in Left Ventricular Assist Device Recipients
Ranjit John,
MD,
Sandhya Panch,
MBBS,
Jennifer Hrabe,
BS,
Peng Wei,
MPH,
Anna Solovey,
PhD,
Lyle Joyce,
MD, PhD,
and Robert Hebbel,
MD
Division of Cardiothoracic Surgery, Department of Surgery and Division of Hematology, University of Minnesota, Minneapolis, Minnesota
Background. The paucity of organ donors has necessi-tated 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 complica-tions 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, intercellu-lar adhesion molecule, and tissue factor on circulating endothelial cells, thrombin generation (prothrombin fragments 1,2 and thrombin/antithrombin), and fibrino-lysis (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 mol-ecule, E-selectin, tissue factor, thrombin/antithrombin, and D-dimer were significantly higher in LVAD rec-ipients than the normal range. Markers of thrombin generation (thrombin/antithrombin and prothrombin
fragments 1,2) and fibrinolysis (D-dimer) peaked postop-eratively and declined to baseline levels or below by 3 months. But the expression of inducible endothelial markers (intercellular adhesion molecule, E-selectin, tis-sue 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 throm-bin/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 recip-ients 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.
(Ann Thorac Surg 2009;88:1171–9) © 2009 by The Society of Thoracic Surgeons
L
eft ventricular assist device (LVAD) placement is anestablished 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 im-proved results. Nonetheless, hemorrhagic and thrombo-embolic 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
selec-tion, and recipient care have improved outcomes, yet the
incidence of hemorrhagic and thromboembolic compli-cations 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 dimen-sion to the hemorrhagic and thromboembolic risks inher-ent with LVAD recipiinher-ents. The need for anticoagulation with the newer devices imposes a bleeding risk through-out LVAD support and does increase the risk of bleeding at the time of the cardiac transplant. However, discon-tinuation of anticoagulation (for a variety of reasons) could potentially increase the thromboembolic risks.
Previous studies have demonstrated various coagula-tion and hemostatic abnormalities in LVAD recipients, such as hypercoagulation, fibrinolysis, and increased
platelet activation[7–11]. Abnormalities in the
coagula-tion, 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 dysfunc-tion exists in patients with heart failure. Prolonged or 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; e-mail:johnx008@umn.edu.
© 2009 by The Society of Thoracic Surgeons 0003-4975/09/$36.00
Published by Elsevier Inc doi:10.1016/j.athoracsur.2009.06.095
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repeated exposure to cardiovascular risk factors or the presence of cardiovascular disease can ultimately ex-haust the protective effect of endogenous antiinflamma-tory 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 estab-lishes 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 sys-tems 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
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 institu-tional protocols. Monitoring included standard modali-ties (electrocardiogram, temperature, invasive blood pressure, pulse oximetry, and gas monitoring) plus cen-tral venous pressure or pulmonary artery catheter mon-itoring and transesophageal echocardiography. Ap-rotinin was used for repeat sternotomy procedures;
ε-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, anticoagula-tion was reversed with protamine. All 28 study patients were monitored with continuous telemetry until their discharge from the hospital.
Fig 1. Circulating endothelial cells (CECs) in blood enumerated by immunohistochemical staining of buffy-coat smears. Surface pheno-type was evaluated by immunofluorescence microscopy of circulating endothelial cell preparations. (DAPI⫽ 4’,6-diamidino-2-phenylindole.)
Fig 2. Measured study markers in relation to the coagulation cas-cade. (ICAM⫽ intercellular adhesion molecule; PF 1⫹2 ⫽ pro-thrombin fragments 1,2; TAT⫽ thrombin/antithrombin III; VCAM ⫽ vascular cell adhesion molecule; vWA⫽ von Willebrand antigen.)
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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 out-put 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
cen-trifugal pump with hydrodynamic bearings and an elec-tromagnetically 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
Fig 3. Baseline hematologic data between the two types of left ventricular assist devices. (HM II⫽ HeartMate II; INR ⫽ international normal-ized ratio.)
Table 1. Patient Demographics
Variable Total HM II VentrAssist p Value
Number 21 11 10
Age (y) 55.9⫾ 13.5 56.2⫾ 14.9 55.6⫾ 12.7 0.92
Sex Males: 81% (17/21) Males: 82% (9/11) Males: 80% (8/10) 0.31
Diagnosis Ischemic cardiomyopathy (86%) 100% 70% 0.05
Baseline EF 0.206⫾ 0.0883 0.227⫾ 0.109 0.186⫾ 0.060 0.34
Baseline creatinine (mg/dL) 1.46⫾ 0.57 1.5⫾ 0.6 1.4⫾ 0.6 0.62
EF⫽ ejection fraction; HM⫽ HeartMate.
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aortic valve opening. We optimize the revolutions per minute speed, both hemodynamically and echocardio-graphically, at the time of LVAD placement, before the patient is discharged from the hospital (ie, after admis-sion 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 biven-tricular pacing settings. All patients underwent a stan-dard 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 adhe-sion molecule 1 (ICAM-1) or vascular-cell adheadhe-sion mole-cule 1 (VCAM-1; South Biotechnology, Birmingham, AL); and murine monoclonal antibodies against E-selectin (Gen-zyme, 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,
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). Table 2. Mean Values of Tests for Cases a Test Normal Values Day 0 (preop) Day 1 (postop) Day 7 (postop) Day 30 Day 90 Day 180 Mixed Model Time Trends Plasma Hb (mg/dL) ⬍ 15 7.5 ⫾ 1.6 3.7 ⫾ 0.9 3.0 ⫾ 0.7 7.6 ⫾ 0.9 12 ⫾ 4.6 7.9 ⫾ 0.6 No change Platelets (⫻ 10 6/L) 150–450 223.7 ⫾ 26.7 142 ⫾ 13 b 267.4 ⫾ 27 318.5 ⫾ 26.1 b 267.6 ⫾ 13.4 231.8 ⫾ 18 Cubic INR 0.8–1.2 1.3 ⫾ 0.06 1.4 ⫾ 0.03 1.9 ⫾ 0.1 b 2.0 ⫾ 0.16 b 2.0 ⫾ 0.17 b 2.0 ⫾ 0.12 b Linear APTT (s) 25–35 39.5 ⫾ 2.5 38.35 ⫾ 1.0 .. . 42.6 ⫾ 1.9 39.7 ⫾ 1.9 39.1 ⫾ 1.3 Quadratic CECs (cells/mL) 2.6 ⫾ 1.6 (0–5) 3.7 ⫾ 0.91 5.37 ⫾ 1.6 6.12 ⫾ 1.46 5.76 ⫾ 1.41 3.72 ⫾ 1.99 2.8 ⫾ 0.97 No change VCAM-1 (%) 13 ⫾ 3 49.89 ⫾ 3.24 56.52 ⫾ 4.86 73.3 ⫾ 4.79 b 54.3 ⫾ 4.23 48.2 ⫾ 6.43 53.38 ⫾ 5.53 Cubic E-selectin (%) 2 ⫾ 5 53.36 ⫾ 4.5 65.42 ⫾ 4.59 b 73.78 ⫾ 3.01 b 58.33 ⫾ 5.2 52.5 ⫾ 7.1 65.62 ⫾ 5.19 Cubic ICAM (%) 25 ⫾ 15 55.3 ⫾ 4.5 55 ⫾ 4.7 69.9 ⫾ 4.33 62.5 ⫾ 4.66 63.68 ⫾ 4.92 62.75 ⫾ 6.56 No change TF (%) 10 ⫾ 13 57.06 ⫾ 4.68 70.52 ⫾ 4.05 78.5 ⫾ 3.66 b 54.75 ⫾ 4.95 50.25 ⫾ 4.58 76 ⫾ 7.79 Cubic TAT ( g/L) 1–4.1 10.3 ⫾ 2.04 18.5 ⫾ 2.3 b 11.2 ⫾ 1.12 7.32 ⫾ 1.06 5.55 ⫾ 0.58 8.1 ⫾ 2.25 Cubic PF 1⫹ 2 (nmol/L) 0–0.22 0.3 ⫾ 0.03 0.48 ⫾ 0.06 b 0.5 ⫾ 0.08 b 0.3 ⫾ 0.03 0.2 ⫾ 0.02 0.24 ⫾ 0.05 Cubic VWA (%) 55–160 183.09 ⫾ 8.94 216.8 ⫾ 10.79 b 267.87 ⫾ 10.29 b 170.7 ⫾ 10.3 168.2 ⫾ 11.4 146.8 ⫾ 16.4 Cubic D-dimer (FEU/mL) ⬍ 0.5 2.1 ⫾ 0.45 1.77 ⫾ 0.24 5.94 ⫾ 0.71 b 4.27 ⫾ 0.61 b 1.9 ⫾ 0.22 1.89 ⫾ 0.42 Quadratic aValues are mean ⫾ standard error of the mean. bSignificantly dif ferent from baseline values (p ⬍ 0.01). APTT ⫽ activated partial thromboplastin time; CECs ⫽ circulating endothelial cells; FEU ⫽ fibrinogen equivalent units; Hb ⫽ hemoglobin; ICAM ⫽ intercellular adhesion molecule; INR ⫽ international normalized ratio; PF 1⫹ 2 ⫽ prothrombin fragments 1,2; postop ⫽ postoperative; preop ⫽ preoperative; TAT ⫽ thrombin/antithrombin III; TF ⫽ tissue factor; VCAM ⫽ vascular cell adhesion molecule; VWA ⫽ von Willebrand antigen. ADULT CARDIAC
MO); rhodamine-conjugated goat anti-rabbit immunoglob-ulin (Jackson IRL); and alkaline phosphatase–conjugated antimouse immunoglobulin (Sigma or Chemicon Interna-tional, Temecula, CA).
The serum markers measured included prothrombin frag-ment 1.2 monoclonal antibody (Behring kit); von Willebrand factor (BCS VWA LIA ASSAY; using STAGO KIT:LIATEST); D-dimers, (Diagnostica Stago STA-R); and thrombin/ antithrombin III complexes (enzyme-linked immunosorbent
assay test). These four tests were performed at the clinical laboratory of the University of Minnesota Medical Center, Fairview, MN, according to standard methods.
The measured study markers in relation to the
coagu-lation cascade have been depicted inFigure 2.
Statistical Analysis
The changes in the biomarker levels with time were studied by using a linear mixed model with random
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).
Table 3. Mean Values for Control Subjectsa
Test Normal Values Day 0 (preop) Day 1 (postop) Day 7 (postop) Day 30 (postop)
CECs (cells/mL) 2.6⫾ 1.6 (0–5) 0.5⫾ 0.29 2.25⫾ 0.75 3⫾ 1.73 . . . VCAM-1 (%) 13⫾ 3 48.25⫾ 1.75 45.25⫾ 3.35 51.5⫾ 4.11 0 E-selectin (%) 2⫾ 5 30⫾ 10.64 45⫾ 3.32 41.5⫾ 4.35 48 ICAM (%) 25⫾ 15 39.33⫾ 3.18 46.33⫾ 8.67 49.67⫾ 4.33 33.2 TF (%) 10⫾ 13 36.67⫾ 5.24 32.67⫾ 2.03 63.67⫾ 5.21 23 TAT (g/L) 1–4.1 9.88⫾ 2.32 16.63⫾ 3b 6.28⫾ 1.08 3.8 PF 1⫹2 (nmol/L) 0–0.22 0.26⫾ 0.04 0.35⫾ 0.08 0.34⫾ 0.04 0.24 VWA (%) 55–160 134.67⫾ 12.6 206.87⫾ 18.2b 227.67⫾ 33.96b 160 D-dimer (FEU/mL) ⬍0.5 0.78⫾ 0.48 0.57⫾ 0.11 0.22⫾ 0.34b 0.4
aValues are mean⫾ standard error of the mean. bSignificantly different from baseline values (p⬍ 0.01).
CECs⫽ circulating endothelial cells; FEU⫽ fibrinogen equivalent units; ICAM⫽ intercellular adhesion molecule; PF 1⫹2 ⫽ prothrombin
fragments 1,2; postop⫽ postoperative; preop⫽ preoperative; TAT⫽ thrombin/antithrombin III; TF⫽ tissue factor; VCAM⫽ vascular
cell adhesion molecule; VWA⫽ von Willebrand antigen.
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effects. The advantage of the mixed model over stan-dard analysis of variance is to take into account the correlations between repeated measurements within the same subject and estimate the effects of covariates (cases versus controls, device) using all available data. Linear mixed model analysis was carried out by using PROC MIXED procedures of SAS software V8.0 (SAS Institute, Inc, Cary, NC). Linear, quadratic, and cubic curves were fitted to the biomarker levels to model the changes with time. F tests were used to determine the specific parametric forms (horizontal line indicating constant with time, linear line with slope not equal to zero, and quadratic or cubic curves) as well as the significance of covariate effects (cases versus control and device difference among cases). Statistical tests with probability values less than 0.05 were considered significant.
Paired Student’s t test was used to compare postoper-ative levels in cases with their baseline (preoperpostoper-ative) levels. Because there were five postoperative measure-ments (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. Spe-cifically, a paired Student’s t test was considered signif-icant only if its probability value was less than 0.05/5, or 0.01.
Results
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 inTable 1andFigure 3.
Circulating Endothelial Cells and Endothelial
Activation
We saw no significant differences in the number of circulating endothelial cells in either our LVAD recipi-ents or our control patirecipi-ents, as compared with the normal
range (Fig 4; Tables 2 and 3). However, markers of
endothelial activation (including VCAM-1, ICAM, E-selectin, and TF) were all significantly higher at baseline in our LVAD recipients, as compared with our normal range and in our control patients. All these markers further peaked on postoperative day 7 and remained significantly elevated until postoperative day 180.
Fur-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).
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ther, there appeared to be a secondary rise in E-selectin
and TF in LVAD recipients (p ⬍ 0.05), suggesting a
biphasic response (Fig 5;Tables 2and3). All endothelial
dysfunction markers were significantly higher in LVAD
recipients than in control patients at each time point (p⬍
0.05). In our control patients, all markers except E-selectin returned to the normal range by postoperative
day 30 (Fig 5).
Serum Markers
Serum markers (including von Willebrand antigen, pro-thrombin fragment 1.2, D-dimers, and pro-thrombin/ antithrombin III) were all significantly higher at baseline in our LVAD recipients, as compared with the normal
range and our control patients (p ⬍ 0.05). All these
markers peaked on postoperative day 7 (except throm-bin/antithrombin III, which peaked on postoperative day 1) and remained significantly elevated until
postopera-tive day 90 (Fig 6;Tables 2and3). Similarly, in our control
patients, all these markers peaked between postoperative days 1 and 7; however, unlike in our LVAD recipients, all these markers returned to the normal range by
postop-erative day 30 (Fig 6).
Comment
The discrepancy between the limited availability of do-nor organs and the ever-increasing number of patients with heart failure has led to the increasing use of LVADs
[1]. The excellent medium-term results with LVADs have
led to the use of permanent LVAD placement for patients
with end-stage heart failure[2]. Nevertheless, the clinical
success of LVADs has been accompanied by significant complications, including thromboembolic and hemor-rhagic events in as many as 30% of recipients.
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
sys-tem, 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 veloc-ities of blood flow and blood stasis in the LVAD recipient
heart. Spanier and associates[15] described a
pheno-menon 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 circulat-ing endothelial cells expressed TF in sickle cell patients; this expression was further increased during vasoocclu-sive 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 hemo-static 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 abnor-malities 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 dysfunc-tion in LVAD recipients may be equally responsible for the coagulation abnormalities. Wilhelm and coworkers
[21]previously suggested a role for complement in
me-diating formation of leukocyte-platelet aggregates, thereby indirectly contributing to thrombin generation through monocyte TF expression.
Endothelial cell activation leads to increased expres-sion of inflammatory cytokines and adheexpres-sion 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 conse-quences 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.
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rent 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 interven-tions, 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 consis-tently examined the endothelial and coagulation alter-ations in our LVAD recipients with a variety of biomar-kers 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 procoagu-lant 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 conclu-sion, although previous reports have shown that the coagulation abnormalities in LVAD recipients were at-tributed to plasma protein adsorption and intrinsic path-way activation, this current study showed for the first time that activation of the extrinsic (TF) pathway of thro-mbosis mediated by sustained endothelial dysfunction in LVAD recipients may be equally responsible for the coagulation abnormalities. Continued and further under-standing of these abnormalities is essential to reduce adverse events after LVAD placement and thereby im-prove long-term outcomes. An imim-proved 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.
Ranjit John received funding for the study from the W. Gerald Austen Young Investigator Award, Society of Thoracic Surgeons.
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Notice From the American Board of Thoracic Surgery
The 2009 Part I (written) examination will be held onMonday, November 30, 2009. It is planned that the examination will be given at multiple sites throughout the United States using an electronic format. The closing date for registration was August 1, 2009. Those wishing to be considered for examination must apply online at www.abts.org.
To be admissible to the Part II (oral) examination, a candidate must have successfully completed the Part I (written) examination.
A candidate applying for admission to the certifying examination must fulfill all the requirements of the Board in force at the time the application is received.
Please address all communications to the American Board of Thoracic Surgery, 6333 N St. Clair St, Suite 2320, Chicago, IL 60611; telephone: (312) 202-5900; fax: (312) 202-5960; e-mail: info@abts.org.
© 2009 by The Society of Thoracic Surgeons Ann Thorac Surg 2009;88:1179 • 0003-4975/09/$36.00 Published by Elsevier Inc
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