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Ann Thorac Surg 2005;80:945-948
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Human Leukocyte Antigen Sensitization in Ventricular Assist Device Recipients: A Lesser Risk With the DeBakey Axial Pump

Jean-Michel Grinda, MD a , * , Marie-Odile Bricourt, MD a , Catherine Amrein, MD a , Suzanne Salvi, MD a , Romain Guillemain, MD a , Anne Francois, MD b , Pierre Guibourt, MD a , Alain Deloche, MD a , Jean-Noel Fabiani, MD a

a Department of Cardiovascular Surgery and Thoracic Transplantation, Hôpital Européen Georges Pompidou, Paris, France
b Blood Bank, Hôpital Européen Georges Pompidou, Paris, France

Accepted for publication March 23, 2005.

* Address reprint requests to Dr Grinda, Cardiac Surgery Department, Hôpital Europeen Georges Pompidou, 21 rue Leblanc, 75908, Paris cedex 15, France; (Email: jean-michel.grinda{at}egp.ap-hop-paris.f).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: Previous reports, all concerning pulsatile devices, have indicated an increased risk of development of circulating antileukocyte antigen (HLA; human leukocyte antigen) antibodies during ventricular assist device (VAD) support. We investigated sensitization in patients implanted with the DeBakey VAD (MicroMed Technology, Inc, Houston, TX) axial flow pump as a bridge to heart transplantation.

METHODS: Inclusion criteria for this prospective study were the following. Patients implanted with the DeBakey VAD axial flow pump, without HLA antibodies prior to implantation, with a duration of support of at least one month. The HLA antibody testing for IgG and IgM class I and II antibodies was performed weekly during support, using both a complement dependant cytotoxicity assay and an enzyme-linked immunosorbent assay (ELISA). Retrospective cross match was performed for all patients transplanted. The occurrence of graft rejection was determined by regular endomyocardial biopsies after heart transplantation, graded according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines. Additionally, the transfusion history was reviewed for all patients.

RESULTS: Fourteen patients were included representing 1,220 cumulative patient-days of support (mean duration time on support, 87 days). No patient developed detectable IgG antibodies to class I or II. One patient had a positive ELISA, corresponding to nonsignificant (6/30) class I IgM antibodies at 3 weeks postimplantation. Ten patients underwent successful heart transplantation, representing 156 cumulative months. No retrospective cross match was positive. The percentage of significant acute rejection episodes (ISHLT grade 3A or more) was 6% and 4.3% in the first 6 months and from 6 to 12 months, respectively. No vascular rejection was noted. The posttransplantation survival rate was 87% at 6 months and 75% at 1 year, respectively.

CONCLUSIONS: Patients implanted with the DeBakey VAD axial flow pump as a bridge to heart transplantation do not appear to be exposed to an increased risk of sensitization.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The development of circulating alloantibodies against foreign antihuman leukocyte antigen (HLA) molecules may result from previous pregnancy, transfusions, or previous allografts [1–3]. Recently several studies, all concerning pulsatile devices, have reported left ventricular assist device (LVAD) implantation as being a risk factor as high as 60% [3–9] for increased HLA levels. The consequences of circulating anti-HLA class I and II antibodies in recipients of VADs are many: (1) A prolonged waiting time to transplantation; (2) a longer time on mechanical support, increasing the number of infections or thromboembolic complications; (3) the necessity to realize a prospective cross match prior to transplantation, difficult because of the constraints of prolonged ischemic time and resulting in lesser organ availability; (4) an increased incidence of allograft rejection, affecting survival [2, 3, 5, 6, 8, 10]. Pretransplantation immunosuppressive therapy has been tested in such patients [6, 10].

An axial flow pump is a new generation of implantable LVAD [11, 12]. Axial pumps are miniaturized pumps providing a continuous flow [13]. The DeBakey VAD (MicroMed Technology, Inc, Houston, TX), which has become the most used axial pump worldwide, is considered to have an increased biocompatibility [14]. The goal of this study was to determine if the use of a miniaturized axial flow pump, with less blood activating surfaces, could lead to a lower rate of sensitization.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Between February 1999 and March 2004, 21 patients without any anti-HLA antibodies prior to implantation were implanted with a DeBakey VAD in our institution. A short time on support (less than one month) was a criterion of exclusion for seven patients (early death in five patients and early explantation as a bridge to recovery in two patients). Fourteen patients with the DeBakey VAD as a bridge to heart transplantation were included in the study. Patients’ characteristics are summarized in Table 1.


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  		Table 1. Patients Characteristics
 
Device Implantation
The DeBakey VAD is a totally implantable pump made of titanium with an electromagnetic control. It has a 30.5 mm diameter, a 76.2 mm length, and a total weight of 95 g. Operations were strictly performed through medial sternotomy without any pocket in the abdominal wall. All implantations were performed under cardiopulmonary bypass (CPB) with beating heart in the following order: implantation of the apical inflow cannula, tunneling of the percutaneous cable, implantation of the outflow graft under ascending aortic side clamping, removal of air, and starting of the DeBakey VAD while gradually weaning-off CPB.

Transfusion History
The transfusion history of all patients was reviewed. We have used only leuko-reduced blood components since 1998 in our institution. All red blood cells (RBC) are phenotyped for D-C-e-E-c-K. Platelets are pooled platelets; we routinely do not obtain platelets from a unique donor.

Measurement of HLA Sensitization
Screening for major histocompatibility complex (MHC) class I and II anti-HLA antibodies was performed just before implantation and weekly after implantation by the same histocompatibility laboratory (St Louis Hospital, Paris). It was performed using both a complement dependant cytoxicity assay (CDC) and an enzyme-linked immunosorbent assay (ELISA). The CDC is a commonly used method for panel reactive antibodies (PRA) determination. The sera are tested against a comprehensive 30 cell panel of HLA-typed donors selected to represent most of the defined HLA specificities. Positive reactions are expressed quantitatively as a percentage of the total T and B cell panel. It is considered significant when at least 10% of the cells show cytotoxicity. The ELISA is an easy, rapid, and highly sensitive solid phase method, with either positive (antibody present) or negative results. This is advantageous in that it avoids false positive reactions when no HLA antigens are present. The ELISA detects both class I and class II antibodies.

Transplantation Procedure
Routinely prospective cross matching was not realized before heart transplantation except in case of pretransplantation sensitization. Patients underwent standardized orthotopic heart transplantation with a bicaval anastomosis. A retrospective cross match was performed for all patients after transplantation.

Immunosuppressive Regimen
All patients received sequential protocols consisting of anti-thymocyte globulines/ cyclosporine, steroids, and mycophenolate mofetil. Rejection episodes, according to International Society for Heart and Lung Transplantation (ISHLT) guidelines, were treated with intravenous pulses of steroids for 3 days (grade 1B) associated with anti-thymocyte globulins (grade 3A).

Evaluation of Acute Rejection
Endomyocardial biopsies were performed weekly during the first month, every second week for the next 2 months, and every month for the next 9 months. Biopsy specimens were graded according to ISHLT guidelines. The occurrence of acute rejection episodes was noted.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Support
Fourteen patients, responding to the inclusion criteria, were supported for a mean duration of 87 days (ranging from 31 to 224 days). This represented 1,220 cumulative patient-days of support. Four patients died on support. Causes of death were multiorgan failure (n = 2), right ventricular dysfunction (n = 1), and suicide (this patient developed a psychiatric syndrome; he was found disconnected from support at day 109) (n = 1).

Transfusions
Only one patient had a history of extensive transfusion (during previous cardiac surgery 8 years prior). At the time of implantation neither anti-ABO antibodies nor anti-HLA antibodies were detected. Mean transfusion during support (preoperatively and postoperatively) was 34 RBC/patient (range, 4 to 153), 4 pooled platelet units/patient (range, 0 to 38), and 12 fresh frozen plasma/patient (range, 0 to 45). Five patients were considered as having required extensive blood transfusions (more than 40 RBC). Transfusion data are presented in Table 2. No anti-ABO antibodies were found during support.


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  		Table 2. Preoperative and Postoperative Blood Product Consumption Used in 14 Patients Supported With DeBakey Axial Pump
 
Sensitization
No patient developed detectable IgG antibodies to MHCC class I or II. One patient had a positive ELISA for MHC class I antigens at three weeks post implantation, with detectable class I IgM antibodies (6/30) (Fig 1). No study convincingly supports nor refutes the clinical relevance of IgM HLA antibodies. General practice tends to disregard donor reactive HLA specific IgM antibodies, and we have the same position in our institution. This particular patient received 13 RBC, 9 fresh frozen plasma, and 2 pooled platelets units. Therefore, we concluded that no patients developed significant anti-HLA antibodies during support.



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  		Fig 1. Quantitative analysis in the patient with positive enzyme linked immunosorbent assay test. (PRA = panel reactive antibody; CDC = complement dependent cytotoxicity.)

 
Transplantation
Orthotopic heart transplantation was performed in 10 patients. No retrospective cross match was positive for these 10 patients. Two patients died early after transplantation (right heart failure and septic shock on postoperative days 2 and 3, respectively). Eight patients are doing well after transplantation representing 156 cumulative months (range, 3 to 55 months).

Rejection
The percentage of significant acute rejection episodes (ISHLT grade 3A or more) was, respectively, 6% and 4% from 0 to 6 months and 6 to 12 months after transplantation (Fig 2). No vascular rejection was noted.



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  		Fig 2. Rejection according to International Society for Heart and Lung Transplantation after transplantation in patients previously supported with DeBakey axial pump. Black bars = 0–6 months; grey bars = 6–12 months.

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
We have found a rate of sensitization extremely low compared to published reports [4–10]. The most usual recognized risk factors of sensitization before heart transplantation are gender (women, previous pregnancies), younger age (enhanced immune responsiveness), and most of all red blood cell and platelet transfusions [2, 3, 5, 6, 8]. Additionally, sensitization has become a well-known complication during pulsatile LVAD support. Many recent studies, realized with different pulsatile devices, have reported a risk of HLA sensitization from 28% up to 66% [3–9]. Most of the studies were focused on the ThermoCardiosystems Inc (TCI) HeartMatedevice (Thoratec Corp, Pleasanton, CA) [3–8]. Pagani and colleagues [5] and McKenna and colleagues [4] have reported a 28% (9/32 and 8/29, respectively) rate of sensitization with the TCI Heart Mate. DeNofrio and colleagues [8] have reported a 30% (6/18) rate. In the study by Massad and colleagues [3], the rate of immunization with the HeartMate rose to 65.8% (27/41). No statistical difference, whatever the type of pulsatile device, was found by Kumpati and colleagues [10]: in 166 patients supported with TCI Heart Mate, in 55 patients with Novacor (Baxter Healthcare Corp, Novacor Division, Oakland, CA), and in 10 patients with Thoratec (Thoratec Corporation, Pleasanton, CA). We have found no sensitization in our patients supported with the DeBakey VAD. We have found no previous studies with axial pumps to support or refute our results.

The reasons for sensitization under device are still debated. Is it mainly due to structural device characteristics, or to surgical implantation consequences, or both?

Polytransfusion, and eventually infections, as the consequences of surgical device implantation are usually considered as risk factors of immunization [3, 4, 7, 8]. McKenna and colleagues [4] found a significant difference in total perioperative transfusions between patients who developed antibodies after VAD implantation and those who remained negative. We did not find the same results in our patients despite an average blood product transfusion of 53 units (range, 9 to 236).

Platelet transfusion has been previously reported as the primary risk factor for the development of HLA antibodies [3, 4, 7]. Massad and colleagues [3] found that only platelet transfusions correlated with the peak value of HLA antibodies. John and colleagues [7] found a higher risk for patients receiving more than 6 units. None of our patients who received an average of 4 units (range, 0 to 38) presented with a significant positive PRA. As mentioned previously, we have used only leuko-reduced blood products, and pooled platelets. Nevertheless, considering the volume and type of transfusions used, we cannot explain the disparity encountered in the sensitization rate.

The hypothesis of this sensitization in the recipients of LVADs is that VADs have immune activating properties [7, 9, 14, 15]. Furthermore, biomaterials on the VAD surface are in close contact with the blood circulation, inducing a direct modulation of lymphocyte function [7]. Concerning lymphocyte T function, the following mechanism has been described: an aberrant T cell activation through IL2 receptor dependent pathway, with an increase of CD 95 expression in both CD4 and CD8 T cells, and increased levels of T cell apoptosis, these leading to progressive defects in cellular immunity and increased risk of infection. Concerning B lymphocyte function, the following mechanism has been described: a polyclonal B cell hyperactivity responsible for an excessive production of various antibodies, including these directed against HLA and phospholipids-related antigens. Pulsatile devices, especially the textured surface of the TCI Heart Mate device, induce a colonization of LVAD surface with T cells and macrophage or monocytes, and the formation of a pseudointima inside the device [16].

A study on the immunologic response after implantation of the DeBakey VAD concluded that the small size and titanium blood flow path of the axial flow pump might have increased biocompatibility because of increased material inertness and less surface area, resulting in less immunologic consequence [14]. The results we report are in agreement with this study. Previous studies have shown an increased risk of cellular rejection in sensitized bridged patients [7, 9]. As expected, in our nonsensitized patients bridged with the DeBakey VAD, the episodes of cellular rejection did not increase and were quite similar to the nonbridged patients.

Our report suggests that HLA alloimmunization is less with the DeBakey VAD than with the pulsatile devices previously studied. The miniaturization and the inert properties of the DeBakey VAD titanium flow pathway, including less blood contacting surface area, and less immunologic exposure, may explain the low rate of HLA immunization.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Betkowski AS, Graff R, Chen JJ, Hauptman PJ. Panel-reactive antibody screening practices prior to heart transplantation J Heart Lung Transplant 2002;21:644-650.[Medline]
  2. Bishay ES, Cook DJ, El Fettouh H, et al. The impact of HLA sensitization and donor cause of death in heart transplantation Transplantation 2000;70:220-222.[Medline]
  3. Massad MG, Cook DJ, Schmitt SK, Smedira NG, McCarthy JF. Factors influencing HLA sensitization in implantable LVAD recipients Ann Thorac Surg 1997;64:1120-1125.[Abstract/Free Full Text]
  4. McKenna Jr DH, Eastlund T, Segall M, Noreen HJ, Park S. HLA alloimmunization in patients requiring ventricular assist device support J Heart Lung Transplant 2002;21:1218-1224.[Medline]
  5. Pagani FD, Dyke DB, Wright S, Cody R, Aaronson KD. Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantationeffects on subsequent allograft rejection and survival. J Heart Lung Transplant 2001;20:646-653.[Medline]
  6. Tsau PH, Arabia FA, Topobroff B, Paramesh V, Sethi GK, Copeland JG. Positive panel reactive antibody titers in patients bridged to transplantation with a mechanical assist devicerisk factors and treatment. ASAIO J 1998;44:634-637.
  7. John R, Lietz K, Schuster M, et al. Immunologic sensitization in recipients of left ventricular assist devices J Thorac Cardiovasc Surg 2003;125:578-591.[Abstract/Free Full Text]
  8. DeNofrio D, Rho R, Morales FJ, et al. Detection of anti-HLA antibody by flow cytometry in patients with a left ventricular assist device is associated with early rejection following heart transplantation69 Transplantation 2000;15:814-818.
  9. Itescu S, Schuster M, Burke E, et al. Immunobiologic consequences of assist devices Cardiol Clin 2003;21:119-133.[Medline]
  10. Kumpati GS, Cook DJ, Blackstone EH, et al. HLA sensitization in ventricular assist device recipientsdoes type of device make a difference?. J Thorac Cardiovasc Surg 2004;127:1800-1807.[Abstract/Free Full Text]
  11. Noon G, Morley D, Irwin S, Abdelsayed S, Benkowski R, Lynch B. Clinical experience with the Micromed DeBakey ventricular assist device Ann Thorac Surg 2001;71:S133-S138.[Abstract/Free Full Text]
  12. Goldstein DJ. Worldwide experience with the MicroMed DeBakey ventricular assist device as a bridge to transplantation Circulation 2003;108(suppl 1):II272-II277.
  13. Grinda JM, Latremouille C, Chevalier P, et al. Bridge to transplantation with the DeBakey axial pumpa single center report. Eur J Cardiothorac Surg 2002;22:965-970.[Abstract/Free Full Text]
  14. Ankersmit HJ, Wieselthaler G, Moser B, et al. Transitory immunologic response after transplantation of the VAD continuous-axial-flow pump J Thorac Cardiovasc Surg 2002;123:557-561.[Abstract/Free Full Text]
  15. Stringham JC, Bull DA, Fuller TC, et al. Avoidance of cellular blood product transfusions in LVAD recipients does not prevent HLA allosensitization J Heart Lung Transplant 1999;18:160-165.[Medline]
  16. Houel R, Moczar M, Clerin V, Loisance DY. Pseudointima in inflow conduits of left ventricular assist devices Ann Thorac Surg 1999;68:717-723.



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