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Ann Thorac Surg 1998;65:1071-1076
© 1998 The Society of Thoracic Surgeons

Monocyte Tissue Factor Expression and Ongoing Complement Generation in Ventricular Assist Device Patients

^a Department of Surgery and Artificial Heart Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA

Accepted for publication November 23, 1997.

Address reprint requests to Dr Wagner, Department of Surgery, University of Pittsburgh Medical Center, 328 Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213
e-mail: (wagner{at}pittsurg.nb.upmc.edu)

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Ongoing complement activation in patients with a ventricular assist device may contribute to observed hemostatic abnormalities and cellular aggregation by mediating leukocyte and platelet activation, formation of leukocyte-platelet conjugates, and the tissue factor pathway of coagulation.

Methods. Blood from 30 patients was collected before ventricular assist device implantation and during the implantation period. Plasma levels of thrombin–antithrombin III complexes, C3a, and SC5b-9 were measured by commercial enzyme-linked immunosorbent assay. Flow cytometry was used to measure circulating monocyte tissue factor expression and circulating monocyte–platelet and granulocyte–platelet conjugates.

Results. Thrombin–antithrombin III complex level and monocyte tissue factor expression peaked in the early postoperative period, with maxima occurring on postoperative days 5 and 3, respectively. Levels of C3a and SC5b-9 remained dramatically elevated over normal values for the duration of the study (6 and 5 times upper normal, respectively). Levels of monocyte–platelet conjugates were normal before implantation, decreased during the first 4 postoperative days, and then increased and remained elevated. Levels of granulocyte–platelet conjugates were elevated over the normal range before implantation and remained elevated from postoperative days 3 to 21. A positive correlation was found between levels of SC5b-9 and granulocyte–platelet conjugates (Spearman R = 0.66; p < 0.001), and between levels of C3a and thrombin–antithrombin III complex (Spearman R = 0.13; p = 0.021).

Conclusions. The data suggest a model in which complement mediates formation of leukocyte–platelet aggregates and may indirectly contribute to thrombin generation through monocyte tissue factor expression.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The effects of short-term blood–biomaterial contact on the hemostatic and complement systems have been well characterized in patients undergoing cardiopulmonary bypass (CPB) [1]. Generation of the complement membrane attack complex (C5b-9) and anaphylatoxins (C3a, C5a), as well as monocyte tissue factor expression (MONO-TF) and thrombin generation have been observed both in vitro and in vivo [2–4]. Complement C5b-9, C3a, and C5a are known platelet and leukocyte agonists, and recent evidence has indicated a potential link between complement activation and formation of leukocyte-platelet aggregates [5, 6]. Flow cytometric studies of patients undergoing CPB describe changes in platelet and leukocyte activation, adhesion receptor expression, microparticle formation, and leukocyte-platelet aggregation [7, 8].

In contrast to acute studies with CPB circuits, ventricular assist device (VAD) patients present an opportunity to study in vivo the effects of chronic blood–biomaterial contact on hemostatic and inflammatory mechanisms. Ventricular assist device implantation is analogous to serial placement of two large-diameter vascular grafts, two prosthetic (bioprosthetic or mechanical) valves, and a polyurethane pumping chamber. Therefore, it is not surprising that transient ischemic attacks (TIAs) and cerebrovascular accidents (CVAs) precipitated by thromboembolism remain serious complications after VAD implantation and impediments to achieving the goal of permanent, chronic VAD patient support for the transplant-ineligible end-stage heart failure population.

Studies of the hemostatic alterations associated with VAD implantation have shown elevated thrombin generation in the early implantation period, with increased thrombin activity (fibrinogen conversion) and fibrinolysis throughout the course of device implantation [9–11]. Perturbations in hemostasis in VAD patients are attributed to plasma protein adsorption and intrinsic pathway activation, whereas the potential contribution of the tissue factor pathway to thrombin generation and activity has not been well characterized [12, 13]. Additionally, there is a need to address the role of complement in mediating platelet and leukocyte activation and formation of leukocyte-platelet conjugates, as well as thrombin generation via the tissue factor pathway, in these patients.

Heart failure, like CPB, is associated with generation of inflammatory mediators [14, 15]. Therefore, VAD biomaterials as well as the underlying disease state may result in ongoing inflammatory activity, which can activate cells directly, as is the case with anaphylatoxin-mediated leukocyte activation and membrane attack complex activation of platelets, or indirectly, such as with neutrophil-mediated platelet activation [5, 16]. Adhesion receptor expression, cellular aggregation, and MONO-TF–mediated thrombin generation are potential consequences of ongoing complement generation, and each may contribute to observed hemostatic abnormalities, thromboemboli formation, and precipitation of TIAs and CVAs in VAD patients. In the current study, we measured complement and thrombin generation, MONO-TF expression, and formation of leukocyte–platelet conjugates in VAD patients over the course of device implantation by using enzyme-linked immunosorbent assays (ELISAs) and whole-blood flow cytometry. We then tested the hypothesis that ongoing complement generation might be positively correlated with thrombin generation and circulating cellular aggregates in vivo, each of which may be directly or indirectly responsible for observed hemostatic abnormalities and precipitation of stroke in VAD patients.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Patient selection
A group of 30 patients scheduled for left ventricular assist device or biventricular assist device implantation were entered into the study after informed consent was obtained (University of Pittsburgh Medical Center institutional review board #9505108-9606). Seventeen patients received the Novacor Left Ventricular Assist System (Baxter Healthcare, Oakland, CA), and 13 were supported with the Thoratec system (Thoratec Laboratories, Berkeley, CA). Nineteen of the patients were supported by an intraaortic balloon pump (IABP) before device implantation, and 5 of the 13 Thoratec recipients were placed on both left and right ventricular assist. The median age of participants was 51 years (range, 23 to 68 years); 21 were men and 9 were women. The median implantation period was 77 days (range, 9 to 236 days). After the VAD implantation operation, patients were anticoagulated with dextran 6 to 8 hours postoperatively. Within 12 to 24 hours, all patients were started on a heparin regimen to maintain the partial thromboplastin time at 1.5 times the upper normal range. After extubation and removal of chest tubes, heparin administration was discontinued and oral warfarin administered to maintain the international normalized ratio between 3.0 and 4.0. Suspected thromboembolic neurologic events were confirmed by neurologic consultation or computed tomographic scan and recorded.

Flow cytometric analysis
Whole-blood flow cytometry was used for analysis of MONO-TF expression and formation of leukocyte-platelet conjugates. Blood was collected into 3-mL Monovette blood collection tubes containing 3.8% sodium citrate (Sarstedt, Nümbrecht, Germany) from a radial arterial catheter (while in intensive care) or via venous access lines or peripheral venipuncture after transfer to patient units. To determine if differences in levels of CD42b-positive conjugates exist between blood obtained from the radial arterial catheter or a venous access line, we compared arterial and central venous catheter blood in a subgroup of 12 VAD patients. Control blood samples, collected over a 3-year period, were obtained by peripheral venipuncture from healthy, nonsmoking, and nonpregnant donors aged 19 to 31 years who were medication free for at least 2 weeks before donation.

Samples were collected before VAD implantation and on postoperative days 1 through 5, 7, 10, 15, 21, 28, 45, and 60. Immediately after blood draws, aliquots of whole blood were incubated with monoclonal antibodies specific for platelet glycoprotein Ib (CD42b; Gentrak, Plymouth Meeting, PA), the monocyte marker CD14, the granulocyte marker CD15 (both from Becton-Dickinson, San Jose, CA), MONO-TF (American Diagnostica, Greenwich, CT) or immunoglobulin G and immunoglobulin M isotype controls (Gentrak). Anti-CD42b, anti-MONO-TF, anti-CD15, and their immunoglobulin G or immunoglobulin M isotype controls were obtained conjugated to fluorescein-isothiocyanate (FITC), and an additional anti-CD42b monoclonal antibody, anti-CD14, and their immunoglobulin G isotype controls were obtained conjugated to phycoerythrin (PE) to allow for two-color flow cytometric analysis. The following antibody combinations were used: (1) anti-CD14-PE and anti-CD42b-FITC for analysis of monocyte–platelet (MONO-PLT) conjugates, (2) anti-CD15-FITC and anti-CD42b-PE for analysis of granulocyte–platelet (GRAN-PLT) conjugates, and (3) anti-CD14-PE and anti-tissue factor-FITC for analysis of MONO-TF.

After incubation with monoclonal antibodies in the dark for 40 minutes, whole-blood samples were fixed with 1% paraformaldehyde and measured on a FACScan flow cytometer (Becton-Dickinson Immunocytometry Systems, San Jose, CA). For each sample, 5,000 events were acquired by live gating on events positive for CD42b-FITC, CD14-PE, or CD15-FITC with a positive fluorescence threshold determined by excluding 98% of matched isotype control fluorescence. Monocyte–platelet conjugates and MONO-TF were quantified as the percentage of the CD14-positive population also positive for the platelet marker CD42b or tissue factor by two-color analyses. Granulocyte–platelet conjugates were similarly measured as the percentage of the CD15-positive population also positive for the platelet CD42b markers. Blood samples from 15 of the 30 patients were analyzed for MONO-PLT conjugates, 13 were analyzed for GRAN-PLT conjugates, and 16 for MONO-TF.

Enzyme-linked immunosorbent assay technique
Commercial ELISA kits were used to determine plasma concentrations of thrombin–antithrombin complexes (TAT; Behring Diagnostics, Westwood, MA), complement anaphylatoxin C3a, and the inactivated membrane attack complex SC5b-9 (both from Quidel, San Diego, CA). Blood was collected into 3-mL Monovette blood collection tubes containing 3.8% sodium citrate for TAT and into 3-mL Vacutainer tubes containing 7.5% EDTA (Becton-Dickinson) for C3a and SC5b-9. Samples were drawn simultaneously with flow cytometry blood draws. Blood from all of the patients was analyzed for TAT, C3a and SC5b-9.

Statistical analysis
Although the blood draw schedule was followed carefully, on several occasions samples were not obtained on the scheduled day. Preoperative samples were not collected from 4 patients because of the urgency of their condition upon arrival and immediate device implantation. Data for several later postoperative days were not obtained because of difficulties with venipuncture. Similarly, on several days inadequate plasma was obtained to allow all assays to be performed. Finally, transplantation occurred for patients across the implantation periods reported; thus fewer data points are reported for later postoperative days.

Statistical analyses were carried out using commercially available software (CSS Statistica, Statsoft, Tulsa, OK). Comparisons of means and correlations were calculated with ranked patient and control data, after the determination was made by the Shapiro-Wilks’ W test that patient data were not normally distributed. To investigate the influence of IABP implantation on the measured parameters, we compared preoperative means of all assays for IABP-supported patients with non–IABP-supported patients by a Student’s two-sided unpaired t test with Bonferroni correction.

The mean and standard error of the mean from control samples were calculated to generate the normal range for ELISAs and flow cytometric assays. Temporal trends for patient data over the VAD implantation period were determined by averaging data for each postoperative day on the sampling protocol and plotting mean ± standard error of the mean versus postoperative day. Data for each postoperative day were compared with both normal control and preimplantation (baseline) data using a two-way analysis of variance with a least significant difference post hoc comparison of means. This analysis was carried out on ranked data. Relationships between flow cytometric and ELISA data were determined by calculation of the nonparametric Spearman R correlation coefficient on ranked patient data.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
No significant difference in CD42b-positive conjugates was found between arterial and venous catheter blood (arterial, 41% ± 5% of the CD42b-positive population, versus venous, 38% ± 5%). No significant differences were found in any of the measured indices between IABP-supported and non-IABP–supported patients preoperatively.

Figure 1 shows the temporal trend in plasma TAT levels for the study period. The level of TAT was significantly elevated above the normal range before and throughout the course of device implantation. After implantation, the TAT level increased markedly and remained significantly elevated over preoperative levels from postoperative day 1 to postoperative day 45. The maximum concentration of 22 ng/mL (7 times upper normal) occurred on postoperative day 5. After this maximum was reached, the TAT level steadily decreased toward preoperative levels, although it remained significantly elevated over the normal range through postoperative day 60.

View larger version (18K): [in this window] [in a new window]   Fig 1. Plasma thrombin–antithrombin III complex (TAT) concentration before and during the course of ventricular assist device support (mean + standard error of the mean; n for each postoperative day is indicated). (*p < 0.05 versus normal data; **p < 0.05 versus preoperative levels.)

View larger version (19K): [in this window] [in a new window]   Fig 2. Plasma C3a concentration before and during the course of ventricular assist device support (mean + standard error of the mean). (*p < 0.05 versus normal data; **p < 0.05 versus preoperative levels.)

View larger version (20K): [in this window] [in a new window]   Fig 3. Plasma SC5b-9 concentration before and during the course of ventricular assist device support (mean + standard error of the mean). (*p < 0.05 versus normal data.)

View larger version (19K): [in this window] [in a new window]   Fig 4. Monocyte tissue factor (TF) expression measured by flow cytometry (mean + standard error of the mean). (*p < 0.05 versus normal data.)

View larger version (19K): [in this window] [in a new window]   Fig 5. Monocyte–platelet microaggregate formation, indicated by CD42b (platelet marker)-positive monocytes as measured by flow cytometry (mean + standard error of the mean). (*p < 0.05 versus normal data.)

View larger version (20K): [in this window] [in a new window]   Fig 6. Granulocyte–platelet microaggregate formation, indicated by CD42b-positive granulocytes as measured by flow cytometry (mean + standard error of the mean). (*p < 0.05 versus normal data.)

View larger version (19K): [in this window] [in a new window]   Fig 7. The correlation coefficient between granulocyte–platelet conjugates (indicated by CD42b-positive granulocytes) and plasma SCb5-9 levels in ventricular assist device patient blood samples was calculated using ranked data (Spearman R = 0.66; p < 0.001; n = 77).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The complement pathway was continuously activated over the course of VAD implantation, indicated by elevated plasma C3a and SC5b-9 concentrations. Protein adsorption and activation of the alternative complement pathway in CPB patients suggest that a similar mechanism of complement activation may result in alternative pathway activation in VAD patients and explain the highly elevated levels of C3a and SC5b-9 [17, 18]. In addition, because end-stage heart failure is associated with inflammatory mediator generation and complement activation, the preexisting disease state may serve as a source of complement activation [14, 15]. An elevated SC5b-9 level during the implantation period suggests that C5a, a potent leukocyte and platelet agonist, has been generated. Both C5a and C5b-9 activate platelets as well as leukocytes, a means by which ongoing inflammation may contribute to platelet and leukocyte activation and aggregation, and formation of leukocyte-platelet conjugates [5, 6].

Formation of GRAN-PLT and MONO-PLT conjugates is mediated by platelet p-selectin expression, which may be the result of platelet agonist generation or cross-activation of platelets by leukocytes [16, 19]. Although the physiologic consequences of leukocyte-platelet microaggregate formation remain largely undescribed, a previous study by our group found the levels of circulating GRAN-PLT aggregates doubled before thromboembolic neurologic events in VAD patients, implying a role for these conjugates in precipitation of stroke [20]. In the present study, GRAN-PLT conjugates were significantly elevated over normal controls before device implantation when no strokes were observed. However, VAD implantation resulted in significant increases in leukocyte and platelet agonists. Detection of an increased number of circulating leukocyte-platelet conjugates may thus be indicative of formation of larger and potentially more dangerous aggregates on or near VAD biomaterial surfaces. The significant correlation found between SC5b-9 levels and GRAN-PLT conjugates and the ongoing elevations in C3a and SC5b-9 levels suggest that there may be an important role for complement in mediating the formation of leukocyte-platelet conjugates, and stroke.

Monocyte engagement of p-selectin, such as may occur during formation of MONO-PLT conjugates, results in tissue factor expression [21]. Although MONO-PLT conjugates and MONO-TF were not correlated in our data, it is possible that monocytes with the highest tissue factor expression are rapidly removed from the circulation. The quantification of circulating MONO-TF and MONO-PLT conjugates may therefore underestimate the magnitude of the activation events that are occurring. Circulating MONO-TF expression increased in the early postimplantation period and qualitatively paralleled TAT formation, suggesting MONO-TF as a potential source of thrombin generation. Postoperative days 1 through 15 were the period of greatest MONO-TF expression and TAT elevation, with peaks for both occurring within the first 5 postoperative days.

The elevation in MONO-TF in the early postimplantation period is likely caused by a combination of surgical trauma and contact of patient blood with VAD biomaterials. Recent studies of patients undergoing CPB have found perioperative increases in tissue factor expression on circulating and pericardial monocytes, and increased expression on circulating monocytes, immediately after and 20 hours after the operation [22, 23]. Similarly, an in vitro study of monocyte tissue factor expression during simulated extracorporeal circulation (without surgical trauma) found an increase in monocyte tissue factor expression after 6 hours of recirculation, indicating the important role of blood-biomaterial interactions in mediating MONO-TF expression [4]. Although the potential effects of surgical trauma in mediating tissue factor expression cannot be ignored, it seems likely that elevations seen throughout the first week of VAD implantation are related to substantial biomaterial implantation as opposed to surgical trauma.

Preoperative elevations in levels of C3a, SC5b-9, and GRAN-PLT conjugates were not found to be related to IABP support, and are likely associated with the preexisting disease state [14, 15]. Because inflammatory mediator and anaphylatoxin generation is found with severe heart failure, it is not surprising that these patients exhibited significant elevations in these parameters over nondisease or age-matched controls. In this regard, preoperative levels of these indices may be considered as the "normal" range for this particular population of heart failure patients. It is of interest, however, that the increased cardiac output and tissue perfusion associated with ventricular support did not reduce complement activation and circulating leukocyte-platelet conjugates. On the contrary, these species increased after VAD implantation. The possibility of offsetting effects between blood–biomaterial interactions and increased tissue perfusion must be considered.

We have shown elevated levels of circulating leukocyte-platelet conjugates, thrombin generation, and ongoing complement generation in VAD patients, as well as evidence of tissue factor-mediated thrombin generation in this patient group. Levels of C3a, SC5b-9 and GRAN-PLT conjugates were elevated before device implantation, most likely because of the disease state, whereas levels of TAT, MONO-TF, and MONO-PLT conjugates increased during VAD support and appear to be more strongly affected by VAD biomaterial implantation. The current study suggests a scenario in which complement activation mediates formation of granulocyte-platelet conjugates, which may be important in precipitation of thromboemboli in VAD patients. In addition, complement may also mediate thrombin generation by stimulating tissue factor expression on monocytes directly, or via platelet activation and p-selectin mediated MONO-TF expression, although this evidence is tenuous. Further studies of inflammatory–coagulation interactions in VAD-supported patients are indicated, along with studies of the potential role of antiinflammatory therapy in the clinical management of coagulation and thromboembolism in these patients.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Supported by a grant-in-aid from the American Heart Association (William R. Wagner) and the McGowan Center for Artificial Organ Development. Additional clinical and technical support provided by Carla Nastala, Donna Urbanowicz, and Stephen Winowich of the University of Pittsburgh Medical Center Artificial Heart Program, and Cathy Haluszczak of the University of Pittsburgh School of Medicine Department of Surgery.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert L. Kormos William R. Wagner Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wilhelm, C. R. Articles by Wagner, W. R. Search for Related Content PubMed PubMed Citation Articles by Wilhelm, C. R. Articles by Wagner, W. R.