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J Thorac Cardiovasc Surg 1999;118:404-413
© 1999 Mosby, Inc.
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Departments of Surgery, Physiology, and Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Address for reprints: Talia B. Spanier, MD, c/o Craig R. Smith, MD, Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, Milstein Hospital, Room 7-435, 177 Fort Washington Ave, New York, NY 10032.
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Abstract |
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, interleukin 2, and tumor necrosis factor , in addition to vascular cell adhesion molecule-1 consistent with their capacity to continually recruit and activate circulating cells, thereby propagating their response. In the periphery, elevated levels of tissue factor were found in the plasma of patients with LVADs, along with enhanced procoagulant activity. |
Introduction |
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1-6 Compared with early-design LVADs, whose surfaces were mainly of smooth contour, textured-surface LVADs were developed with a polyurethane diaphragm, intended to minimize the potential for thromboembolic complications by facilitating the formation of a tightly adherent "pseudoneointima" on the blood-contacting surface. 7-12 The goal of this strategy was to reduce the risk of development of thromboemboli by eliminating direct contact between the device and circulating blood. 11 The apparent success of this modification in LVAD design has been suggested by studies reporting a thromboembolic rate of less than 2% associated with use of this modified surface in patients receiving no systemic anticoagulation. 12
The physiologic consequences of this biologic lining, however, are many and varied, owing to the nature and characteristics of those cells that adhere to the LVAD surface. 13-16 We 17 have previously described a clinical phenomenon of a "compensated coagulopathy" underlying the apparent autoanticoagulation in recipients of textured-surface LVADs and have attributed this finding to procoagulant stimuli elicited from the LVAD cell surface microenvironment. Our findings of increased thrombin generation and fibrinolysis have been further confirmed by those of Bibiokis and associates, 18 who similarly demonstrated significant perioperative activation of coagulation in LVAD recipients when compared with control subjects undergoing coronary artery bypass operations.
Although these results have implicated host-device interactions as the nidus for this activation, no study to date has comprehensively characterized the specific nature of these interactions and their development and change over time. Although previous investigators have suggested that the activation of coagulation was due largely to the continuous contact of blood with the foreign LVAD surface, 18 we propose that specific cells, which progressively adhere to the textured surface and become activated, may account for the observed compensated coagulopathy. Furthermore, the dynamic nature of this cell-surface microenvironment likely reflects changes in cellular phenotypes, themselves a function of ongoing host-device interactions.
We undertook the current study to evaluate further the time-dependent generation of the sustained procoagulant response that follows implantation of textured-surface LVADs. We hypothesized that changes in the cell-surface microenvironment over time would likely parallel clinically apparent systemic phenomena. We therefore prospectively evaluated clinical indicators of this procoagulant phenotype in LVAD recipients, as well as characterizing cellular aspects of their LVAD surface milieu.
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Methods |
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TISSUE FACTOR ACTIVITY.
For the evaluation of tissue factor activity in peripheral blood, assays were conducted as previously described. 19 In brief, 18 mL of blood was drawn by peripheral venipuncture into 3.8% sodium citrate (9:1 vol/vol), diluted with an equal volume of 25 mmol/L HEPES buffer in Hanks’ balanced salt solution, pH 7.4 (Gibco BRL, Life Technologies, Inc, Rockville, Md), and layered onto a Histopaque-1077 gradient (Sigma Chemical Co, St Louis, Mo) for mononuclear cell isolation. Mononuclear cells from the original blood samples (2.5 x 106 cells/well) were then incubated in the presence or absence of lipopolysaccharide (10 µg/mL) from Escherichia coli serotype 026:B6 (Sigma) in human plasma (20%) for 2 hours at 37°C. Procoagulant activity of lysed mononuclear cells was measured by a 1-step recalcification time. Cells were lysed by the addition of octyl ß-D glucopyranoside (15 mmol/L; Calbiochem, San Diego, Calif) and HEPES (25 mmol/L) in Hanks’ balanced salt solution (Gibco). The resulting suspension was incubated with pooled normal plasma (Sigma) at 37°C for 3 minutes, after which time CaCl2 (0.001 mol/L) was added and the clotting time determined by visual detection of clot formation. Each sample was run in triplicate. Serial dilutions of recombinant native tissue factor (American Diagnostica, Greenwich, Conn) were used to generate a standard curve.
LVAD cellular microenvironment analysis
HARVEST AND STUDIES ON CELLS FROM THE LVAD.
At explantation, LVADs were opened with a device provided for this purpose by the manufacturer (TCI), and the surfaces immediately rinsed in sterile, cold phosphate-buffered saline solution (without magnesium or calcium; Gibco). A standard tissue culture–type cell scraper (Baxter, McGraw Park, Ill) was then used to gently detach cells adherent to the polyurethane diaphragm. Aliquots of harvested cells were immediately immersed in RPMI 1640 test medium, which was subsequently supplemented with either fetal calf serum (10%) or autologous serum (10%), as well as antibiotics, as described earlier. Aliquots of cells were also immersed in cold Trizol Reagent (Gibco), snap-frozen in liquid nitrogen, and stored at –80°C after homogenization for subsequent total RNA isolation.
Cells harvested from the LVAD were incubated for the indicated time in tissue culture wells either alone or in the presence of sterilized, endotoxin-free LVAD polyurethane diaphragm (107 cells/well). Experiments were performed in RPMI 1640 medium supplemented with either fetal calf serum (10%) or autologous serum (10%) collected at the time of explantation and separated from the patients’ blood by centrifugation at 6000 rpm. Experiments were performed both in the presence and absence of lipopolysaccharide, 50 ng/mL. 20 Aliquots of cellular supernatants were removed immediately (0 time point), at 72 hours, at 1 week, and at 10, 14, and 21 days and then assayed for levels of tissue factor as described earlier.
IMMUNOHISTOCHEMISTRY.
Cells were harvested as described earlier, resuspended in Dulbecco’s modified Eagle’s medium supplemented with fetal calf serum (10%), plated in 4-well plates (Nunc, Naperville, Ill), and placed in an incubator at 37°C. At 24 hours, cells were washed once with Hanks’ balanced salt solution (Gibco) and resuspended in fresh medium as described earlier. After 48 to 72 hours of incubation, viable cells were fixed in paraformaldehyde (2%) and solubilized with 0.1% Nonidet P-40 (Sigma) as indicated. After an overnight fixation at 4°C, slides were washed with phosphate-buffered saline solution and hydrogen peroxide (0.3%; Sigma). They were blocked with phosphate-buffered saline solution containing bovine serum albumin (1%) and serum (4%), species depending on the animal in which the secondary antibody was prepared, for 30 minutes at 37°C. Primary antibody was added at the appropriate dilution (as suggested by the manufacturer), followed by incubation for 1 hour at 37°C. Antibody for tissue factor (1:100) (mouse monoclonal antibody) was obtained from American Diagnostica. Antibodies to CD34 (1:10), CD14 (1:100), CD68 (1:100), smooth muscle actin (1:50), and nonimmune immunoglobulin G (1:100), all mouse monoclonal antibodies, were obtained from DAKO (Carpenteria, Calif). The fixed cells were then washed and incubated with appropriate secondary antibody (1:100 dilution) for 1 hour and developed for 5 minutes at room temperature in buffer containing aminoethylcarbamazole (Sigma), hydrogen peroxide (0.1%), and acetate buffer (0.50 mol/L; pH 5.0).
REVERSE TRANSCRIPTION–POLYMERASE CHAIN REACTION (RT-PCR).
Cells were harvested directly from the LVAD surface at explantation, as described earlier. An aliquot was immediately placed in cold Trizol reagent (5 mL; Gibco) and homogenized with a Polytron homogenizer (Brinkmann Instruments, Westbury, NY) for 60 seconds before being snap frozen in liquid nitrogen for extraction of total cellular RNA at a later time. Homogenized samples were then incubated at room temperature for 5 minutes (to permit the total dissolution of the nucleoprotein complexes), and phase separation was achieved by incubation with chloroform followed by centrifugation at 12,000g for 30 minutes at 4°C. The RNA was then precipitated from the aqueous phase with isopropyl alcohol followed by another centrifugation at 12,000g for 30 minutes. The RNA was washed twice with cold ethanol (75%) and resuspended in diethyl pyrocarbonate–treated water to a concentration of 1 µg/µL. RT-PCR was then performed according to previously described methods. 21,22 Primers for ß-actin, yielding an amplicon of 661 base pairs (bp), were obtained from Stratagene (La Jolla, Calif). For ß-actin, thermocycling parameters were as follows: 5 minutes at 94°C, 5 minutes at 60°C; and 35 cycles of 1.5 minutes each at 72°C, 45 seconds at 94°C, 45 seconds at 60°C, with a final extension of 10 minutes at 72°C. Primers for tumor necrosis factor- (TNF-) (644 bp), interleukin 2 (IL-2) (605 bp), and interleukin l (IL-1) (691 bp) were obtained from Clontech (Palo Alto, Calif). For the latter primers, thermocycling conditions were as follows: 40 cycles of 45 seconds at 94°C, 45 seconds at 60°C, and 2 minutes at 72°C, with a final extension of 7 minutes at 72°C. Primers for identification of transcripts for vascular cell adhesion molecule-1 (505 bp) were prepared as described. 23 Thermocycling conditions were run over 30 cycles after 5 seconds at 96°C, 15 seconds at 51°C, 60 seconds at 72°C, with a final extension of 7 minutes at 72°C.
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Results |
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Peripheral blood analysis
PROCOAGULANT PLASMA MARKERS.
Consistent with previous reports, 17,18 as demonstrated inTable II, prospective evaluation revealed an initial perioperative rise in markers of thrombin generation as measured by elevated levels of prothrombin fragment 1+2 and thrombin-antithrombin III complex. The data demonstrated an increase in each of these variables in the immediate perioperative period, which declined progressively by 1 week after the operation. Subsequently, indices of thrombin generation rose in a time-dependent manner, reaching an apparent maximum by 6 weeks. These values were then sustained through at least day 335 (as measured in the 1 patient who was followed up to this point after implantation). Similar results were observed for levels of D-dimers.
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TISSUE FACTOR ACTIVITY.
Enhanced mononuclear tissue factor activity of peripheral blood was observed in cells derived from LVAD patients compared with those from normal volunteers both in the absence and presence of lipopolysaccharide(Fig 1).
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, B).
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24 we identified a population of CD34+ cells that morphologically appeared elongated, variably described in the literature as spindle-type cells or dendritic cells, similar to hematopoietic stem cell precursors present in the normal bone marrow and to some extent in peripheral blood (from 0.01% to 0.1% of peripheral blood 25,26(Fig 3, panel A). Evidence for the presence of activated macrophages and monocytes was identified by the presence of CD68- and CD14-positive cells, respectively(Fig 3, panel B, left and right, respectively). Furthermore, the presence of increased immunostaining for tissue factor from cells derived from the LVAD surface(Fig 3, panel C) suggested enhanced procoagulant activity in this setting. In contrast, there was no staining with antibody to smooth muscle actin or nonimmune immunoglobulin G(Fig 3, panel D, left and right, respectively).
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Discussion |
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Previous investigators have suggested that the procoagulant response of LVAD recipients may largely reflect a generalized perioperative inflammatory reaction. 18 Our data, however, indicate that the initial perioperative peak in markers of procoagulant activity resolves by postoperative day 7 and thus may represent overt indices of thrombin generation and fibrinolysis that are acute and procedure related. We propose that this initial rise may indeed reflect systemic responses to a variety of procoagulant stimuli, including the operation itself, in addition to contact between blood components and foreign surfaces associated with the cardiopulmonary bypass circuit and the LVAD. 27,28
Others have further suggested that these perioperative procoagulant abnormalities may persist throughout the period of LVAD support. In contrast, by prospectively evaluating time-dependent changes in this prothrombotic phenotype, we have demonstrated that activation of coagulation and fibrinolysis in patients supported with an LVAD is biphasic. An initial perioperative increase in markers of activation of coagulation and fibrinolysis is followed by a progressive decline in these parameters by day 7 after LVAD placement. Subsequently, a steady increase in hemostatic markers occurs, with peak levels observed by day 35 of treatment. Beyond this period, sustained thrombin generation and fibrinolysis were found in patients having an LVAD.
We propose that this biphasic phenomenon reflects 2 separate procoagulant stimuli. The initial rise in procoagulant markers likely reflects a generalized perioperative response. The later, more gradual rise, however, may result from progressive population of the LVAD surface with cells whose adherence and subsequent activation account for a localized procoagulant microenvironment that ultimately can generate a progressive, sustained systemic effect.
Interestingly, this effect, manifested in elevated plasma levels of tissue factor, was paralleled by increased tissue factor surface expression on cells harvested from the LVAD surface. Furthermore, this was correlated not only by the ability of these cells to secrete tissue factor, but also with their functional procoagulant activity. Taken together, these findings supported the contention that the progressive population of the LVAD surface by monocytic cells that themselves maintained procoagulant activity accounted for the systemic prothrombotic profile.
Characterization of the cells populating the LVAD surface by immunohistochemistry to localize this response revealed evidence of pluripotent hematopoietic stem cells (CD34), as well as monocytes (CD14) and activated macrophages (CD68). All of these cells demonstrated cell-surface expression of tissue factor. Although these findings were suggestive of the integral role of the LVAD cell surface in the activated dynamic microenvironment we had hypothesized, we chose to further evaluate these cells by RT-PCR for confirmation of cellular activation.
The RT-PCR findings of increased proinflammatory cytokine and adhesion molecule expression suggested 2 important phenomena. First, the finding of increased proinflammatory cytokines (IL-1, TNF-) support our contention that these cells maintain the ability to propagate the proinflammatory/procoagulant microenvironment both locally and systemically. Furthermore, the findings of enhanced proinflammatory adhesion molecule expression (vascular cell and intercellular adhesion molecules) additionally provides a mechanism for triggering the further recruitment of inflammatory/ immune effector cells, thus propagating cellular activation on the LVAD.
Taken together, these data suggest that considerable interactions between the LVAD surface cells and the host are occurring throughout the time course of LVAD implantation. We postulate that the mononuclear cells, platelets, and pluripotential stem cells initially trapped by the polyurethane surface—not the titanium housing or Dacron grafts—become activated, thus leading to the generation of a local proinflammatory/procoagulant state responsible for triggering and subsequently sustaining the systemic activation of the coagulation and fibrinolytic cascades. Furthermore, inflammatory cells present on the LVAD surface appear to demonstrate production of proinflammatory cytokines and expression of adherence molecules that promote cell activation, as well as facilitate recruitment of other cell types from the circulating blood, thereby sustaining immune alterations. 29 Our observation that monocyte-derived macrophages seeded on the LVAD surface generate tissue factor, a cell-associated and released form, suggests a direct mechanism for activation of coagulation. This is consistent with the presence of tissue factor antigen in the plasma of patients with LVADs and suggests a mechanism for disseminating the locally intense inflammatory and procoagulant stimuli in the LVAD milieu.
We believe, therefore, that the biology of cells on the LVAD surface resembles a "two-hit" phenomenon, in which the initial placement of the device first results in recruitment of adherent cells (initially CD34+ pluripotent hematopoietic cells and monocytes). Subsequently, these cells undergo differentiation and activation with the capacity to recruit other cells (dendritic-type cells and lymphocytes), thereby sustaining and expanding the local host response. The extent to which the cells populating the LVAD surface actually contribute to this environment is not absolutely determined, however, underlying the major limitation of these studies. It is possible that the device itself promotes coagulation and inflammation independently of these cells, or that the contribution of these cells is relatively minor. Nonetheless, the implantable LVAD clearly emerges as an immune-inflammatory organ, modulating multiple effector systems including coagulation and immune mechanisms with important physiologic implications for its host.
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Appendix: Discussion |
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In the current studies they attribute this sustained response to the selective absorption and activation of dendritic-type and monocytic cells by the textured surface. They have demonstrated elevated peripheral levels of prothrombin fragments, thrombin–antithrombin III complexes, and D-dimers, as well as increased tissue factor activity. Cells scraped from the LVAD surface demonstrated activation by the presence of cytokines and adhesion molecules, and there was strong evidence of immunoregulatory dysfunction characterized by T- and B-cell markers.
In the abstract they suggested that these findings would importantly affect their ability to perform heart transplantation in these patients and perhaps lead to an increased incidence of infection. However, I fail to find in the manuscript or the presentation any clear correlation of these events in the 20 patients described. Therefore, my questions relate primarily to clinical correlates of these events.
Dr Spanier. Thank you, Dr Pennington, for all of those questions. In this presentation, we have described the initial studies that were done at Columbia, which focused on the observed procoagulant phenotype in our LVAD population. Furthermore, we have defined both the proinflammatory and immunoregulatory dysfunction that we have found in our patients with LVADs, both of which have important impact on their clinical management.
The clinical implications of this described procoagulant phenotype or compensated coagulopathy have the advantage of a systemic auto-anticoagulation that allowed these patients to have been maintained without any systemic anticoagulation. However, this compensated coagulopathy, in which there is a delicate balance between thrombin generation and fibrinolysis, presents a potential for any proinflammatory stress to tip this balance toward potential disaster. Either an infection or a proinflammatory stress may be the culprit. The patients are perhaps most vulnerable at the time of LVAD explantation, when they undergo the further stress of cardiopulmonary bypass for their explant and, ideally, cardiac transplantation. At this time, this delicate balance certainly presents the potential for both thrombosis or hemorrhagic complications. The serious impact that these complications can have on these patients has been our main impetus to understand this phenomenon better, so that we can modulate these effects.
To answer your questions specifically: With regard to infections, we at Columbia have described the clinical phenomenon of elevated anti-HLA antibodies, both class I and class II, that develop progressively in these patients over the time course of LVAD implantation. We found that specifically the type 1 antibodies, which are those that are reflected in the panel reactive antibody, do not seem to be correlated with blood transfusions, as was previously thought. However, they do seem to be correlated with the time and duration of LVAD implantation, suggesting that there is a host-device interaction causing the production of these antibodies.
We also find that these patients seem to harbor T-cell defects, which may make them more susceptible to opportunistic infections. We are studying these patients in the hope of understanding these problems and modulating the surface such that we can protect the patients while allowing them to maintain the favorable state of autoanticoagulation.
I think that this also addresses your second question, which concerned the late bleeding complications that develop with this compensated coagulopathy. The patients are all at risk for late bleeding complications, especially during transplantation, when they receive aprotinin as an antifibrinolytic agent to attenuate this response.
At our institution, we have started using aspirin as the anticoagulant in these patients. Our specific reason for doing this, and I think this answers your last question, is that aspirin acts in high doses as a nuclear factor 
B inhibitor. We believe that the mechanism of cellular activation at the LVAD surface is dependent on nuclear factor B. Inhibition of nuclear factor B with aspirin, therefore, may attenuate these responses. Interestingly, in initial clinical trials in patients who have been treated with aspirin starting in the immediate postimplantation period, we found that these patients maintain the systemic autoanticoagulation, but their immunoregulatory dysfunction, specifically the production of anti-HLA antibodies, seems to be attenuated with aspirin. By defining and understanding these host-device interactions on the LVAD surface, therefore, we hope we will be able to maintain the favorable state of autoanticoagulation while modulating the more dangerous outcomes, such as the potential for thrombin generation, thrombosis, and hemorrhage. We also hope to control the immunoregulatory dysfunction that may make transplantation difficult in these patients because of elevated panel reactive antibody, which also may impact on post-transplantation outcome.
Dr Roland Hetzer (Berlin, Germany). The findings from this study are in close agreement with our results as to the inflammatory response with the LVAD that were presented by my coworker, Dr Loebe, at the recent meeting of the American Society for Artificial Internal Organs (ASAIO). Our results showed that this response is very similar in the Novacor (Baxter Healthcare Corp, Novacor Div, Oakland, Calif), as well as in the TCI devices and in our Berlin Heart system (Mediport, Berlin, Germany), and may be less related to the type of device than to the degree of multiorgan failure and blood trauma. The findings also underline the previous experience that it is mandatory to overcome the inflammatory reaction before good results at transplantation can be achieved. I have 3 questions.
Dr Spanier. Thank you for your comments and for bringing out the fact that this phenomenon has been described, although at different levels, in all types of the devices that are implanted, whether smooth or textured surface. This fact highlights the importance of understanding not just the textured surface but the overall host-device interactions with the implantable LVAD, as well as implantable heart replacements.
In answer to your question regarding highly sensitized patients: A great deal of information was presented at the recent International Society for Heart and Lung Transplant meeting about treatment of the highly sensitized patients. This included not just patients with a textured-surface LVAD, but smooth-surface LVADs as well. The highly sensitized patient does need special peritransplantation treatment. Intravenous immunoglobulin treatment and photopheresis have been suggested as efficacious measures.
Concerning the stimulation of the inflammatory response at the LVAD surface, we believe that it is not just the reaction at the textured surface, but that it is the inflammatory response to the implantation of the device that we must better understand.
Your third question addresses the low incidence of thromboembolic complications in the TCI LVAD. We believe that the autoanticoagulation with the TCI LVAD is probably most significantly related to macrophages that populate the textured-surface LVAD and express procoagulant tissue factor, thereby initiating the compensated coagulopathy. That is likely what distinguishes the textured surface from the other devices and allows this autoanticoagulation in that setting. This phenomenon does not appear to be present in smooth-surface devices.
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Footnotes |
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Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.
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. J Exp Med 1995;182:1111-20.This article has been cited by other articles:
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