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Eur J Cardiothorac Surg 2008;33:679-684. doi:10.1016/j.ejcts.2007.12.047
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease

Ulrich Geisena,1, Claudia Heilmannb,1, Friedhelm Beyersdorfb,*, Christoph Benkb, Michael Berchtold-Herzb, Christian Schlensakb, Ulrich Buddec, Barbara Ziegerd

a Department of Clinical Chemistry, University Medical Center Freiburg, Freiburg, Germany
b Department of Cardiovascular Surgery, University Medical Center Freiburg, Freiburg, Germany
c AescuLabor Hamburg, Hamburg, Germany
d Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany

Received 13 September 2007; received in revised form 18 December 2007; accepted 20 December 2007.

* Corresponding author. Address: Department of Cardiovascular Surgery, University Medical Center Freiburg, Albert Ludwigs University Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel.: +49 761 270 2818; fax: +49 761 270 2550. (Email: friedhelm.beyersdorf{at}uniklinik-freiburg.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Objective: Outcomes after ventricular assist device (VAD) implantation have significantly improved during the last decade. However, bleeding episodes remain a serious complication of VAD support. This cannot be explained by the individual anticoagulation regimen alone in several cases, but may be symptomatic of acquired von Willebrand disease (VWD). The leading finding in acquired VWD (AVWD) is the loss of large multimers which results in diminished binding to collagen and to the platelets. We, therefore, analysed patients with two VAD types for laboratory parameters of VWD and compared them with patients after heart transplantation (HTX). Materials and methods: Seven patients with a HeartMate II® left-ventricular assist device and five patients who received a Thoratec biventricular assist device were included in this study. Eight HTX recipients served as controls. Analysis included international normalized ratio (INR), partial thromboplastin time (PTT), platelet count, von Willebrand factor (VWF) antigen, collagen binding capacity, ristocetin cofactor activity, the ratios of the latter two to the VWF antigen and presence of large VWF multimers. Results. The VAD and HTX groups did not differ with regard to age or time-point of analysis after surgery. INR and number of platelets were comparable in both groups, PTT was prolonged in VAD patients. Both VAD and HTX patients had elevated but comparable amounts of VWF antigen. However, large multimers were missing in all of 10 tested VAD patients. In contrast, five of six tested HTX recipients displayed normal multimer pattern. Indeed, collagen binding capacity and ristocetin cofactor activity (which measures binding of VWF to platelets) were lower in VAD patients compared to HTX recipients. Impaired coagulation associated with VADs was also reflected by the diminished ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen. A pathologic collagen binding ratio was found in all 10 tested VAD patients and one of the eight HTX patients, a reduced ristocetin cofactor activity ratio in 10 of 12 VAD and one of eight HTX patients. Conclusion: Non-surgical postoperative bleeding after VAD implantation could be explained by an AVWD. Several pharmacologic treatment options (tranexamic acid, desmopressin, VWF-factor VIII concentrate, recombinant factor VIIa) may arise from our data. Improved VAD design could prevent this problem in the future.

Key Words: Ventricular assist device • Heart transplantation • Bleeding • Coagulation • Acquired von Willebrand disease


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Outcomes after ventricular assist device (VAD) implantation have significantly improved during the last decade. This can be explained by improved VAD technology, improved surgical techniques for VAD implantation, advanced patient care protocols and earlier implantations [1–4]. However, bleeding remains a leading complication of VAD support [1,5,6].

Epistaxis, gastrointestinal and surgical hemorrhage are observed frequently. Life-threatening intracranial bleedings, even though rare, may also occur. These symptoms cannot be explained by the individual anticoagulation regimen in several cases. We hypothesize that non-surgical bleeding after VAD implantation is related to acquired von Willebrand disease (VWD). There are several forms of congenital and acquired VWD. Congenital VWD results from mutations in the gene of the von Willebrand factor (VWF), whereas increased shear stress represents one of the causes of acquired VWD. High shear forces occur also in VADs [7].

VWF is a 250 kDa protein expressed by vascular endothelial cells and megakaryocytes and assembles to dimers which polymerize to multimers. The protein is stored as multimers in the Weibel Palade bodies of endothelial cells and released continuously and to a large extent following activation of the cells. The number of VWF monomers itself is reflected by the laboratory parameter VWF antigen (VWF:Ag). The monomers are able to protect factor VIII from degradation. However, the biologically active form of VWF, with regard to binding to collagen and to platelets, consists of multimers with a molecular weight of up to 20 000 kDa [8]. Therefore, the parameter VWF:Ag gives no information on the coagulation capability of VWF. Inactive VWF flows in the blood. The multimers bind to collagen of denuded vessel walls. Subsequently, platelets adhere through their receptors to VWF. Association with the platelet receptor GPIb/IX requires a conformational change of the VWF (Fig. 1 ). Binding to the platelet induces its activation and subsequent adhesion and aggregation [9]. In vitro, change of the conformation of the GPIb/IX receptor can be mediated by the antibiotic ristocetin [10]. Hence, ristocetin cofactor activity is assessed as a laboratory measure of VWF-platelet binding.


Figure 1
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  		Fig. 1. Binding of von Willebrand factor. Biologically intact VWF consists of multimers which mediate adhesion to collagen and to platelet receptors (GPIb/IX).

 
The leading finding in several types of acquired von Willebrand disease (AVWD) is the loss of the large multimers [11]. Diminished binding to collagen and to the platelets can be tested separately in vitro as described above. Combined analysis of large multimers, collagen binding capacity and ristocetin cofactor activity allows, together with additional analyses for the absolute amount of von Willebrand factor antigen, a conclusion about the individual functionality of the von Willebrand factor.

We, therefore, analysed patients with two VAD types for laboratory characteristics of von Willebrand disease and compared them with a group of patients who had undergone heart transplantation (HTX).


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A
 References
 
2.1 Patients
Seven patients with a HeartMate II® left-ventricular assist device (LVAD; Thoratec Corporation, Pleasanton, CA) and five patients who received a Thoratec biventricular assist device (BiVAD) were included in this study. HTX recipients (n = 8) served as controls since these patients also underwent a major surgical procedure with cardiopulmonary bypass and received a standardized anticoagulation regimen (see Section 2.2). Five of these patients had been on VAD support prior to HTX.

All patients underwent VAD implantation or heart transplantation between June 2006 and July 2007 at our centre. No pre-existing bleeding disorder was known in any of the patients. Data were obtained from samples taken for routine blood analyses. The study was approved by the institutional review board.

2.2 Surgical procedures
Implantation of HeartMate II® was performed via median sternotomy in the routine manner. The inflow graft was inserted into the left ventricular apex and the outflow graft was anastomosed to the ascending aorta. Details of the surgical technique for VAD implantation have been described previously by our group [4,12]. The axial pump of the HeartMate II® has a spinning rotor as its only moving part with no valves and no compliance chamber. The rotor spins on a bearing and is powered by an electromagnetic motor. Only a small single driveline exits the upper right abdomen.

Standard surgical technique was used for paracorporal Thoratec VAD implantation. Whereas the inflow cannula of the right ventricular assist device was implanted in the right atrium in two of the five cases we now use the right ventricular apex as the preferred cannulation site (three of five patients). The right ventricular outflow graft was anastomosed to the main pulmonal artery. The two pump chambers of the device are connected to the inflow and outflow cannulae and driven by pneumatic power. Alternating positive and negative air pressure actuates a flexible blood sac within the rigid outer casing of the pump. Mechanical tilting disc valves in the inflow and outflow ports ensure unidirectional blood flow through the device.

Anticoagulation for both systems was started with heparin with a target PTT of 60–80 s and changed to phenprocoumon with a target INR of 3.0–3.5 for the Thoratec BiVAD and 2.5–3.0 for the HeartMate II® LVAD after removal of the chest drains and sufficient oral ingestion. Platelet aggregation was inhibited by acetylsalicylic acid (ASA) 100 mg/day.

Heart transplantation was performed with biatrial or bicaval anastomosis of the donor heart. Postoperatively, patients received low-dose heparin and ASA 100 mg/day.

2.3 Laboratory analysis
INR (Innovin® Dade Behring, Marburg, Germany), PTT (Pathromtin SL®, Dade Behring, Marburg Germany), VWF:Ag (Dade Behring) and Ristocetin cofactor activity (VWF:RCo; Dade Behring) were measured using the analyser Behring coagulation system (BCS) according to standard protocols. Collagen type I (Nycomed Pharma, Unterschleissheim, Germany) was immobilized on a microtiter plate, and collagen binding capacity (VWF:CB) in plasma was determined photometrically by ELISA technique.

Ratios of VWF:RCo and VWF:CB, respectively, to VWF:Ag (VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag) were calculated. They reflect the biological activity of the available VWF with regard to binding to platelets and to collagen. (Fig. 1 and Table 1 ).


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  		Table 1 VWF parameters
 
VWF multimers were separated on SDS-agarose low-resolution gels (1.2% agarose) and blotted on a PVDF membrane. VWF was detected using appropriate primary and secondary antibodies (DAKO, Hamburg, Germany) and chemiluminescence [13,14].

Laboratory parameters were assessed within 30 days after the surgical procedure.

2.4 Statistics
Data were analysed using the SPSS 15.0 software. All values are expressed as mean ± standard deviation. The Kruskal–Wallis test (H-test) was employed to assess differences between the three groups (BiVAD, LVAD, HTX). The Mann–Whitney test (U-test) was used for comparison of the pooled VAD patient group (BiVAD and LVAD patients considered as one VAD group) with HTX patients or if BiVAD and LVAD patients were compared as separate groups. An exact p < 0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A
 References
 
Patient characteristics are presented in Table 2 . The VAD and HTX groups did not differ with regard to age (46.7 ± 16.7 vs 49.6 ± 15.2 years, p = 0.91) or time-point of laboratory analysis after surgery (12.3 ± 9.6 vs 13.6 ± 9.5 days, p = 0.792).


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  		Table 2 Patient characteristics
 
None of the evaluated parameters was different for left-ventricular HeartMate II® and biventricular Thoratec devices despite the dissimilar mechanical and anatomical working principles of both systems. Postoperative INR was comparable in VAD and HTX patients as well as the number of platelets. PTT was prolonged in VAD patients due to more aggressive anticoagulation (VAD, 51.3 ± 13.8 s; HTX, 36.2 ± 11.7 s, U-test all VAD vs HTX p = 0.039). Both VAD and HTX patients had elevated but comparable values for VWF:Ag and C-reactive protein (CRP) (Table 3 , Fig. 2 ).


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  		Table 3 Laboratory parameters
 

Figure 2
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  		Fig. 2. Coagulation parameters. Twelve patients with VAD (group 1, BiVAD, group 2, HeartMate II®) and eight HTX recipients (group 3; controls) were compared within 30 days after surgery. Platelets, platelet count; VWF:Ag, von Willebrand antigen; VWF:CB, collagen binding capacity, VWF:CB/VWF:Ag, ratio of VWF:CB by VWF:Ag; VWF:Co, ristocetin cofactor activity, VWF:RCo/VWF:Ag, ratio of VWF:RCo by VWF:Ag. The boxes contain the middle 50% of the values (25th and 75th percentile), the median is marked. The whiskers indicate the upper and lower non-extreme values. Circles mark outliers (distance from the box between 1.5 and three-fold length of the box), asterisks mark extreme values (distance from the box more than three-fold length of the box). Numbers of includes cases (n) and p-values are given in Table 3.

 
Collagen binding capacity (VWF:CB) and ristocetin cofactor activity (VWF:RCo; tests binding to platelets) were lower in VAD patients (1.1 ± 0.3 U/ml and 1.8 ± 0.6 U/ml) compared to HTX recipients (3.5 ± 1.0 U/ml and 3.4 ± 1.4 U/ml; VWF:CB, p < 0.001, VWF:RCo, p = 0.01) (compare Table 3, Fig. 2).

The biologically active large multimers were missing in all of 10 tested VAD patients (Fig. 3 ). In contrast, five of six tested HTX recipients displayed normal multimer pattern, only one patient exhibited a loss of large VWF multimers. This person was one of four patients (of the six tested for large multimers) who had been on VAD support prior to transplantation.


Figure 3
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  		Fig. 3. Analysis of VWF multimers of a VAD patient compared to a sample of a normal person. VWF multimers are separated by electrophoresis according to their size on low-resolution SDS-agarose gels. Smaller multimers run faster through the gel and appear, therefore, in the lower part of the gel. Note the missing bands in the upper part of the gel in the VAD patients’ lane. This is reflected by densitometry curves in the right part of the figure (grey line, normal control sample; black line, VAD patient's sample).

 
Impaired coagulation in VAD patients was reflected by the ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen (VWF:CB/VWF:Ag, VAD, 0.4 ± 0.1, HTX, 1.1 ± 0.3, p < 0.001, VWF:RCo/VWF:Ag, VAD, 0.6 ± 0.1, HTX, 0.9 ± 0.2, p = 0.002) (Fig. 2). A pathologic collagen binding ratio was found in all 10 tested VAD patients and only one of the eight HTX patients, a reduced ristocetin cofactor activity ratio in 10 of 12 VAD and in only one of eight HTX patients (Table 3, Fig. 2).

Laboratory parameters which are typical for an AVWD are not a phenomenon occurring only in the early phase after implantation of a VAD. We analysed seven of the 12 VAD patients and three of the eight HTX recipients again after more than 10 weeks after the main surgical procedure and found similar typical results for presence and absence of acquired VWD, respectively (Table 4 ).


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  		Table 4 Parameters of VWF function in long-term analysis
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A
 References
 
Non-surgical bleeding disorders unrelated to individual anticoagulation regimen are known to be associated with VAD therapy. In this study we show, to the best of our knowledge for the first time, that this phenomenon can be explained by an AVWD. This syndrome comprises a group of hemorrhagic disorders in which the VWF is either quantitatively or qualitatively abnormal. We found impaired function of VWF in respect of binding to collagen and to platelet receptor GPIb (reflected by ristocetin cofactor activity) and loss of large biologically active VWF multimers in VAD patients. HTX recipients were analysed as controls and displayed normal VWF function. Notably, the amount of VWF antigen was similar in both groups.

VWF is an acute phase protein. Secretion of VWF from activated endothelial cells may occur following systemic exposure to lipopolysaccharides [15] or local contact with activated platelets [16]. Another typical acute phase protein is C-reactive protein (CRP). Association of elevated levels of VWF and C-reactive protein has been demonstrated [17]. Both VWF antigen (VWF:Ag) and CRP were enhanced in our VAD as well as in HTX patients. The acute phase reaction can be explained by the pre-existing severe disease, surgical trauma, and postoperative stress.

There are basic mechanical differences between the two analysed VAD systems. The extracorporeal Thoratec BiVAD is pneumatically driven and supports both ventricles, whereas the HeartMate II® is an implanted axial pump with a spinning rotor and supports only the left ventricle. In addition, the surfaces with contact to blood are different. It is one of our major findings, however, that both systems cause an acquired VWD. We consider the results quite consistent albeit the small groups. Further systematic analysis of coagulation parameters in VAD and HTX patients is ongoing.

Gastrointestinal bleeding not related to drug therapy has been observed in patients with aortic stenosis and has been attributed to AVWD [18]. The enhanced shear stress which occurs at the stenotic valve may result in mechanical demolition of the large multimers themselves or in disintegration of the tertiary structure of the large multimers which makes them susceptible for proteolytic cleaving [19]. The absolute amount of VWF can be normal or even enhanced, but the capability of VWF to bind to collagen and to platelets is severely diminished [19]. Flow acceleration also occurs in VADs was demonstrated by our group [7]. Frequency and amount of bleeding in VAD patients exceed this complication in patients with aortic stenosis. We found a pathologic ratio of collagen binding capacity to VWF:AG (VWF:CB/VWF:AG) in all and a pathologic ratio of ristocetin cofactor activity to VWF:Ag (VWF:RCo/VWF:AG) in 10 of 12 VAD patients. In contrast, pathologic ratios are reported for five of 10 and three of 10 patients with aortic stenosis, respectively [11]. Moreover, the coagulation disorder in patients with aortic valve stenosis is reversible following valve replacement [18]. Six of our eight HTX patients were analysed for large VWF multimers. Four of these patients had been on VAD support prior to transplantation. Missing large VWF multimers after HTX were observed in only one of these four patients after HTX. No AVWD was present in the three other former VAD patients and the two patients with primary HTX. We hypothesize that the AVWD might be also reversible after explantation of the VAD. More comprehensive studies are necessary to examine the role of AVWD in patients with VADs. Indeed, it might be difficult to distinguish bleeding due to AVWD from the effects of anticoagulative therapy. However, it is very likely that an AVWD enhances bleeding problems in VAD patients, taking in account the findings in patients with aortic stenosis and with congenital VWD.

Analysis of only one time-point after VAD and HTX, respectively, is certainly a limitation. The appropriate time to investigate the coagulation parameters is indeed difficult to determine. Bleeding problems in VAD patients occur predominantly within the first month. Therefore, we decided on a time-point early after the operation during the first 30 days. However, acquired VWD is not a reversible phenomenon only in the early phase after implantation of a VAD according to our observation. Seven patients carrying a VAD were analysed after more than 10 weeks. An AVWD was indicated by typical laboratory findings in all of them.

Several therapeutic options have to be discussed. First, tranexamic acid is an antifibrinolytic which is successfully used in congenital VWD and is already established in cardiac surgery [20]. Second, desmopressin acetate boosts the release of VWF from endothelial cells. However, it is unknown whether already activated cells still store relevant amounts of VWF and rapid degradation of the new multimers has to be suspected. Third, the same concern applies to factor VIII-concentrates, which contain VWF. A relief of bleeding for a short time might be possible with both options. Fourth, recombinant factor VIIa (NovoSeven®) causes, together with tissue factor, a thrombin burst at the site of the injury of the vessel and leads to subsequent formation of a stable fibrin plug independent of VWF.

Further extended data collection is desirable to overcome the limitations of this study. Other control groups should be examined to exclude unknown effects of immunosuppression regimens on VWF and the time-course of coagulation parameters including platelet aggregometry should be monitored more closely.

In conclusion, we show for the first time that bleeding in VAD patients might be related to an AVWD. If this is confirmed in further studies, appropriate treatment and even preventive measures (VAD design) can be initiated to overcome one of today's major problems in mechanical circulatory support treatments.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
References
 
Conference discussion

Dr J. Horisberger (Lausanne, Switzerland): So you would recommend testing for these parameters on all patients who have a VAD immediately postoperatively?

Dr Zieger: If it's available, yes. I mean there should be a design on how to measure the coagulation parameters. It's not only for the von Willebrand factor, but also some testing to see how the platelets function.

Dr P. Tozzi (Lausanne, Switzerland): What do you exactly mean when you say ‘nonsurgical bleeding’? You mean gastrointestinal bleeding, for example, or bleeding coming from the insertion of the VAD?

Dr Zieger: I would say bleedings which are not explained by any surgical reasons, unexpected bleedings, and these can be mucocutaneous, gastrointestinal bleedings, or any bleeding. Mainly they are in the mucocutaneous. But especially these patients bleed after surgery. Coagulation is only a balance between bleeding and thrombosis, and you try to balance this as much as you can, but when you have done a surgery, then it goes more in the direction of bleeding, and you would like that, then, after surgery, the platelets function, the coagulation factors work, and the von Willebrand factor is there and works.

Dr S. Rinaldi (Pomezia, Italy): Have you seen any difference in the incidence of the acquired disease between patients with different devices, different VADs?

Dr Zieger: I think the numbers are too small at the moment, and we only used two devices. We started this study, and this is kind of a pilot study. So we will have more patients to talk about next year.

Dr J. Horisberger: Would you think that there is less shear stress with the continuous flow as opposed to the pulsatile assist?

Dr Zieger: You mean if I associate the shear stress with different devices?

Dr Horisberger: To the von Willebrand, right.

Dr Zieger: To my knowledge, it's only recorded that there is high shear stress or increased shear stress with VADs. I mean it's also the artificial surfaces. The platelets and von Willebrand factor recognize artificial surfaces as an injury, so by that alone they try to attach to it, then the activation of the von Willebrand factor happens, and then by the flow, the shear stress starts. I mean that's obvious. I think one future aspect should be to decrease shear stress in the VAD devices, yes.


   Acknowledgments
 
We thank Ms Astrid Grohmann and Ms Ayten Is for expert technical assistance.


   Footnotes
 
{star} Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.

1 Both authors contributed equally to this work. Back


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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D. Malehsa, A. L. Meyer, C. Bara, and M. Struber
Acquired von Willebrand syndrome after exchange of the HeartMate XVE to the HeartMate II ventricular assist device
Eur. J. Cardiothorac. Surg., June 1, 2009; 35(6): 1091 - 1093.
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 Ann. Thorac. Surg.Home page
B. Steinlechner, M. Dworschak, B. Birkenberg, M. Duris, P. Zeidler, H. Fischer, L. Milosevic, G. Wieselthaler, E. Wolner, P. Quehenberger, et al.
Platelet Dysfunction in Outpatients With Left Ventricular Assist Devices
Ann. Thorac. Surg., January 1, 2009; 87(1): 131 - 137.
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 Ann. Thorac. Surg.Home page
R. Poston
Invited Commentary
Ann. Thorac. Surg., January 1, 2009; 87(1): 137 - 138.
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 ICVTSHome page
A. Joshi, D. Smith, M. Arora, and R. Poston
Anticoagulant monitoring in ventricular assist device patients: a feasibility study
Interactive CardioVascular and Thoracic Surgery, December 1, 2008; 7(6): 1035 - 1038.
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