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Epiphenomena in Hypertrophic Cardiomyopathy: Acquired von Willebrand Syndrome

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Hypertrophic Cardiomyopathy

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Abstract

Acquired von Willebrand syndrome due to cardiac disorders was initially described in aortic stenosis and congenital heart defects. However, case series over several years have reported gastrointestinal bleeding due to angiodysplasia in hypertrophic cardiomyopathy (HCM). The association of gradient to severity of von Willebrand factor dysfunction in aortic stenosis was first defined in 2003 and in hypertrophic cardiomyopathy in 2008. Subsequent studies have further confirmed that platelet function analyzer 100 (PFA) and quantitative VWF multimers are strongly associated with gradients, that they function as biomarkers in demonstrating treatment responses, that bleeding is as prevalent as in aortic stenosis, and that septal reduction therapy can be curative of transfusion-dependent gastrointestinal hemorrhage from angiodysplasia.

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Author information

Authors and Affiliations

  1. Department of Cardiovascular Diseases, Mayo Clinic Florida, Jacksonville, FL, USA

    Joseph L. Blackshear

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  1. Joseph L. Blackshear
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Correspondence to Joseph L. Blackshear .

Editor information

Editors and Affiliations

  1. Westchester Medical Center, Valhalla, NY, USA

    Srihari S. Naidu

Questions

Questions

  1. 1.

    Acquired von Willebrand syndrome is limited to:

    1. A.

      Aortic stenosis

    2. B.

      Myeloproliferative disorders

    3. C.

      Obstructive hypertrophic cardiomyopathy

    4. D.

      Mitral regurgitation

    5. E.

      Not limited, occurs in all of the above

  • Answer: E. In any situation in which a large fraction of the circulating plasma is exposed to elevated shear stress during each cardiac cycle, the possibility of AVWS exists. It also occurs via immune mechanisms in myeloproliferative disorders, for example, monoclonal gammopathy of undetermined significance (MGUS).

  1. 2.

    Which statement best characterizes the post-secretion normal physiology of von Willebrand factor?

    1. A.

      VWF multimers are degraded by proteolysis during microcirculatory passage.

    2. B.

      VWF multimers are shortened by passage through the normal heart.

    3. C.

      VWF monomers are secreted and form multimers in the circulation.

    4. D.

      VWF multimer shortening is nonenzymatic.

    5. E.

      VWF is generated in the liver.

  • Answer: A. Unlike many proteins which are processed in organs, or after incoroporation into cells via specific receptors, the proteolytic enzyme which shortens VWF multimers, ADAMTS 13 circulates in plasma. The A2 domain binding site on VWF multimers is cryptic unless the globular protein is elongated, as during capillary transit, or in a high shear stress field.

  1. 3.

    Which of the following is not a characteristic of VWF

    1. A.

      Regulates angiogenesis

    2. B.

      Facilitates hemostasis in high shear environment

    3. C.

      Is a complex glycoprotein with several genetic variants causing von Willebrand disease

    4. D.

      Is secreted as a prohormone

    5. E.

      Carrier of coagulation factor VIII

  • Answer: D. VWF has numerous functions, including regulation of angiogenesis, and acting as a “molecular bus” for factor VIII. It is secreted as a fully formed ultrahigh molecular weight multimeric protein which is then reduced in size during microcirculatory passage by ADAM TS 13.

  1. 4.

    Which of the following correlate with pressure gradient in hypertrophic cardiomyopathy?

    1. A.

      VWF antigen

    2. B.

      VWF activity to antigen ratio

    3. C.

      Loss of high molecular weight multimers of VWF

    4. D.

      Platelet function analyzer collagen ADP closure time

    5. E.

      B, C, and D

  • Answer: E. Assays of VWF function which reflect the presence of high molecular weight multimers include PFA testing, VWF multimer analysis, and the VWF activity to antigen ratio (in some laboratories, a VWF collagen binding assay is substituted for VWF activity, and a VWF collagen binding activity / VWF antigen ratio is reported).

  1. 5.

    Which intervention most reliably normalized VWF multimers in a bleeding patient with obstructive hypertrophic cardiomyopathy?

    1. A.

      Beta blockers

    2. B.

      Disopyramide

    3. C.

      Pacing induced left bundle branch block

    4. D.

      Correction of atrial fibrillation

    5. E.

      Septal reduction therapy

  • Answer. E. Septal reduction therapy was associated with cessation of bleeding in patients with transfusion dependence, while medical therapy was associated with recurrence.

  1. 6.

    As screening biomarkers, BNP and PFA are:

    1. A.

      Redundant

    2. B.

      Complementarry

    3. C.

      Insensitive

    4. D.

      Non-specific

    5. E.

      Untested

  • Answer. B. As suggested by the prior question, VWF measures correlate with the amount of turbulence present from a combination of high LVOT gradient and significant associated mitral regurgitation. BNP reflects the degree of structural abnormality as measured by degree of hypertrophy and also as reflected in elevation of filling pressures.

  1. 7.

    In patients with severe aortic stenosis, which of the following is incorrect?

    1. A.

      VWF multimers normalize almost immediately after valve replacement.

    2. B.

      If VWM multimers are abnormal prior to valve replacement, use of a mechanical prosthesis and anticoagulation increases bleeding risk.

    3. C.

      VWF multimers may fail to correct if either ≥moderate paraprosthetic regurgitation or patient prosthesis mismatch is present.

    4. D.

      PFA can be a useful test periprocedurally in transcatheter aortic valve replacement as a biomarker of ≥moderate paraprosthetic regurgitation.

    5. E.

      Balloon aortic valvuloplasty rarely causes VWF multimers to normalize.

  • Answer: B. Once the turbulence associated with severe aortic stenosis is relieved, newly secreted multimers retain their high molecular weight status, and values rapidly return to normal. Despite a very high rate of abnormal VWF multimers before aortic valve replacement, bleeding in anticoagulated patients with mechanical valves after surgery is not increased.

  1. 8.

    What percent of severe aortic stenosis or obstructive hypertrophic cardiomyopathy patients have loss of high molecular weight multimers of VWF?

    1. A.

      10%

    2. B.

      25%

    3. C.

      70-90%

    4. D.

      100%

    5. E.

      50%

  • Answer: C. The percentage of abnormal VWF multimers reaches 100% only in the LVAD population. For other entities which physicians categorize as severe by usual echocardiographic and hemodynamic criteria, multimer abnormalities are present in 70–90%.

  1. 9.

    A patient with frequent epistaxis, some requiring emergency room visits, has class III angina and a left ventricular outflow tract resting instantaneous gradient of 55 mm Hg. VWF multimer testing is abnormal. She is to undergo septal myectomy for symptoms. Based on these data, you tell her:

    1. A.

      Nosebleeds are likely to stop after.

    2. B.

      Nosebleeds will not be affected by surgery

    3. C.

      Bleeding risk during surgery is high

    4. D.

      She must have an ENT consult before surgery

    5. E.

      She may not take aspirin or anticoagulation after surgery

  • Answer: A. Mucosal bleeding, i.e., GI and nasal, are the two most common clinical manifestations of AVWS due to cardiac lesions. The high gradient, and abnormal lab tests of VWF function, and the high likelihood of a good hemodynamic response from myectomy suggest that epistaxis will be cured by myectomy.

  1. 10.

    Based on case reporting thus far, transfusion- dependent gastrointestinal bleeding from acquired von Willebrand syndrome in hypertrophic cardiomyopathy occurs in:

    1. A.

      Equal percentages of men and women

    2. B.

      Much higher frequency in women compared to men

    3. C.

      Much higher frequency in men compared to women

    4. D.

      Slightly more prevalent in women versus men

    5. E.

      Slightly more prevalent in men versus women

  • Answer: B. Like takotsubo cardiomyopathy, this entity has shown a much higher occurrence in women versus men. This appears to be unique to hypertrophic cardiomyopathy, since such a gender imbalance of AVWS does not occur with other high shear states such as aortic stenosis or mitral regurgitation. Smaller chamber size in women compared to me could be a factor, but the precise reason why this should be is unknown.

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Blackshear, J.L. (2019). Epiphenomena in Hypertrophic Cardiomyopathy: Acquired von Willebrand Syndrome. In: Naidu, S. (eds) Hypertrophic Cardiomyopathy. Springer, Cham. https://doi.org/10.1007/978-3-319-92423-6_18

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  • DOI: https://doi.org/10.1007/978-3-319-92423-6_18

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  • Online ISBN: 978-3-319-92423-6

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