome may itself provide a new avenue to help diagnose significant prosthetic valve dysfunction. A biomarker of valve dysfunction would assist in the often-difficult clinical determination of when prosthetic valve dysfunction is present and justifies repeated intervention. Aside from prosthetic valve dysfunction, Blackshear et al3 also summarize the occurrence of acquired von Willebrand syndrome in multiple high shear stress cardiovascular lesions. Moderate and severe aortic stenosis, severe aortic regurgitation, severe mitral regurgitation, hypertrophic obstructive cardiomyopathy, congenital heart diseases, left ventricular assist devices, and other vascular lesions also frequently induce acquired vWF functional deficiency, as well as the resulting clinical syndrome.

Oral anticoagulation with warfarin potassium is almost universally required during many stages of managing the patient with valvular heart disease, particularly with concomitant valvular atrial fibrillation. In this setting, recognition of acquired von Willebrand syndrome is more difficult but pivotal. Platelet dysfunction without thrombocytopenia caused by native or prosthetic valve dysfunction may be the primary “culprit” for the bleed, not the oral anticoagulant. Naturally, a history of bleeding and anemia will deter valve replacement. We foresee that the risk of oral anticoagulation after a procedure is begetting further, even life-threatening, bleeding. Paradoxically, there is only 1 permanent treatment (and typically cure) for acquired type 2A von Willebrand syndrome and its attendant bleeding: fixing the source of abnormally high shear stress. An uncomfortably risky de novo or repeated valve procedure must be considered. Because of the disease path leading to this clinical juncture, it is almost a given that the patient is rarely an “ideal candidate” or that the timing for an invariably hazardous procedure is rarely “optimal.” Except when patient-prosthesis mismatch occurs, the correction of the percentage of vWF HMWMs and of Platelet Function Analyzer 100 closure times typically occurs within hours to days after valve treatment, whether percutaneous or surgical.

While the precise incidence and correlation with underlying lesion severity remains poorly defined except in aortic stenosis, reduced vWF HMWMs and subsequent clinical bleeding appear to be quite frequent in patients with several cardiac lesions. As the old “hemolytic” Waring blender syndrome is relegated to a textbook curiosity, Blackshear and colleagues3 describe, confirm, and highlight a more ubiquitous “hemostatic” Waring blender syndrome. This syndrome will not only enter our textbooks but will surely be encountered and increasingly recognized in our practices. With the dramatically expanding capabilities for surgical and transcatheter treatment of valvular disease, we must routinely consider the possibility of acquired type 2A von Willebrand syndrome in every cardiac patient with blood flow exposed to a high shear stress lesion.

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Article Information

Corresponding Author: William B. Hillegass, MD, MPH, Heart South Cardiovascular Group, Department of Biostatistics, University of Alabama at Birmingham, 13 Brush Creek Farm, Columbiana, AL 35051 (hillegas@mail.ad.uab.edu).

Published Online: April 6, 2016. doi:10.1001/jamacardio.2016.0182.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

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