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Original Articles: Adult Cardiac

Activation of Endothelial and Coagulation Systems in Left Ventricular Assist Device Recipients

^a Division of Cardiothoracic Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
^b Division of Hematology, University of Minnesota, Minneapolis, Minnesota

Accepted for publication June 25, 2009.

^_* Address correspondence to Dr John, Division of Cardiothoracic Surgery, University of Minnesota, 420 Delaware St SE, MMC 207, Minneapolis, MN 55455 (Email: johnx008{at}umn.edu).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background: The paucity of organ donors has necessitated redirecting research toward finding alternative means to a heart transplant, such as left ventricular assist devices (LVADs) that will serve not merely as bridge-to-transplant but also as destination therapy. To better understand hemorrhagic and thromboembolic complications that currently limit the use of such devices, we studied the endothelial and coagulation system changes in LVAD recipients with time.

Methods: We studied these markers of endothelial dysfunction: circulating endothelial cells and expression of E-selectin, vascular cell adhesion molecule, intercellular adhesion molecule, and tissue factor on circulating endothelial cells, thrombin generation (prothrombin fragments 1,2 and thrombin/antithrombin), and fibrinolysis (D-dimer). Our study group consisted of 21 LVAD recipients (on day 0 and on postoperative days 1, 7, 30, 90, and 180) and 7 control patients undergoing non-LVAD cardiac surgery.

Results: Baseline values of intercellular adhesion molecule, E-selectin, tissue factor, thrombin/antithrombin, and D-dimer were significantly higher in LVAD recipients than the normal range. Markers of thrombin generation (thrombin/antithrombin and prothrombin fragments 1,2) and fibrinolysis (D-dimer) peaked postoperatively and declined to baseline levels or below by 3 months. But the expression of inducible endothelial markers (intercellular adhesion molecule, E-selectin, tissue factor) on circulating endothelial cells increased postoperatively, then decreased but remained elevated above preoperative levels for up to 6 months. In our control patients, baseline levels of intercellular adhesion molecule, E-selectin, tissue factor, D-dimer, and thrombin/antithrombin were lower and decreased significantly by day 7, as compared with LVAD recipients (p < 0.05).

Conclusions: Left ventricular assist device recipients experienced significant baseline activation of endothelial and coagulation systems, further accentuated in the early postoperative period. Left ventricular assist device recipients also had prolonged activation of the endothelial and coagulation systems, suggesting activation of the extrinsic (tissue factor) pathway of thrombosis mediated by sustained endothelial dysfunction in these patients. Further studies are needed to determine the clinical influence of such changes in LVAD recipients.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Left ventricular assist device (LVAD) placement is an established therapy for patients with end-stage heart failure both as bridge-to-transplant and destination therapy [1, 2]. In the last several years, the application of LVADs has markedly increased, with significantly improved results. Nonetheless, hemorrhagic and thromboembolic complications still have a major impact on the success of LVAD therapy [3, 4]. The intraoperative and postoperative requirements for (often extensive) blood product usage can lead to decreased right ventricular function [5]. Further, the use of blood products may be related to the development of sensitization, which not only affects survival in heart transplant patients but also significantly increases the waiting time for a transplant [6]. Improvements in surgical technique, patient selection, and recipient care have improved outcomes, yet the incidence of hemorrhagic and thromboembolic complications has recently been reported to be as high as 30%.

Moreover, the requirement of anticoagulation for the newer LVAD rotary pumps has added a different dimension to the hemorrhagic and thromboembolic risks inherent with LVAD recipients. The need for anticoagulation with the newer devices imposes a bleeding risk throughout LVAD support and does increase the risk of bleeding at the time of the cardiac transplant. However, discontinuation of anticoagulation (for a variety of reasons) could potentially increase the thromboembolic risks.

Previous studies have demonstrated various coagulation and hemostatic abnormalities in LVAD recipients, such as hypercoagulation, fibrinolysis, and increased platelet activation [7–11]. Abnormalities in the coagulation, inflammatory, and complement systems have also been clearly recognized in patients undergoing cardiac surgery [12]. However, very little research on endothelial dysfunction has been done in LVAD recipients. It is widely established that significant endothelial dysfunction exists in patients with heart failure. Prolonged or repeated exposure to cardiovascular risk factors or the presence of cardiovascular disease can ultimately exhaust the protective effect of endogenous antiinflammatory systems within endothelial cells. As a result, not only does the endothelium become dysfunctional but also endothelial cells can lose integrity and detach into the circulation. Circulating markers of such endothelial cell damage include endothelial microparticles (derived from activated or apoptotic cells) and whole endothelial cells. A broader appreciation of the numerous functions of the endothelium can be obtained by studying the levels of molecules of endothelial origin in circulating blood [13].

As one of the fundamental homeostatic mechanisms of mammalian biology, the blood coagulation system establishes a delicate balance between the procoagulant and anticoagulant functions of blood and of the vessel wall, thereby guarding against excesses in either direction and, normally, preventing unwanted hemorrhage or thrombosis. The vascular endothelium and its various components, such as tissue factor (TF), play an integral role in this homeostasis. We herein report our study of the alterations in the endothelial and coagulation systems in LVAD recipients. The objectives of our study were to (1) identify changes in the endothelial system in LVAD recipients, (2) identify changes in their coagulation system, (3) determine trends in such changes during the course of LVAD support, and (4) compare such changes with those occurring in control patients who underwent non-LVAD cardiac surgery.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
We performed a prospective study of 21 unselected recipients undergoing LVAD placement at the University of Minnesota Medical Center, from July 1, 2006, through December 30, 2007. The study was approved by the University of Minnesota Institutional Review Board for Research on Human Subjects and conducted according to the Declaration of Helsinki. All patients provided written informed consent. Our exclusion criteria for the LVAD study recipients were a history of renal failure requiring dialysis, a requirement for ventilatory support, hepatic dysfunction resulting in coagulopathy, and biventricular failure requiring biventricular assist device support. We also studied a control group of 7 patients undergoing non-LVAD cardiac surgery.

In the LVAD recipients, we measured all markers as follows: on day 0 (preoperative or baseline levels) and on postoperative days 1, 7, 30, 90, and 180; in the control patients, on day 0, and on postoperative days 1, 7, and 30.

Treatment
Anesthetic and surgical care was given per our institutional protocols. Monitoring included standard modalities (electrocardiogram, temperature, invasive blood pressure, pulse oximetry, and gas monitoring) plus central venous pressure or pulmonary artery catheter monitoring and transesophageal echocardiography. Aprotinin was used for repeat sternotomy procedures; -aminocaproic acid, for first-time sternotomy procedures. Anticoagulation for non-LVAD cardiac surgery and LVAD placement consisted of 400 U/kg unfractionated porcine heparin. Standard techniques were used both for LVAD placement and for non-LVAD cardiac surgery. At the conclusion of cardiopulmonary bypass, anticoagulation was reversed with protamine. All 28 study patients were monitored with continuous telemetry until their discharge from the hospital.

Left Ventricular Assist Devices
HeartMate II left ventricular assist device
The HeartMate II (Thoratec Corp, Pleasanton, CA) consists of an internal blood pump with a percutaneous lead that connects the pump to an external system driver and power source. The pump has an implant volume of 63 mL and generates up to 10 L/min of flow at a mean pressure of 100 mm Hg. The inflow cannula is connected to the left ventricular apex; the outflow graft is connected to the ascending aorta. The pump has a rotor that is mobilized by an electromotive force generated by the motor. Pump output depends on the speed of the rotor and on the difference in pressures between the inflow and outflow cannulas.

VentrAssist left ventricular assist device
The VentrAssist (Ventracor, Sydney, Australia) is a third-generation centrifugal pump with hydrodynamic bearings and an electromagnetically driven impeller. The pump is treated with a diamond-like carbon coating on blood-contacting surfaces to enhance neointimalization. The pump is small and measures 67 mm in diameter and 298 grams; it can provide flows from 2 to 10 L/min with average pressure from 50 to 160 mm Hg. Similar to the HeartMate II, the inflow cannula is connected to the left ventricular apex; the outflow graft is connected to the ascending aorta.

Device Management
Per our local practice at the University of Minnesota, we usually adjust the fixed-rate speed of the continuous-flow LVADs (both HeartMate II and VentrAssist) to maximize left ventricular decompression and to improve cardiac output, simultaneously allowing for at least a 1:3 ratio of aortic valve opening. We optimize the revolutions per minute speed, both hemodynamically and echocardiographically, at the time of LVAD placement, before the patient is discharged from the hospital (ie, after admission for LVAD placement), and if clinical events (eg, new symptoms or suction events) warrant further adjustment.

Anticoagulation involved a combination of warfarin and aspirin for the continuous-flow groups. After LVAD placement, we did not change defibrillator and biventricular pacing settings. All patients underwent a standard postoperative rehabilitation program.

Blood Sampling and Biochemical Assays
Blood samples were drawn from patients on day 0 (baseline or preoperative levels) and on postoperative days 1, 7, 30, 90, and 180. After discarding the initial blood obtained from venipuncture, venous blood was collected in Vacutainer tubes (BD Vacutainer Systems, Franklin Lakes, NJ) containing EDTA (for endothelial cell analysis) and sodium citrate (for serum markers). We processed the blood samples immediately for study.

For endothelial studies, we used immunohistochemical examination of buffy-coat smears to enumerate circulating endothelial cells, and evaluated the surface phenotype by applying immunofluorescence microscopy to preparations of circulating endothelial cells. The panel of antibodies used included a specific anti–endothelial cell antibody (detecting CD-148), P1H12, polyclonal blocking antibody to TF (Fig 1; provided by Dr. Ron Bach, Veterans Affairs Administration Medical Center, Minneapolis, MN), fluorochrome-labeled murine monoclonal antibodies against intercellular adhesion molecule 1 (ICAM-1) or vascular-cell adhesion molecule 1 (VCAM-1; South Biotechnology, Birmingham, AL); and murine monoclonal antibodies against E-selectin (Genzyme, Cambridge, MA) We used secondary antibodies as required: goat antimouse immunoglobulin conjugated to Lissamine rhodamine (Jackson IRL, Westgrove, PA) or fluorescein isothiocyanate (Sigma Chemical Co, St. Louis, MO); rhodamine-conjugated goat anti-rabbit immunoglobulin (Jackson IRL); and alkaline phosphatase–conjugated antimouse immunoglobulin (Sigma or Chemicon International, Temecula, CA).

View larger version (28K): [in this window] [in a new window]   Fig 1. Circulating endothelial cells (CECs) in blood enumerated by immunohistochemical staining of buffy-coat smears. Surface phenotype was evaluated by immunofluorescence microscopy of circulating endothelial cell preparations. (DAPI = 4',6-diamidino-2-phenylindole.)

The measured study markers in relation to the coagulation cascade have been depicted in Figure 2.

View larger version (23K): [in this window] [in a new window]   Fig 2. Measured study markers in relation to the coagulation cascade. (ICAM = intercellular adhesion molecule; PF 1+2 = prothrombin fragments 1,2; TAT = thrombin/antithrombin III; VCAM = vascular cell adhesion molecule; vWA = von Willebrand antigen.)

Paired Student's t test was used to compare postoperative levels in cases with their baseline (preoperative) levels. Because there were five postoperative measurements (days 1, 7, 30, 90, 180), five paired Student's t tests were conducted for each marker. Bonferroni procedure was used to adjust for multiple hypothesis testing. Specifically, a paired Student's t test was considered significant only if its probability value was less than 0.05/5, or 0.01.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patient Characteristics
Of our 21 LVAD recipients, 11 received the HeartMate II, and 10 received the VentrAssist. Of our 7 control patients, 5 underwent coronary artery bypass grafting, and 2, valve replacement. The mean age of the LVAD recipients was 57 ± 3 years; control patients, 68 ± 2 years (p = 0.01). The percentage of males among the LVAD group was 82% (18 of 22); control group, 85.8% (6 of 7; not significant). Baseline demographic data as well as hematologic data for LVAD recipients for each of the two device types are presented in Table 1 and Figure 3.

View larger version (17K): [in this window] [in a new window]   Fig 3. Baseline hematologic data between the two types of left ventricular assist devices. (HM II = HeartMate II; INR = international normalized ratio.)

View larger version (18K): [in this window] [in a new window]   Fig 4. Levels of circulating endothelial cells in 21 left ventricular assist device recipients (day 0 and postoperative days 1, 7, 30, 90, and 180) and in 7 control patients undergoing non–left ventricular assist device cardiac surgery (day 0 and postoperative days 1, 7, and 30).

View larger version (26K): [in this window] [in a new window]   Fig 5. Markers of endothelial activation (intercellular adhesion molecule [ICAM], vascular cell adhesion molecule [VCAM], E-selectin, tissue factor) in 21 left ventricular assist device recipients (day 0 and postoperative days 1, 7, 30, 90, and 180) and in 7 control patients undergoing non–left ventricular assist device cardiac surgery (day 0 and postoperative days 1, 7, and 30).

View larger version (27K): [in this window] [in a new window]   Fig 6. Serum markers (von Willebrand antigen, prothrombin fragments 1,2, D-dimers, and thrombin/antithrombin III) in 21 left ventricular assist device recipients (day 0 and postoperative days 1, 7, 30, 90, and 180) and in 7 control patients undergoing non–left ventricular assist device cardiac surgery (day 0 and postoperative days 1, 7, and 30).

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

The development of novel materials used for implant surgery and the increasing use of implanted devices has made it evident that no material is biologically inert. Commonly used biomaterials, so-called inert compounds such as titanium, polytetrafluoroethylene, and acrylics, may trigger an array of iatrogenic effects, including inflammation, fibrosis, coagulation, and infection.

In the case of LVADs, in which the biomaterial is in direct contact with the blood circulation, significant changes in systemic immunologic and thrombostatic functions have been well documented. Like most other implanted devices, LVADs activate the coagulation system, resulting in device-related thrombus [7, 14]. The major reasons for this are (1) the contact between blood components and the foreign surfaces of the LVADs and (2) the altered rheologic conditions with different velocities of blood flow and blood stasis in the LVAD recipient heart. Spanier and associates [15] described a phenomenon of a "compensated coagulopathy" underlying the apparent autoanticoagulation in textured-surface HeartMate XVE recipients, attributing this finding to procoagulant stimuli elicited from the LVAD cell-surface environment. Some investigators suggested that such activation of anticoagulation was attributable largely to the continuous contact of blood with the foreign LVAD surface; however, others showed that specific cells that progressively adhere to the textured LVAD surface and become activated may also contribute to the coagulopathy [16, 17].

Our study demonstrated significant activation of both the endothelial and the coagulation systems in patients with end-stage heart failure requiring LVAD placement. In addition, the findings from our current study extend others' previous observations of significant activation of the procoagulant as well as fibrinolytic pathways in LVAD recipients. We clearly demonstrated that these serum procoagulant and fibrinolytic markers returned to baseline levels by postoperative days 30 to 90. In contrast to the coagulation system, we found persistent activation of the endothelial system up to postoperative day 180.

Hebbel and colleagues [18] found activation of the vascular endothelium in patients with sickle cell disease. They also showed that an increased number of circulating endothelial cells expressed TF in sickle cell patients; this expression was further increased during vasoocclusive episodes. The TF expressed on the antigen-positive circulating endothelial cell is functional, as demonstrated by a binding assay for factor VIIa and a chromogenic assay sensitive to generation of factor Xa [19, 20]. Before this latter study, the role of the vascular endothelium in activating the coagulation system was uncertain because there is little evidence indicating that endothelial cells in vivo express TF, the system's triggering mechanism. By establishing that endothelial cells in vivo can express TF, the study demonstrated that the vast endothelial surface can provide an important pathophysiologic trigger for coagulation activation. Until now, studies of the hemostatic alterations associated with LVADs showed elevated thrombin generation in the early postoperative period, with increased thrombin activity and fibrinolysis throughout the course of LVAD support. Those abnormalities were attributed to plasma protein adsorption and intrinsic pathway activation. Our current study showed a late secondary rise in TF, demonstrating for the first time that activation of the extrinsic (TF) pathway of thrombosis mediated by sustained endothelial dysfunction in LVAD recipients may be equally responsible for the coagulation abnormalities. Wilhelm and coworkers [21] previously suggested a role for complement in mediating formation of leukocyte-platelet aggregates, thereby indirectly contributing to thrombin generation through monocyte TF expression.

Endothelial cell activation leads to increased expression of inflammatory cytokines and adhesion molecules that trigger leukocyte homing, adhesion, and migration into the subendothelial space, processes fundamental to cardiovascular disease in general. Well-characterized molecules that can be measured in the circulation with commercial microassays include E-selectin, VCAM, ICAM, and P-selectin. Similarly, the procoagulant consequences of endothelial activation can be measured and include tissue plasminogen activator and von Willebrand factor. Circulating endothelial cells that detach in the context of endothelial activation and loss of integrity can be measured in the circulation by flow cytometry. Current evidence suggests that endothelial function is an integrative marker of the net effects of damage on the cardiovascular system. Importantly, strategies to reverse endothelial function have now been examined in a wide range of patients with cardiovascular disease. Benefit has been shown with a number of pharmacologic interventions, which include drugs that lower lipids and blood pressure, as well as with novel therapies based on new understanding of endothelial biology. These have mostly shown that recovery of endothelial function occurs in response to strategies known to reduce cardiovascular events [22–26]. More recently, it has been shown that clopidogrel may improve endothelial dysfunction in patients with coronary artery disease independent of changes in platelet oxidative stress and platelet-derived nitric oxide availability favoring direct stimulating effects on the endothelium [27]. Combining different agents, such as statins and clopidogrel, may have synergistic effects on endothelial cell dysfunction [28]. Whether these data can be applied to benefit LVAD recipients is unknown.

Our single-center study was limited by its relatively small number of patients. Also, we were not able to follow up our control patients for more than 1 month. However, it should be noted that other than E-selectin, all other biomarkers tested in control patients returned to normal levels by 1 month. In addition, we did not have a large enough sample size to adjust for the effect of medications (primarily warfarin). However, all of our LVAD recipients underwent LVAD placement during a relatively short period (1 year), so their perioperative treatment protocols were consistent. And, we consistently examined the endothelial and coagulation alterations in our LVAD recipients with a variety of biomarkers at different times during a 6-month period. We were also able to compare these alterations in our LVAD recipients with those of our control patients during the first month.

The exact clinical implications for LVAD recipients of our findings remain uncertain. Certainly, a larger study would help validate our findings; a sufficient sample size would possibly be able to correlate clinical events such as bleeding and thromboembolism with changes in the endothelial and coagulation systems. The significant baseline activation that we found suggests a procoagulant tendency in patients even before LVAD placement. The decline of serum prothrombotic markers to or below baseline levels with time may reflect a lower requirement of anticoagulation in some LVAD recipients. In conclusion, although previous reports have shown that the coagulation abnormalities in LVAD recipients were attributed to plasma protein adsorption and intrinsic pathway activation, this current study showed for the first time that activation of the extrinsic (TF) pathway of thrombosis mediated by sustained endothelial dysfunction in LVAD recipients may be equally responsible for the coagulation abnormalities. Continued and further understanding of these abnormalities is essential to reduce adverse events after LVAD placement and thereby improve long-term outcomes. An improved understanding may even allow potential therapeutic interventions in a timely fashion so as to decrease the incidence of bleeding and thromboembolic complications in high-risk patients.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Ranjit John received funding for the study from the W. Gerald Austen Young Investigator Award, Society of Thoracic Surgeons.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Frazier OH, Rose EA, Oz MC, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation J Thorac Cardiovasc Surg 2001;122:1186-1195.[Abstract/Free Full Text]
2. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-stage heart failure N Engl J Med 2001;345:1435-1443.[Medline]
3. Gross DR. Concerning thromboembolism associated with left ventricular assist devices Cardiovasc Res 1999;42:45-47.[Free Full Text]
4. Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices N Engl J Med 1998;339:1522-1533.[Medline]
5. Kavarana MN, Pessin-Minsley MS, Urtecho J, et al. Right ventricular dysfunction and organ failure in left-ventricular assist device recipients: a continuing problem Ann Thorac Surg 2002;73:745-750.[Abstract/Free Full Text]
6. John R, Lietz K, Naka Y, et al. Immunologic sensitization in recipients of left ventricular assist devices J Thorac Cardiovasc Surg 2003;125:578-591.[Abstract/Free Full Text]
7. Spanier TB, Oz MC, Levin HR, et al. Activation of coagulation and fibrinolytic pathways in patients with left ventricular assist devices J Thorac Cardiovasc Surg 1996;112:1090-1097.[Abstract/Free Full Text]
8. Hampton CR, Verrier ED. Systemic consequences of ventricular assist devices: alterations of coagulation, immune function, inflammation, and the neuroendocrine system Artif Organs 2002;26:902-908.[Medline]
9. Koster A, Loebe M, Hansen R, et al. Alterations in coagulation after implantation of a pulsatile Novacor LVAD and the axial flow MicroMed DeBakey LVAD Ann Thorac Surg 2000;70:533-537.[Abstract/Free Full Text]
10. Livingston ER, Fisher CA, Bibidakis EJ, et al. Increased activation of the coagulation and fibrinolytic pathways leads to hemorrhagic complications during left ventricular assist implantation Circulation 1996;94(Suppl2):II-227-II-234.
11. Himmelreich G, Ullmann H, Riess H, et al. Pathophysiologic role of contact activation in bleeding followed by thromboembolic complications after implantation of a ventricular assist device ASAIO J 1995;41:M790-M794.[Medline]
12. Edmunds Jr LH. Blood-surface interactions during cardiopulmonary bypass J Card Surg 1993;8:404-410.[Medline]
13. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction. Testing and clinical relevance. Circulation 2007;115:1285-1295.[Free Full Text]
14. Menconi MJ, Prockwinse S, Owen TA, Dasse KA, Stein GS, Lian GB. Properties of blood contacting surfaces of clinically implanted cardiac assist devices: gene expression, matrix composition, and ultra structural characterization of cellular linings J Cell Biochem 1995;57:557-573.[Medline]
15. Spanier TB, Chen JM, Oz MC, Stern DM, Rose EA, Schmidt AM. Time-dependent cellular population of textured-surface left ventricular assist devices contributes to the development of a biphasic systemic procoagulant response J Thorac Cardiovasc Surg 1999;118:404-413.[Abstract/Free Full Text]
16. Rose EA, Levin HR, Oz MC, et al. Artificial circulatory support with textured interior surfaces: a counterintuitive approach to minimize thromboembolism Circulation 1994;90(5 pt 2):II-87-II-91.
17. Graham TR, Dasse K, Coumbe A, et al. Neointimal development on textured biomaterial surfaces during clinical use of an implantable left ventricular assist device Eur J Cardiothoracic Surg 1990;4:182-190.[Abstract/Free Full Text]
18. Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia N Engl J Med 1997;337:1584-1590.[Medline]
19. Solovey A, Gui L, Key N, Hebbel RP. Tissue factor expression by endothelial cells in sickle cell anemia J Clin Invest 1998;101:1899-1904.[Medline]
20. Hebbel RP. Adhesive interactions of sickle erythrocytes with endothelium J Clin Invest 1997;99:2561-2564.[Medline]
21. Wilhelm CR, Ristich J, Kormos RL, Wagner WR. Monocyte tissue factor expression and ongoing complement generation in ventricular assist device patients Ann Thorac Surg 1998;65:1071-1076.[Abstract/Free Full Text]
22. Blann AD, Woywodt A, Bertolini F, et al. Circulating endothelial cells. Biomarkers of vascular disease. Thromb Haemost 2005;93:228-235.[Medline]
23. Boldt J, Kumle B, Papsdorf M, Hempelmann G. Are circulating adhesion molecules specifically changed in cardiac surgical patients? Ann Thorac Surg 1998;65:608-614.[Abstract/Free Full Text]
24. Gearing AJH, Newman W. Circulating adhesion molecules in disease Immunol Today 1993;14:506-512.[Medline]
25. Boos CJ, Lip GYH, Blann AD. Circulating endothelial cells in cardiovascular disease J Am Coll Cardiol 2006;48:1538-1547.[Abstract/Free Full Text]
26. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function and cardiovascular risk N Engl J Med 2003;348:593-600.[Medline]
27. Warnholtz A, Ostad MA, Velich N, et al. A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: Results of a double-blind, randomized study Atherosclerosis 2008;196:689-695.[Medline]
28. Bledsoe SL, Barr JC, Fitzgerald RT, et al. Pravastatin and clopidogrel combined inhibit intimal hyperplasia in a rat carotid endarterectomy model Vasc Endovascular Surg 2006;40:49-57.[Abstract/Free Full Text]

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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): Ranjit John Lyle Joyce Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by John, R. Articles by Hebbel, R. Search for Related Content PubMed PubMed Citation Articles by John, R. Articles by Hebbel, R. Related Collections Mechanical Circulatory Assistance