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Ann Thorac Surg 1997;64:1120-1125
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Factors Influencing HLA Sensitization in Implantable LVAD Recipients

Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio

Accepted for publication May 6, 1997.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
Background. Patients bridged to transplantation (TX) with the implantable left ventricular assist device (LVAD) may be at increased risk for the development of panel-reactive antibodies (PRA) during support.

Methods. To investigate that, we evaluated 60 patients who received the HeartMate LVAD at our institution, of whom 53 had PRA results available for analysis. T lymphocyte PRA levels were examined before LVAD, at the peak PRA level during LVAD support (PEAK), and just before TX. A PRA level more than 10% was considered indicative of sensitization against HLA antigens.

Results. The only factor that had a significant effect on PRA levels before LVAD was patient's sex (1.3% for men versus 7.4% for women; p = 0.005). During LVAD support, peak PRA levels increased significantly and the sex-associated differences were no longer evident (33.3% men, 34.3% women; not significant). At the time of TX, PRAs decreased to 10.9% (men) and 7.0% (women) (not significant). We examined the influence of blood products received before TX on PRA levels. Patients who received less than the median number of total units (<median) had lower peak PRA values (22.3% versus 49.2%; p = 0.01) and TX PRA values (3.5% versus 22.1%; p = 0.02) than those receiving more than the median (>median). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (<median: 24% versus >median: 46.9%; p = 0.03). Patients who received blood that was leukocyte-depleted tended to have lower TX PRA levels (2.9%) compared with those who did not (13.9%, p = 0.18). Forty-two patients were successfully bridged to TX, with three early and two late deaths after TX. Whereas 39 patients received transplants without intervention, 3 were treated by plasmapheresis with a 77% reduction in their HLA antibody levels at TX as measured by flow cytometry.

Conclusions. Patients with the implantable LVAD are at significant risk for the development of anti-HLA antibodies during support. Although this sensitization is often transient, intervention using plasmapheresis may be useful for some patients.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
The rationale behind testing the panel-reactive antibody (PRA) levels in candidates for heart transplantation is based on the well-established data of kidney transplant recipients whose graft survival is inversely related to the PRA level [1–4]. Further data indicate that sensitization in cardiac allograft recipients, as evident by PRA values more than 10%, constitutes a risk factor for acute rejection during the early posttransplant period, as well as for death from acute or chronic rejection [1]. We have observed that patients bridged to transplantation with the implantable left ventricular assist device (LVAD) system at our institution are at increased risk for the development of antibodies to human leukocyte antigens (HLA) during support. We investigated the incidence of production of anti-HLA antibodies after LVAD implantation in patients who are bridged to cardiac transplantation, and examined the relationship between the presence of these antibodies and several factors that may have predisposed to their production. The underlying hypothesis of the present study is that patients who are bridged to transplantation with the implantable LVAD are at increased risk of HLA sensitization during support, which may affect subsequent graft outcome.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
Patient Characteristics
From January 1992 to July 1995, 60 patients at the Cleveland Clinic Foundation (CCF) were supported on the HeartMate (Thermo Cardiosystems, Woburn, MA) LVAD as a bridge to cardiac transplantation. Of these, 53 patients had PRA assay results available for analysis and were included in this study. The clinical records of these patients were reviewed retrospectively. There were 46 male (87%) and 7 female patients (13%). The mean age of the patients at the time of bridging was 51 years (range, 27 to 64 years). The cause of the congestive heart failure was ischemic cardiomyopathy in 38 patients (72%) and nonischemic dilated cardiomyopathy in 15 patients (28%). Previous cardiac surgical operations had been performed in 24 patients (45%). All patients were on inotropic support. Forty-three patients (81%) were on intraaortic balloon pump, and 34 patients (64%) were on mechanical ventilatory support. Extracorporeal membrane oxygenation (ECMO) was instituted preoperatively as a bridge to the HeartMate LVAD in 12 patients (23%), either for postcardiotomy acute heart failure or after an acute myocardial infarction. The pneumatic HeartMate LVAD was used in 44 patients (83%) and the electric HeartMate LVAD in 9 (17%). Seven patients (13%) required an average of 3.5 days of mechanical right ventricular assistance because of right ventricular failure refractory to medical treatment. The mean duration of LVAD support was 64 days (median, 66 days; longest, 153 days).

Serologic Tests
Assessment of PRAs against T lymphocytes was examined before LVAD, during the period of LVAD support, and just before transplantation (TX). The highest PRA level during the period of support was identified as the peak PRA level. The patients' sera were heat treated to remove immunoglobulin M reactivity and tested by complement-dependent lymphocytotoxicity against a comprehensive 25- to 50-member cell panel of HLA-typed donors selected to represent most of the defined HLA specificities [5]. The screening test was considered positive when at least 10% of the cells in the well showed cytotoxicity. In this series, prospective crossmatching was not always performed. All patients underwent retrospective donor-specific flow cytometry crossmatching (FCXM). The technique of FCXM has been described in detail by one of us in previous publications [6–8].

Blood Use Criteria
Blood use during support was recorded from the time of LVAD implantation (including intraoperative blood use) to the time of transplantation (excluding blood use during the transplant operation). Blood use during operative interventions performed while on LVAD support was also included. Red cell transfusions were administered while on LVAD support for active bleeding or for symptomatic anemia or for patients with asymptomatic anemia when the hematocrit dropped below 28% (serum hemoglobin 9 g/dL or less). ABO compatible platelets were transfused when platelet counts dropped below 20 x 10⁹/L, before operative procedures when counts were below 100 x 10⁹/L, or for hemorrhage. Fresh frozen plasma and cryoprecipitate concentrations were administered when indicated in patients with suspected clotting factor deficiencies. The cytomegalovirus (CMV) status of the blood used during support was not routinely checked before transfusion. However, CMV-negative blood products were given on support whenever available and routinely after transplantation. Sensitization was compared among two groups of patients: those who received, among the blood transfused, one or more units of non–leukocyte-depleted blood (34 patients or 64%), and those who did not (19 patients or 34%).

	Study Design and Statistical Analysis

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
The data were evaluated during three period intervals: (1) the support period before LVAD referred to the duration of hospital stay before LVAD implantation, (2) the period of LVAD support (LVAD), and (3) the time of transplantation (TX). The patients before LVAD were compared with 129 consecutive nonbridged patients who received transplants, to assure that the former group was not biased toward sensitization from the outset. Univariant analysis was performed to study the influence of the following factors on HLA sensitization: the patient's sex, previous cardiac operations, duration of LVAD support, blood use, infection, and plasmapheresis. We retrospectively defined two groups of patients who received less than or more than the median number of blood transfusions before transplantation to compare the effect of blood use on infection and HLA sensitization during support. A PRA level more than 10% was chosen to be indicative of sensitization in view of reports in the literature associating it with increased risk of rejection and death after transplantation [1].

Statistical analysis was performed using the "Stata" software computer package (Stata Corporation, College Station, TX). Univariant analysis was performed using Fisher's exact test. Pearson ² test was used to compare groups. A p value less than 0.05 was considered statistically significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
The frequency of HLA sensitization (PRA > 10%) among 53 LVAD recipients before LVAD support was compared with that of 129 consecutive nonbridged patients before the time of transplantation. There was no significant difference between the two groups (3.7% versus 11.6%; not significant). Sensitization was present in 27 of 41 (65.8%) of the LVAD recipients, and this decreased to 8 of 36 (22%) at the time of transplantation (Fig 1). The overall mean PRA level before LVAD increased significantly from 2.1% to 33.5% during LVAD support (p < 0.0001), and decreased to 10.2% at transplantation (p = 0.04, Fig 2). Levels of PRA before LVAD in the two subgroups of bridged patients with ischemic and nonischemic cardiomyopathy were similar.

View larger version (14K): [in this window] [in a new window]   Fig 1. . Frequency of human leukocyte antigen (HLA) sensitization in left ventricular assist device (LVAD) recipients. (PRE-LVAD = before LVAD; PEAK LVAD = peak level of panel-reactive antigen [PRA] during LVAD support; LVAD TX = at time of transplantation.)

View larger version (18K): [in this window] [in a new window]   Fig 2. . Mean panel-reactive antigen (PRA) levels showed significant increase during left ventricular assist device (LVAD) support and at the time of transplantation (TX).

	Sex

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

	Previous Cardiac Operations

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
The impact of previous cardiac operations on T-cell PRA levels was also evaluated. Before LVAD, there was no significant difference in PRA levels between the group of patients who underwent previous cardiac operations and the group who did not (1.6% versus 2.4%, not significant). Despite the significant increase in the peak PRA levels, the difference between the two values was not statistically significant (35.6% versus 31.6%, respectively). The TX PRA levels were 2.9% and 14.9%, respectively (not significant).

	Duration of LVAD support

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
We found no significant difference in the peak PRA (36.3% versus 31.8%) and TX PRA values (10.5% versus 10.1%) between the patients whose duration of LVAD bridging was less than the median or more than the median number of days on support.

	Infection

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
Device-related infection (of the LVAD pocket or drive-line or LVAD pump) occurred in 28 patients (53%) (Table 1). Septicemia occurred in 29 patients (55%) and was related to a device-related infection in 22 patients (42%) and to a non–device-related infection in 7 (8%). Fungal sepsis occurred in 13 patients and was associated with an increase in the peak PRA (infected, 54.5% versus uninfected, 28.4%; p < 0.05) and TX PRA levels (22.4% versus 7.3%, p = 0.12). Bacterial sepsis did not demonstrate a similar effect during the two LVAD periods evaluated, although a similar trend was noted (peak: 35.5% versus 32.0% uninfected, not significant; TX: 18.2% versus 4.5% uninfected, p = 0.07). Likewise, non–blood-borne nosocomial or incisional wound infections (bacterial or fungal) had no significant influence on PRA levels.

	Blood Use

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

Twenty-eight percent of the patients before LVAD and all patients on LVAD received transfusions of homologous blood with unverified CMV status. Furthermore, 26% of the patients before LVAD and 64% of patients on LVAD received non–leukocyte-depleted red blood cell transfusions. The group of patients who received less than the median number of total units (< median) had lower peak PRA levels (22.3% versus 49.2%, p = 0.01) and TX PRA values (3.5% versus 22.1%, p = 0.02) than the group receiving more than the median (> median) (Fig 3). When examined by the type of blood product, only the number of platelet transfusions significantly increased the peak PRA (< median: 24.0% versus > median: 46.9%; p = 0.03). Transplantation PRA levels among the individual types of blood products were not different for the two groups (Table 2).

View larger version (17K): [in this window] [in a new window]   Fig 3. . Mean panel-reactive antigen (PRA) levels of left ventricular assist device (LVAD) recipients compared with the median number of blood products transfused before transplantation (TX).

	Leukocyte Depletion of Used Blood

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

View larger version (17K): [in this window] [in a new window]   Fig 4. . Effect of leukocyte depletion (LD) and cytomegalovirus (CMV) status of transfused platelet (PLTS) concentrates on mean panel-reactive antigen (PRA) levels during left ventricular assist device (LVAD) support and at the time of transplantation. (NEG = negative; ? = unknown status.)

	Cytomagalovirus Status of Used Blood

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

	Outcome of Patients Successfully Bridged to Transplantation

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
Of the 53 patients who were reviewed, 11 patients (21%) experienced multisystem organ failure and died on support. HLA sensitization was not a factor in these patients as their medical conditions alone prevented transplantation. Forty-two patients were successfully bridged to transplantation, constituting a transplantation rate of 79%. Details regarding crossmatching and posttransplantation management of these patients will be reported elsewhere. Whereas 39 patients (74%) received transplants without intervention, plasmapheresis was performed during support in 3 patients with extremely high peak PRA levels (mean PRA, 97%), who were otherwise ready for transplantation, to reduce their level of anti-HLA antibodies and create a window for them to be transplanted. The mean duration of support of these 3 patients was 134 days (105, 144, and 153 days). Plasmapheresis was able to achieve an average reduction of 77% in their HLA antibody levels at the time of transplantation as measured by flow cytometry. Plasmapheresis was continued after transplantation in all. The 3 patients continue to do well at 8, 16, and 25 months after transplantation. Plasmapheresis was performed after transplantation in an additional patient who had a positive retrospective flow cytometry cross-match and died 2 months after transplantation after episodes of severe cellular and vascular rejection. There were four additional deaths after transplantation; two early non–rejection-related and two late deaths caused by graft atherosclerosis at 30 and 32 months after transplantation. The 1-year survival for the 42 LVAD recipients who were successfully bridged to transplantation was 93%.

	Comment

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
In this study, we examined HLA sensitization in LVAD recipients. Our data indicate that LVAD recipients are not biased toward sensitization before LVAD support as evident from the lower number of patients sensitized before support (3.7%) in comparison with that of non-LVAD transplant recipients (11.6%). Although sensitization in these two groups was not statistically different, the trend toward a lower frequency of sensitization in the group before LVAD may be accounted for by the lower number of women who received LVAD support (7 of 53 patients, 13%), compared with the number of female patients who were transplanted without requiring LVAD support (33 of 129 patients, 26%).

Alloimmunization to leukocyte antigens may occur after previous organ transplantation, pregnancy, and transfusions [9]. Our data do not show a correlation between sensitization from remote blood transfusions received during previous cardiac operations and mean PRA levels before LVAD support. This lack of association might be accounted for by the fact that either antibodies against homologous blood antigens are not long lived, and sensitization is transient, or the association is masked by a higher number of sensitized patients in the group that did not receive previous operations (7 women with previous pregnancies) compared with the all-male group of patients who underwent previous cardiac operations. The trend toward the higher mean PRA level at the time of transplantation in the group of patients who did not have previous cardiac operations may have also been related to the larger representation of the female patients who survived to transplantation (constituting 21% of the patients with no previous cardiac operations) compared with the all-male patients who had previous cardiac operations.

Although the degree of HLA sensitization was similar in the two groups of patients who were supported less than or more than the median LVAD duration, we have noted that the 3 highly sensitized patients who required pretransplantation plasmapheresis remained on support for a longer period of time (mean, 134 days). Several factors contributed to their prolonged length of support, including sepsis, need for frequent sessions of plasmapheresis to decrease their level of sensitization, and waiting for the optimal donor. Patients who were supported on the implantable LVAD received a large amount of blood transfusions before transplantation, which included blood products transfused during operative procedures before or after LVAD implantation, products given during implantation, and those given while on support. Except in the first eight implantations, we have used aprotinin during LVAD implantation in all of our patients. Data from our institution indicate that hepatic dysfunction secondary to right ventricular failure or as a component of the developing multiorgan dysfunction have contributed to the perioperative state of coagulopathy that develops in some of these patients [10]. We have maintained our LVAD recipients on platelet-inhibiting agents (aspirin, dipyridamole) during support and found that they are prone to develop complications of peptic ulcer disease, including upper gastrointestinal bleeding requiring multiple blood transfusions. About 15% of our patients who were supported on the LVAD experienced abdominal complications requiring operative interventions. In 6 patients, severe device-related hemorrhage occurred and necessitated emergent operative intervention and multiple transfusions of blood products. Thrombocytopenia has been observed in 40% of LVAD recipients during support in conjunction with heparin-associated antibodies [11]. All of these factors may have contributed to the large amount of perioperative blood use.

Reports of the association between transfusion of homologous blood components and elevated rates of nonviral infections merit a close look [9, 12]. Recent work has shown a dose-dependent effect of blood transfusion on postoperative infection in patients undergoing coronary artery bypass graft operations [12]. In the present study we found that 34.5% of the patients who received more than the median number of blood products had fungal blood infections compared with 10.3% of the patients who were transfused less than the median (p < 0.03). This blood transfusion-related, dose-dependent increase in the incidence of fungal blood infections may explain the increased degree of sensitization in the patients who had fungal blood infections during LVAD support. It seems likely that fungal blood infections are a marker of multisystem organ failure in a group of patients who are extremely morbid, who received multiple blood transfusions, and who have been on long courses of broad-spectrum systemic antibiotic coverage. A possible explanation for this observation could be the nonspecific activation of memory B cells resulting from cytokine release, as essentially all such patients have been exposed to foreign HLA by the time of sepsis. We were not able to demonstrate a significant effect of blood transfusions on bacterial blood infections nor a significant impact of bacterial blood infections on HLA sensitization; we believe that a larger patient cohort is required to fully resolve this issue.

Repeated exposure to leukocytes from different blood donors exposes the transfusion recipient to many different HLA class I antigen types and frequently results in the development of antibodies directed against many or most HLA class I antigen types [9]. Our data indicate that bridged patients receive a considerable amount of blood transfusions during LVAD support and develop a significant amount of HLA antibody reactivity. One possible explanation for the significant increase in the LVAD mean peak PRA level seen with platelet transfusions is the significantly higher number of platelet units transfused during support compared with the other blood products (platelets, 57.8 units; packed red blood cells, 35.2 units). Brand and coworkers [13] transfused patients with filtered red blood cells and leukocyte-depleted platelet concentrates prepared by centrifugation in a large nonrandomized prospective study and reported that HLA antibodies developed in 19% of the non-presensitized patients. Kooy and associates [14] reported a 42% incidence of HLA alloimmunization among patients receiving centrifuged platelet concentrates and 11% sensitization in patients who were transfused with filtered platelet concentrates.

Cytomegalovirus, a member of the human herpes family, is present in 50% of the general population [15]. The limited availability of CMV-seronegative blood products for use in transplant patients and the large amount of blood requirements in LVAD recipients may have a significant impact on blood bank resources and have led us in some instances to use blood products during LVAD support without determining their CMV status. Because CMV is exclusively transmitted by leukocytes, we implemented a policy at our institution to use leukocyte-depleted cell products on a routine basis in transplant candidates, hoping to minimize the rate of CMV infection in that population [16].

As evidence accumulates that it is the contaminating leukocytes that are mostly responsible for alloimmunization against HLA antigens [17], the transfusion of leukocyte-free blood components should be considered in prospective cardiac transplant recipients such as patients bridged on LVAD support. Although we recommend that, it is worth mentioning that leukocyte-free units are in fact blood units without detectable leukocytes but that they contain pieces of HLA-expressing leukocyte membranes, cytokines, and antigens shed by these cells.

The deleterious effects of the humoral immune responses in cardiac transplant recipients have been reported by several previous investigators [18–21]. Anti-HLA antibody production has been associated with the development of graft arteriosclerosis [18], and with the vascular deposition of complement and immunoglobulin in that subset of transplant recipients [19, 20]. The group of patients who are highly sensitized at the time of transplantation and continue to have high quantitative antibody binding after transplantation as measured by flow cytometry merits a closer follow-up and perhaps more intense immunosuppression with the use of perioperative induction with agents such as monoclonal murine antibodies to the CD3 receptor (OKT3) [21]. Our preliminary data suggest that plasma exchange during LVAD support and after transplantation in patients with continued sensitization may ameliorate some of these deleterious humoral immune responses.

In conclusion, although a retrospective study might be subject to biases, our data strongly suggest that patients with the implantable LVAD are at a significant risk for developing anti-HLA antibodies during support. Both blood use and infection may increase this risk. Although these antibodies may be transient, aggressive intervention using plasma exchange may be useful for some patients. Leukocyte-depleted, CMV-negative platelet concentrate transfusions decreased the risk of sensitization. The impact of HLA sensitization during LVAD support on transplant outcome warrants further investigation to determine whether it adversely affects the incidence of rejection, graft atherosclerosis, or survival.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 
Address reprint requests to Dr McCarthy, Department of Thoracic and Cardiovascular Surgery, The Cleveland Clinic Foundation, One Clinic Center, 9500 Euclid Ave, F-25, Cleveland, OH 44195-5066.

	References

Top Footnotes Abstract Introduction Material and Methods Study Design and Statistical... Results Sex Previous Cardiac Operations Duration of LVAD support Infection Blood Use Leukocyte Depletion of Used... Cytomagalovirus Status of Used... Outcome of Patients Successfully... Comment References

 

1. Lavee J, Kormos RL, Duquesnoy RJ, et al. Influence of panel-reactive antibody and lymphocytotoxic crossmatch on survival after heart transplant. J Heart Lung Transplant 1991;10:921–30.[Medline]
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3. Terasaki P, Mickey M, Iwaki Y, et al. Long-term survival of kidney grafts. Transplant Proc 1989;21:615–7.[Medline]
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6. Hurley JP, Cook DJ, McCarthy PM, et al. Flow cytometry crossmatching: a method for monitoring antidonor antibodies in heart transplant recipients. Transplant Proc 1995;27:1301–3.[Medline]
7. Cook DJ, Klingman LL, Koo AP, Goldfarb D, Dennis VW, Hodge EE. Quantitative flow cytometry cross-matching for precise measurement of donor-specific alloreactivity. Transplant Proc 1994;26:2866–7.[Medline]
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15. Hart S, Roe JA. Leukocyte depleted filters and cardiothoracic surgery. Perfusion 1993;8:477–82.[Abstract/Free Full Text]
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17. Meryman HT. Transfusion-induced alloimmunization and immunosuppression and the effects of leukocyte depletion. Transfus Med Rev 1989;3:180–93.[Medline]
18. Hess ML, Hastillo A, Mohanokumar T, et al. Accelerated atherosclerosis in cardiac transplantation. Circulation 1983;68(Suppl 2):94–101.
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