Ann Thorac Surg 2006;81:1114-1116
© 2006 The Society of Thoracic Surgeons
Case report
Acquired von Willebrand Disease Type IIA in Patients with Aortic Valve Stenosis
Kazunori Yoshida, MD
a
,
*
,
Satoshi Tobe, MD
a
,
Masahito Kawata, MD
b
a Department of Cardiovascular and Thoracic Surgery, Akashi Medical Center, Akashi, Japan
b Department of Cardiology, Akashi Medical Center, Akashi, Japan
Accepted for publication January 3, 2005.
* Address correspondence to Dr Yoshida, Department of Cardiovascular and Thoracic Surgery, Akashi Medical Center, Akashi, 743-33 Okubo-cho Yagi, Akashi, 674-0063 Japan (Email: kazu.y-akashi{at}amc1.jp).
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Abstract
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The authors report the case of a 72-year-old woman with severe aortic stenosis who had a bleeding tendency develop due to type IIA acquired von Willebrand disease. She underwent aortic valve replacement with a 19-mm Freestyle stentless valve (Medtronic Inc, Minneapolis, MN). The postoperative course was uneventful and the bleeding tendency resolved. A review of this operative case from our institution demonstrated that aortic valve replacement was one of the most effective treatments of this disease, which can be potentially lifesaving.
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Introduction
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When blood flows through a stenosed aortic valve, increased shear stress causes a vicious circle of progressive endothelial damage and inflammation. Some authors have reported that shear forces directly affect the molecular conformation of large von Willebrand factor multimers, giving rise to acquired von Willebrand disease type IIA; they have also noted significant increases in shear-induced platelet aggregation and von Willebrand factor collagen-binding activity and antigen levels after correction of aortic valve stenosis [1–5].
A 72-year-old woman with cutaneous and mucosal bleeding was admitted because of increasing generalized fatigue and dyspnea on effort. She was being followed-up for severe aortic stenosis. On admission, a chest roentgenogram showed marked cardiomegaly (cardiothoracic ratio, 65%) and mild pulmonary congestion. Electrocardiography was normal with the exception of mild left ventricular hypertrophy. Laboratory results revealed a hemoglobin of 9.0 g/dL, hematocrit of 28.6%, platelets of 27 x 104/µl, prothrombin time of 95%, prothrombin international normalized ratio of 1.0, fibrinogen of 253 mg/dL, and bleeding time of 10 minutes plus. Von Willebrand factor was reduced at 45% (normal range, 60% to 160%). Von Willebrand factor circulates as a gigantic, multimeric protein that may exceed 20,000 Kd in size; a single molecule may be longer than 4 µm, or twice the diameter of a platelet. Endothelial cells secrete this factor into the blood, which contributes to the formation of platelet plugs. Immunoblotting analysis was conducted to compare the subunit composition of plasma von Willebrand factor in the present patient with that of a control subject (N) and with that of this patient before surgery (A) (Fig 1). In the immunoblotting analysis, L, M, S, and SS represent large, middle, small and very small multimers, respectively. The black arrow shows the deficit zone of large multimers (L zone in the A). This revealed that the present patient exhibited a deficit of large multimers due to direct mechanical disruption of von Willebrand factor during passage through the stenotic orifice affecting the molecular conformation of large von Willebrand factor multimers. Echocardiography and cardiac catheterization revealed an aortic valve gradient of 100 mm Hg peak-to-peak, a valve area of 0.6 cm2, and normal coronary arteries. The patient underwent aortic valve replacement with a 19-mm Freestyle stentless valve (Medtronic Inc, Minneapolis, MN) after initiation of standard cardiopulmonary bypass with the usual dose of heparin. The aortic valve was found to be severely calcified. Full-root replacement was performed using a 19-mm Freestyle bioprosthesis (Medtronic, Inc). The postoperative course was uneventful and bleeding tendency resolved; postoperative bleeding time was 1 minute and von Willebrand factor increased to 622%. Results of postoperative immunoblotting analysis are shown in Figure 2. Normal protein bands were visualized, indicating normalization of the molecular conformation of von Willebrand factor, which was now able to form large multimers. Valve replacement appeared to offer optimal resolution of bleeding in this patient.
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Fig 1. Preoperative immunoblotting analysis. A deficit of von Willebrand factor large multimers is seen indicating type IIA von Willebrand syndrome. Black arrow shows the deficit zone of large multimers (L zone in the A). (A = patient before surgery; L = large multimers; M = middle multimers; N = control subject; S = small multimers; SS = very small multimers.)
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Fig 2. Postoperative immunoblotting analysis. Protein bands have normalized due to the increase in large multimers. (A = patient after surgery; L = large multimers; M = middle multimers; N = control subject; S = small multimers; SS = very small multimers.)
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Comment
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Many researchers have reported that severe aortic stenosis is encountered in 15% to 25% of patients with repeated bleeding episodes such as cutaneous or mucosal bleeding, and in a few percent of those exhibiting lethal hemorrhage such as that occurring from the gastrointestinal tract [1, 2]. According to some investigators, increased platelet fragility occurs in patients with severe aortic valve disease and calcified aortic stenosis interferes with the clotting mechanism by causing mechanical damage leading to consumption of other clotting factors [5–6]. Moreover, it has been suggested that primary hemostatic abnormalities are completely corrected after aortic valve replacement but tend to recur in patients with a size mismatch between patient and prosthesis [1–4, 7]. However, the relation of bleeding and severe aortic stenosis has been still unclear.
Recently other researchers have reported that the increased shear stress causes further direct mechanical disruption and cleavage of von Willebrand factor by ADAMTS 13 during passage through the stenotic orifice and that this affects the molecular conformation of large von Willebrand factor multimers [1–4, 6]. This situation is described as acquired von Willebrand syndrome type 2A and is believed to be the result of the cleavage of large multimers in von Willebrand factor by ADAMTS 13 related to primary hemostatic abnormalities in patients with severe aortic valve stenosis [1–4, 6]. We examined 23 patients with aortic stenosis who were operated on at our institution and in whom platelets were subject to high shear stress. We measured von Willebrand factor collagen-binding activity and antigen levels at baseline and at 1 month after aortic valve replacement. Although leukocyte and red platelet counts were unchanged after surgery, shear-induced platelet aggregation and von Willebrand factor collagen-binding activity and antigen levels were significantly increased after correction of aortic valve stenosis without size mismatch.
In conclusion, we believe that aortic valve replacement not complicated by size mismatch can yield excellent results for patients with aortic valve stenosis who have type IIA von Willebrand syndrome develop.
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References
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- Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis N Engl J Med 2003;349:343-349.[Abstract/Free Full Text]
- 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;102:1290-1295.[Abstract/Free Full Text]
- Sadler JE. Aortic stenosis, von Willebrand factor, and bleeding N Engl J Med 2003;349:323-325.[Free Full Text]
- Goldsmith IR, Blann AD, Patel RL, Lip GY. Effect of aortic valve replacement on plasma soluble P-selectin, von Willebrand factor, and fibrinogen Am J Cardiol 2001;87:107-110.[Medline]
- Boley JS, Sammartano R, Adams A, et al. On the nature and etiology of vascular ectasias of the colon Gastroenterology 1977;72:650-660.[Medline]
- Tsai HM. Shear stress and von Willebrand factor in health and disease Semin Thromb Hemost 2003;29:479-488.[Medline]
- King RM, Pluth JR, Giuliani ER. The association of unexplained bleeding with calcific aortic stenosis Ann Thorac Surg 1987;44:514-516.[Abstract]
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Abstract
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