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Ann Thorac Surg 2006;81:490-494
© 2006 The Society of Thoracic Surgeons

Original article: Cardiovascular

Acquired and Reversible von Willebrand Disease With High Shear Stress Aortic Valve Stenosis

Kazunori Yoshida, MD a , * , Satoshi Tobe, MD a , Masahito Kawata, MD b , Masahiro Yamaguchi, MD a

a Department of Cardiovascular and Thoracic Surgery, Akashi Medical Center, Akashi, Japan
b Department of Cardiology, Akashi Medical Center, Akashi, Japan

Accepted for publication July 25, 2005.

* Address correspondence to Dr Yoshida, Department of Cardiovascular and Thoracic Surgery, Akashi Medical Center, 743-33 Okubo-cho Yagi, Akashi, 674-0063, Japan (Email: kazu.y-akashi{at}amc1.jp).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
BACKGROUND: Severe aortic valve stenosis is relatively more prevalent in patients with repeated bleeding episodes. The goal of the present study was to determine the effect of aortic valve replacement on von Willebrand factor levels in patients with aortic stenosis.

METHODS: Von Willebrand factor levels were assessed by using immunoblotting electrophoresis techniques before and 1 month after surgery in 29 consecutive patients with severe aortic valve stenosis.

RESULTS: Eight of 29 patients reported episodes of bleeding, including three episodes of major bleeding, in the 6 months before surgery. None of the patients were receiving anticoagulation therapy. Although there was no difference in platelet count before and after surgery, von Willebrand factor levels were significantly greater at 1 month after surgery (p = 0.05) when compared with preoperative values. Further, von Willebrand factor levels were significantly lower in patients with aortic valve prosthesis mismatch than in those patients without this phenomenon (p < 0.05). Electrophoresis experiments showed a deficit in large multimers of von Willebrand factor preoperatively but not postoperatively, except for in those patients with aortic valve prosthesis mismatch.

CONCLUSIONS: In conclusion, valve replacement can result in increases in von Willebrand factor in patients with aortic valve stenosis.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Increases in wall shear stress (SS) secondary to aortic valve stenosis (AS) can result in endothelial damage and inflammation, platelet aggregation, and decreases in von Willebrand factor (vWf) levels. Indeed, several studies have demonstrated that shear forces can modulate molecular conformation of large vWf multimers [1–4] and promote cleavage of these multimers to lower molecular weight multimers, resulting in acquired von Willebrand disease type IIA. Thus, the goal of the present study was to determine the effect of aortic valve replacement on vWf levels in patients with AS.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Patients
Twenty-nine consecutive patients with severe AS who underwent aortic valve replacement between March 2003 and December 2004 at Akashi Medical Center were enrolled in this study. All patients had severe AS, as reflected by a mean pressure gradient of greater than 50 mm Hg or indexed effective orifice area of less than 0.5 cm2 per square meter of body surface area. Written informed consent regarding the surgical approach and purpose of the study was obtained from each patient. All protocols were approved by the local institutional ethics committee.

Surgical Technique
All patients underwent aortic valve replacement after initiation of standard cardiopulmonary bypass with the usual dose of heparin. After the patient was placed on cardiopulmonary bypass, valve replacement was performed under single aortic cross-clamp with retrograde blood cardioplegia through the coronary sinus. A mechanical bileaflet prosthetic valve (St. Jude Medical Inc, St. Paul, MN) was used in 17 patients, and a biologic valve (Mosaic, Carpentier-Edwards, Freestyle Stentless Bioprosthesis) was used in 12 patients older than 70 years of age.

Echocardiographic Evaluation
Patient–prosthesis mismatch (PPM) was defined as an indexed effective orifice area (effective orifice area per body surface area) of less than 0.85 cm2/m2 by echocardiography. Mean transvalvular pressure gradients were calculated using the modified Bernoulli equation (pressure gradient = 4 x velocity2), and effective orifice area was calculated from the continuity equation. Shear stress was calculated according to the following formula, as reported by Gnasso and colleagues [5]: Blood viscosity x Blood velocity / Internal diameter = 4µ x Vm/r, where µ is the blood viscosity, estimated at 0.035 poise; Vm is the mean velocity; and r is the radius of the stenosis [5–7].

Baseline Biologic Data
Blood was collected by venipuncture of the arm under tourniquet pressure before and 1 month after surgery for evaluation of shear-induced platelet aggregation and vWf levels. Platelet aggregation assays were performed using a platelet aggregation profiler (model PA-200; Kowa, Tokyo, Japan), adenosine diphosphate (1.0 and 3.0 µmol/L), and collagen (0.25 and 2 µg/mL). From the aggregation tracings, the optical density before aggregation was designated as 100%, and the maximum decrease in optical density was then expressed as a percentage of the initial 100%.

The multimeric structure of vWf was evaluated before and at 1 month after surgery using sodium dodecylsulfate–agarose gel electrophoresis on a high-resolution gel system (1.4% high-gelling-temperature agarose) and a discontinuous buffer system, according to the method of Ruggeri and Zimmerman [8]. The bands corresponding to vWf multimers were identified in the gels by reaction with polyclonal rabbit anti-human vWf–horseradish peroxidase (Dako-Cytomation SA, Trappes, France). Von Willebrand factor circulates as a gigantic, multimeric plasma protein that ranges from 0.4 to 20 x 106 daltons in size. As a result, vWf resolves into 15 different molecular weight bands when subjected to electrophoresis, with small multimers (S or SS) located at the bottom to the fifth band and the large multimers (L) located at the 11th to 15th bands. Acquired type IIA von Willebrand disease is characterized by decreasing amounts of vWf and the loss of the large multimers (L zone).

Clinical Data Analysis
Clinical data were obtained by retrospective review of patient medical records. Statistical analysis was performed with StatView (version 4.5) software. Values are expressed as mean ± standard deviation. Continuous variables were compared using paired Student's t tests. Correlations between vWf and hemodynamic variables were established by simple regression models. A p value of less than or equal to 0.05 was considered to represent statistical significance.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Prevalence of Bleeding
Among the 29 patients with severe AS, 8 patients had reported episodes of bleeding, most frequently cutaneous or mucosal bleeding, in the 6 months before surgery. Of these 8 patients, 3 had PPM and 3 patients had a history of major bleeding (cerebrovascular or gastrointestinal hemorrhage; Table 1). All such episodes occurred in the absence of oral anticoagulant treatment. Postoperatively, all patients were initiated on oral anticoagulation therapy with warfarin and underwent monitoring of anticoagulation with routine prothrombin time and international normalized ratio measurements. One patient with PPM in whom postoperative vWf antigen was 78 IU/ mL (normal range, 60 to 180 IU/dL) had an episode of cerebrovascular bleeding 2 months after surgery.


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  		Table 1. Preoperative Hemorrhagic Events in Patients With Severe Aortic Valve Stenosis
 
Postoperative Course
Cardiopulmonary bypass time and aortic cross-clamp time were longer in patients with PPM than in those without (212 versus 150 minutes and 131 versus 107 minutes, respectively; p = 0.04 and 0.2). Mean blood loss was greater in patients with PPM than in patients without PPM (377 versus 213 mL; p = 0.03). However, there was no difference in the ratio of valve types used when comparing patients with PPM and those without PPM. One patient with PPM underwent reexploration for hemorrhage after aortic valve replacement, and 1 patient died of pneumonia 30 days postoperatively.

Wall Shear Stress
Mean SS was significantly greater before valve replacement than after valve replacement (100.3 dyne/cm2 versus 32.4 dyne/cm2; p = 0.01). However, postoperative SS was significantly higher in patients with PPM than in those without PPM (42.4 dyne/cm2 versus 28.7 dyne/cm2; p < 0.01; Fig 1). Further, vWf levels were inversely related to SS (r 2 = 0.391; p < 0.01; Fig 2).


Figure 1
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  		Fig 1. Shear stress before (Pre) and 1 month after (Post) surgery.

 

Figure 2
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  		Fig 2. Inverse correlation between von Willebrand factor levels and wall shear stress (r2 = 0.391; p < 0.01).

 
Postoperative Biologic Data and von Willebrand Factor
Platelet count was within normal range before surgery (>150 x 109/L), but shear-induced aggregation was decreased in all patients with severe AS. Although there was no difference in platelet counts when comparing preoperative and postoperative values, shear-induced platelet aggregation increased in all patients after aortic valve replacement when compared with preoperative values. Mean preoperative bleeding time was greater preoperatively than postoperatively (188 seconds versus 120 seconds; p = 0.3; Table 2), but postoperative bleeding time was greater in patients with PPM than in patients without PPM (160.0 seconds versus 85.7 seconds; p = 0.04).


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  		Table 2. Mean Echocardiographic and Biologic Data Before and 1 Month After Surgery
 
Mean preoperative vWf antigen was greater postoperatively than preoperatively (186.4 IU/dL versus 53.3 IU/dL; p = 0.05; Fig 3). Preoperative vWf levels were particularly low in patients with bleeding episodes (49 IU/mL). Further, postoperative vWf antigen was significantly lower in patients with PPM than in those without PPM (119.3 IU/dL versus 190.2 IU/dL; p = 0.05), despite postoperative improvement in hemodynamic variables. Figure 4 shows the correlation between vWf and indexed effective orifice area (r 2 = 0.216; p = 0.02). This fact indicates that the increased SS and primary hemostatic abnormalities related to a decrease of vWf still persist in patients with PPM after surgery.


Figure 3
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  		Fig 3. Von Willebrand factor levels before (Pre) and 1 month after (Post) surgery.

 

Figure 4
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  		Fig 4. Correlation between von Willebrand factor and indexed effective orifice area (EOA/BSA; r2 = 0.216; p = 0.02).

 
The multimeric structure of vWf was evaluated by sodium dodecylsulfate–agarose gel electrophoresis on a high-resolution gel system. Figure 5 shows the subunit composition of plasma vWf in five representative postoperative cases in comparison with a control subject (N) and with preoperative patients with severe aortic valve stenosis (Fig 5A–5E). A black arrow indicates the zone with a deficit of large multimers (L zone in Fig 5) in all 5 of the preoperative patients. This deficit was attributed to direct AS-induced mechanical disruption of vWf and suggests that SS-induced proteolysis may play a primary role in the pathogenesis of acquired type IIA von Willebrand disease. Normal protein bands, representing the full complement of vWf multimers, were present in the electrophoresis using blood samples taken from patients without PPM postoperatively (Fig 6A, 6C, 6D) but not in those with PPM postoperatively (Fig 6B, 6E).


Figure 5
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  		Fig 5. Preoperative immunoblotting analysis. Electrophoresis of human von Willebrand factor typically yields 15 bands, reflecting the range of multimers (S, M, and L indicate small, middle, and large multimers, respectively). Small multimers are represented by the bottom to fifth bands, whereas large multimers are presented by the 11th to 15th bands. The black arrow indicates a deficit of large multimers (L zone). Acquired type IIA von Willebrand disease is characterized by loss of the large von Willebrand factor multimers (L zone). (SS = shear stress.)

 

Figure 6
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  		Fig 6. Postoperative immunoblotting analysis. Normalization of large von Willebrand factor multimers occurred in patients without patient–prosthesis mismatch but not in patients with patient–prosthesis mismatch (S, M, and L indicate small, middle, and large multimers, respectively). Panels A, C, and D represent the postoperative electrophoresis of the patients without patient–prosthesis mismatch. Panels B and E represent the postoperative electrophoresis of those with patient–prosthesis mismatch. (SS = shear stress.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Severe AS is present in up to 15% to 25% of patients with repeated bleeding episodes. Several studies have suggested that bleeding episodes in patients with AS result from low submucosal perfusion pressure related to low-output AS and tissue hypoxia [1–3, 9–12]. Other investigators have demonstrated increased platelet fragility [13–15] and suggested that calcified aortic valve may induce consumption of other clotting factors [9, 14, 16].

Recent studies suggest that these hemorrhagic symptoms may be attributed to acquired type IIA von Willebrand syndrome, which is characterized by a loss of the largest vWf multimers [1–4, 16–19]. Von Willebrand factor is a coagulation factor that is synthesized as an extra–high molecular weight polymer and that circulates as a gigantic, multimeric plasma protein that may exceed 0.4 to 20 x 106 daltons in size (1 dalton = atomic unit of mass, 1.66054 x 10–27 kg). In fact, a single molecule of vWf may be longer than 4 µm (twice the diameter of a platelet). Endothelial cells secrete this factor into the blood, where it contributes to the formation of platelet plugs and mediates the adhesion of platelets to site of vascular damage, particularly under conditions of high fluid SS in the microcirculation [5, 2, 20–22]. However, increased SS during passage through the stenotic orifice can also cause mechanical disruption and cleavage of vWf by ADAMTS 13 [1–3, 19, 23–25] and result in primary hemostatic abnormalities in patients with severe AS.

Patient–prosthesis mismatch is a frequent problem in patients with AS and is a cause of high postoperative gradients in normally functioning prostheses [26, 27]. The present study demonstrated that correction of AS resulted in increased vWf levels and shorter bleeding times and that PPM was associated with decreased vWf levels and longer bleeding times than in patients without PPM. Further, 1 patient with PPM whose vWf was 78 IU/ mL postoperatively had an episode of cerebrovascular bleeding 2 months after surgery. Finally, loss of large vWf multimers, which is consistent with acquired type IIA von Willebrand disease, was present in patients with AS preoperatively and, to a lesser degree, in patients with PPM postoperatively but in patients without PPM postoperatively.

Cardiopulmonary bypass activates inflammatory cytokines and can result in a transient increase in systemic vWf levels [28]. It may be a possible marker to evaluate deleterious effects such as endothelial injury or activation [24, 28]. We examined 50 consecutive patients with severe mitral valve regurgitation at the same period and demonstrated that both preoperative and postoperative amounts of vWf were in the normal range (141.0 and 203.8 IU/dL, respectively). Von Willebrand factor levels were significantly lower in patients with severe AS than in patients with mitral valve disease (p = 0.05).

In conclusion, surgical correction of AS appears to result in normalization of vWf levels and vWf multimer composition, likely through resolution of AS-induced increases mechanical stress. However, patients with PPM may still have deficits in vWf levels and multimer composition that may leave them at an increased risk of bleeding events, despite a relative correction of hemodynamic variables. Studies with larger numbers of patients will be of benefit in confirming these observations and establishing the clinical significance of low vWf levels in patients with severe AS.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  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.[Abstract/Free Full Text]
  2. 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]
  3. Sadler JE. Aortic stenosis, von Willebrand factor, and bleeding N Engl J Med 2003;349:323-325.[Free Full Text]
  4. Sucker C, Feindt P, Scharf RE. Aortic stenosis, von Willebrand factor, and bleeding N Eng J Med 2003;349:1773-1774.[Free Full Text]
  5. Gnasso A, Carallo C, Irace C, et al. Association between intima-media thickness and wall shear stress in common carotid arteries in healthy male subjects Circulation 1996;94:3257-3262.[Abstract/Free Full Text]
  6. Irace C, Cortese C, Fiaschi E, Carallo C, Farinaro E, Gnasso A. Wall shear stress is associated with intima-media thickness and carotid atherosclerosis in subjects at low coronary heart disease risk Stroke 2004;35:464-468.[Abstract/Free Full Text]
  7. Bank AJ, Wang H, Holte JE, Mullen K, Shammas R, Kubo SH. Contribution of collagen, elastin, and smooth muscle to in vivo human brachial artery wall stress and elastic modulus Circulation 1996;94:3263-3270.[Abstract/Free Full Text]
  8. Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/von Willebrand factor Blood 1981;57:1140-1143.[Abstract/Free Full Text]
  9. Apostolakis E, Doering C, Kartartzis M, Winter J, Shulte HD. Calcific aortic valve stenosis and angiodysplasia of the colonHeyde syndrome report 2 cases. Thorac Cardiovasc Surg 1990;38:374-376.[Medline]
  10. Greenstein RJ, McElhinney AI, Reuben D, Greenstein AJ. Colonic vascular ectasias and aortic stenosiscoincidence or causal relationship?. Am J Surg 1986;151:347-351.[Medline]
  11. Galloway SJ, Casarella WJ, Shimkin PM. Vascular malformations of the right colon as a cause of bleeding in patients with aortic stenosis Radiology 1974;113:11-15.[Medline]
  12. Pate GE, Mulligan A. An epidemiological study of Heyde's syndromean association between aortic stenosis and gastrointestinal bleeding. J Heart Valve Dis 2004;13:713-716.[Medline]
  13. Scheffer SM, Leathermann LL. Resolution of Heyde's syndrome of aortic stenosis and gastrointestinal bleeding after aortic valve replacement Ann Thorac Surg 1986;42:477-480.[Abstract]
  14. Baciewicz F, Terrance D. Heyde's syndromefailure of a mechanical prosthesis and the possibility of a coagulation defect. Ann Thorac Surg 1987;44:554-555.[Abstract]
  15. King RM, Pluth JR, Giuliani ER. The association of unexplained bleeding with calcific aortic stenosis Ann Thorac Surg 1987;44:514-516.[Abstract]
  16. Warkentin TE, Moore JC, Anand SS, Morgan DG. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome Transfus Med Rev 2003;17:272-286.[Medline]
  17. 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.[Abstract/Free Full Text]
  18. 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]
  19. Tsai HM. Shear stress and von Willebrand factor in health and disease Semin Thromb Hemost 2003;29:479-488.[Medline]
  20. Fressinaud E, Veyradier A, Truchaud F, et al. Screening for von Willebrand disease with a new analyzer using high shear stressa study of 60 cases. Blood 1998;91:1325-1331.[Abstract/Free Full Text]
  21. Froom P, Margulis T, Grenadier E, et al. Von Willebrand factor and mitral valve prolapse Thromb Haemost 1988;60:230-231.[Medline]
  22. Ginsburg D, Konkle BA, Gill JC, et al. Molecular basis of human von Willebrand diseaseanalysis of platelet von Willebrand factor mRNA. Proc Natl Acad Sci USA 1989;86:3723-3727.[Abstract/Free Full Text]
  23. Penny WF, Weinstein M, Salzman EW, Ware JA. Correlation of circulating von Willebrand factor levels with cardiovascular hemodynamics Circulation 1991;83:1630-1636.[Abstract/Free Full Text]
  24. Holdright DR, Hunt BJ, Parratt R, et al. The effects of cardiopulmonary bypass on systemic and coronary levels of von Willebrand factor Eur J Cardiothorac Surg 1995;9:18-21.[Abstract]
  25. Lopes AA, Maeda NY. Circulating von Willebrand factor antigen as a predictor of short-term prognosis in pulmonary hypertension Chest 1998;114:1276-1282.[Medline]
  26. Pibarot P, Dumesnil JG, Cartier PC, Metras J, Lemieux MD. Patient-prosthesis mismatch can be predicted at the time of operation Ann Thorac Surg 2001;71(Suppl):S265-S268.[Medline]
  27. Rao V, Jamieson WR, Ivanov J, Armstrong S, David TE. Prosthesis-patient mismatch affects survival after aortic valve replacement Circulation 2000;102(Suppl 3):III-5-III-9.[Medline]
  28. Valen G, Blomback M, Sellei P, Lindblom D, Vaage J. Release of von Willebrand factor by cardiopulmonary bypass, but not by cardioplegia in open heart surgery Thromb Res 1994;73:21-29.[Medline]



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