(Stroke. 1999;30:2554.)
© 1999 American Heart Association, Inc.
Original Contributions |
Measurement of Hemostatic Indexes in Conjunction With Transcranial Doppler Sonography in Patients With Ventricular Assist Devices
From the Department of Surgery (Cardiothoracic) and McGowan Center for Artificial Organ Development (C.R.W., J.R., R.L.K., W.R.W.), the Department of Bioengineering (C.R.W., W.R.W.), the Department of Neurology (L.E.K.), and the Department of Epidemiology (R.H., S.R.W.), University of Pittsburgh, Pittsburgh, Pa.
Correspondence to William R. Wagner, PhD, Department of Surgery, 328 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261. E-mail wagnerwr{at}msx.upmc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose—Clinical thromboembolism (TE) remains an impediment to the chronic application of ventricular assist devices (VADs). Microembolic signals (MES) have been detected by transcranial Doppler ultrasound (TCD) in patients with VADs, although their origin and relation to TE remain undefined. We have investigated the hypothesis that hemostatic alterations are related to MES and that MES are associated with TE in a group of 27 VAD patients.
Methods—Indexes of coagulation, fibrinolysis, and cellular activation and aggregation were measured before and during the VAD implantation period in conjunction with TCD. Groups were defined on the basis of presence of MES, degree of MES showering, and incidence of TE.
Results—MES were observed in 67 (58%) of 115 of individual postoperative TCD measurements and in 21 (78%) of 27 patients. Of patients with TE, 10 (83%) of 12 had detectable MES compared with 11 (73%) of 15 patients without TE (P=0.66). MES were significantly associated with elevated thrombin generation during the implantation period, as reflected by plasma prothrombin fragment F1.2. Elevations in indexes of coagulation, platelet activation, and fibrinolysis relative to normal control subjects were found for patients with VADs with and without detected MES.
Conclusions—Although no significant relation between MES and TE in VAD patients was found, the data support the hypothesis that MES are related to increased hemostatic activity in this patient group despite aggressive anticoagulant therapy.
Key Words: heart assist • flow cytometry • hemostasis • ultrasonography, Doppler, transcranial
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Transcranial Doppler ultrasound (TCD) has been used to measure microembolic signals (MES) during cardiopulmonary bypass and carotid endarterectomy and in patients implanted with prosthetic heart valves and ventricular assist devices (VADs). MES are consistently encountered during cardiopulmonary bypass, particularly after aortic cross-clamp release.1 2 An association between a higher rate of MES during surgery and postsurgical neurological dysfunction has been described in patients undergoing cardiopulmonary bypass.3 MES are frequently observed in patients with carotid endarterectomy, and postoperative cerebral ischemia has been associated with a high rate of MES during surgery and in the immediate postoperative period.4 5 In patients with prosthetic heart valves, asymptomatic MES are frequently detected, with the rate of MES dependent on valve type, number, and placement.6 7 Elevated levels of platelet activation, indicated by elevated plasma levels of the platelet
-granule release product
ß-thromboglobulin (ßTG), have been reported in
patients with prosthetic heart valves with MES and recurrent
cerebral ischemia.8 TCD observations of MES in patients with VADs are far less numerous in the literature. MES are consistently encountered in patients with VADs, but published results are inconclusive in demonstrating a definitive relation between MES rate and clinical neurological thromboembolism (TE). Several studies have reported elevated MES rates in patients with TE,9 10 whereas others have used TCD in patient groups that remained asymptomatic or that have sample populations too small to offer conclusions.11 12 Changes in hemostasis, fibrinolysis, and cellular aggregation after VAD implantation are well documented.13 14 15 However, no studies to date have measured indexes of coagulation, fibrinolysis, or cellular activation and aggregation simultaneously with TCD in patients with VADs to examine the possible role of hematologic perturbations in MES formation and precipitation of TE. With an incidence between 0% and 30%, dependent on device type and implantation center, TE remains a significant impediment to the chronic application of VADs.16 Considering the demonstrated utility and increasing use of VADs in maintaining patients with cardiomyopathy until heart transplantation, identification of mechanisms of TE is important in improving patient care and potentially decreasing the number of strokes in this patient population.
In the current study, thrombin generation, fibrinolysis, and platelet activation were measured in patients with VADs with the use of enzyme-linked immunosorbent assays (ELISAs). Whole-blood flow cytometry was used to measure platelet activation, monocyte-tissue factor expression (Mono-TF), and leukocyte-platelet conjugate formation in the same patient group. TCD measurements were made on the same postoperative days that blood samples were taken for ELISA and flow cytometry to test the hypothesis that MES in patients with VADs are related to perturbations in coagulation, fibrinolysis, platelet activation, or cellular aggregation caused by blood-biomaterial contact. The hypothesis that MES are related to TE was also tested in this patient group.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patient Selection
Over a 4-year period beginning in November 1993, a group of 27 patients (21 male, 6 female) scheduled for VAD implantation were entered into the study after informed consent was given (University of Pittsburgh Medical Center institutional review board No. 9505108 and No. 9506117). Twelve patients received the Novacor Left Ventricular Assist System (Baxter Healthcare) and 15 the Thoratec System (Thoratec Laboratories). Six of the patients with the Thoratec received both left and right ventricular support (BiVAD). The median time on device was 84 days (range 11 to 236) and the median age of participants was 49 years (range 15 to 68). The anticoagulation regimen after VAD implantation consisted of dextran at 6 to 8 hours after surgery. Heparin was started at 12 to 24 hours to maintain the activated partial thromboplastin time (PTT) at a target of 1.5 times the upper normal range (45 to 55 seconds); after chest tube removal and extubation (5 to 7 days after implantation), oral coumarin was started to maintain the international normalized ratio (INR) within a target range of 3.0 to 4.0. Oral antiplatelet agents were given to 25 out of the 27 patients in the study. Four patients received aspirin at 325 mg/d prophylactically, 12 received 81 mg/d prophylactically, and 6 were started on 81 mg/d after the first postoperative week. Three patients received 225 mg/d of persantine, and 2 patients were not given antiplatelet agents subsequent to a history of thoracic and gastrointestinal bleeding and epistaxis, respectively. The mean PTT for each postoperative day during the first week after implantation (while on heparin) and the mean INR for each postoperative day for the time period after the first week (after initiation of coumarin) were recorded. Suspected thromboembolic neurological events were confirmed by neurological consultation and, if necessary, computed tomographic scan and recording.
Transcranial Doppler Technique
Transcranial Doppler measurements were performed
before VAD implantation and on postoperative days 1 to 5, 7, 10, 15,
21, 28, 45, and 60. The right and left middle cerebral arteries were
isonated for 10 to 15 minutes each at a depth of 45 to 55 mm with
a 2-MHz probe (Medasonics Transpect-2000), with data recorded onto
videocassette for visual analysis by counting the total number
of emboli and calculating the mean MES rate (MES/min). The criteria for
identification of MES were those recommended by the Consensus Committee
of the Ninth International Cerebral Hemodynamic
Symposium.17 Briefly, MES were identified by their short
duration (<300 ms) and greater amplitude than the background blood
flow. They had a random appearance within the cardiac cycle and the
associated characteristic "snap" or "chirping" sound. All
patients had at least 1 TCD measurement, for a total of 123
measurements (8 preimplantation and 115 postimplantation). Patient
compliance was an issue with TCD measurements, with several patients
choosing not to continue in the study after only a few measurements.
Since some patients were discharged with the device during the
implantation period, and transplants occurred throughout this time, all
but 2 of the TCD measurements occurred within the first 30 days after
VAD implantation.
ELISA Technique
Commercial ELISA kits were used to quantify thrombin generation,
fibrinolysis, and platelet activation by
measurement of plasma concentrations of thrombin-antithrombin III
complex (TAT; Behring Diagnostics), prothrombin fragment
1.2 (F1.2; Behring Diagnostics), D-dimer,
ßTG, and platelet factor 4 (PF4; the latter all from American
Bioproducts). Blood samples were obtained from
peripheral arterial catheter (while in
intensive care) or through venous access lines or
peripheral venipuncture (after transfer to
patient units) after the TCD measurement schedule. Samples for ßTG
and PF4 were drawn into 3- or 5-mL Vacutainer tubes (Becton-Dickinson)
containing an anticoagulant and antiplatelet cocktail consisting of
citric acid (0.11 mol/L), theophylline (15 mmol/L),
adenosine (3.7 mmol/L), and dipyridamole
(0.198 mmol/L).18 Samples for the remaining tests
were drawn into 3-mL Monovette blood collection tubes containing 3.8%
citrate (Sarstedt). On several occasions, sample volumes obtained were
not adequate to permit all tests to be performed.
Flow Cytometric Analysis
Whole-blood flow cytometry was used to measure platelet
surface expression of p-selectin, Mono-TF, and formation of
monocyte-platelet (Mono-plt) and granulocyte-platelet
(Gran-plt) conjugates. Samples were drawn into 3-mL Monovette tubes
containing 3.8% sodium citrate on the same schedule as ELISA samples
and TCD measurements. Immediately after sample collection, aliquots
were incubated for 40 minutes with monoclonal antibodies specific for
platelet glycoprotein Ib (CD42b; Gentrak or
Becton-Dickinson Immunocytometry Systems), platelet p-selectin
(CD62), the monocyte marker CD14, the granulocyte marker CD15 (all from
Becton-Dickinson), tissue factor (TF; American
Diagnostica), or immunoglobulin G (IgG) isotype controls
(Becton-Dickinson). Anti-CD42b, anti-TF, anti-CD15, and their IgG
isotype controls were obtained conjugated to
fluorescein-isothiocyanate (FITC), and p-selectin,
anti-CD14, and an additional anti-CD42b and their IgG isotype controls
were obtained conjugated to phycoerythrin (PE) for 2-color flow
cytometric analysis.
After incubation, samples were fixed with 1% paraformaldehyde and analyzed within 24 hours on a FACScan flow cytometer (Becton-Dickinson Immunocytometry Systems). For each sample, 5000 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. Single platelets were identified by positive fluorescence for CD42b and characteristic forward scatter profile, and platelet activation was quantified by the percentage of the CD42b-positive population also positive for CD62. Monocytes and granulocytes were identified by positive fluorescence for either CD14 or CD15 and characteristic forward and side scatter profiles. Mono-plt and Gran-plt conjugates were defined as the percentage of the CD14- or CD15-positive populations, respectively, which were also positive for the platelet marker CD42b, and Mono-TF expression was similarly defined as the percentage of the CD14-positive population also positive for tissue factor.
Control Studies
Control blood samples for all ELISA and flow cytometric indexes,
collected over a 3-year period, were obtained after informed consent
(IRB No. 9505133) by antecubital venipuncture from 23
healthy, nonsmoking, nonpregnant donors 19 to 31 years of age who were
medication free for at least 2 weeks before sampling. Normal ranges
represent the mean±SEM of control data.
Statistical Analysis
Fisher’s exact test was used to test the significance of
differences in the occurrence of MES between patients with and those
without thromboembolic events and between patients with a Novacor VAD,
a Thoratec VAD, and Thoratec BiVADs. Mean MES rates (MES/min) for the
different patient groups are presented for comparison to MES
rates previously reported in the literature. Formal statistical
comparison of MES rates between patient groups was not pursued because
of differing numbers of measurements per patient and a strong
association of time with MES. The variation of the mean MES rate over
time was evaluated with the use of an ANOVA with post-hoc Neuman-Keuls
testing for differences between postimplantation MES rates and
preoperative levels.
To evaluate the association of MES showering with measured hemostatic
parameters MES showering data were grouped based on the
presence of MES (any number of MES detected vs no MES detected) and the
degree of MES (no MES showering vs light MES showering vs heavy MES
showering). Light MES showering was defined as an observed rate of >0
and <10 MES/min. Heavy MES showering was defined as 
10 MES/min.
Repeated-measures ANOVA was used for the primary analysis to account for the correlation between measurements on the same patients. Two approaches were applied for the evaluation of continuous outcomes (hemostatic variables). The first, termed the mixed models approach, implemented a random patient effect to introduce this correlation in the model as described by Laird and Ware.19 This was accomplished by use of the PROC MIXED routine in the SAS programming language. The robustness and stability of these analyses were also examined by use of a generalized estimating equation approach in which an exchangeable correlation matrix was implemented to model the repeated measures structure.20 A SAS IML program was used for this technique21 and MES data obtained in the first 28 days of VAD implantation was evaluated. For maximum generality, the effect of time, which observationally appeared quite complex, was modeled as arbitrary (different mean for each time point) rather than assuming a polynomial or other underlying effect in both techniques. To compare hemostatic variables between VAD patients and normal control subjects, the random-effect model approach was also used with data grouped by the presence of MES showering and the time of the measurement in the implantation period (before or after 5 days).
The use of 2 statistical approaches for determining the relation between the continuous hemostatic variables and MES was used in an effort to address some of the limitations associated with the relatively small number of subjects and the high incidence of missing data. Specifically, the small data set prevented rigorous evaluation of the assumption of a normal error structure in both techniques, and the standard errors for coefficients and resulting probability value were based on asymptotic theory that may not be highly accurate because of the data set size. The small number of subjects and missing data necessitated imposing a correlation structure in both techniques in which the degree of association was identical between all within-subject measurements. This was clearly an approximation because measurements closer in time might be expected to be more highly correlated. Because of these limitations, results from both statistical models are presented and emphasis is placed on results found to have a substantial association with MES as determined by both techniques.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
MES Rates Between Patients With and Those Without Thromboembolic Neurological Events
TE events were classified as transient ischemic attacks (TIA, symptoms resolving within 24 hours) or cerebrovascular accidents (CVA, permanent deficit or symptom duration >24 hours). Thirteen TE events, 5 CVA and 8 TIA, were recorded in 12 of the patients. Temporally, 7 of the events occurred within the first 4 weeks after implantation, with the remaining 6 events occurring between weeks 5 and 12. Six of the patients with the Novacor VAD (3 CVA, 3 TIA), 5 of the patients with the Thoratec VAD (2 CVA, 4 TIA), and 1 of the patients with Thoratec BiVADs (1 TIA) had TE. One of the patients with the Thoratec VAD had 2 TIAs.
MES were not observed in any TCD measurements made before VAD
implantation. After implantation, the MES rate increased between
postoperative days 4 to 7, reaching a maximum of 25±16 MES/min on
postoperative day 7 (Figure 1
). After
postoperative day 7, the rate of MES decreased but remained elevated
over preoperative levels. The mean MES/min for all postoperative
measurements was 8±3. Table 1
summarizes the incidence of MES detection (by patients and by
measurement) for all patients and in the subgroup that had TE. Of the
12 patients with Novacors, one half had MES detected compared with
100% of patients with Thoratec VADs (P=0.001 vs Novacor)
and 100% of patients with Thoratec BiVADs (P=0.014 vs
Novacor). In line with these significant differences, the mean MES rate
for all TCD measurements from patients with Novacors was 0.17±0.07
MES/min compared with 9±2 MES/min for all Thoratec VAD measurements
and 21±9 MES/min for all Thoratec BiVAD measurements. Across the 3
devices, MES were detected in 10 (83%) of 12 patients with TE and 11
(73%) of 15 without TE (P=0.66 vs patients with TE). The
mean MES rate was 11±5 MES/min for patients with TE and 4±1 MES/min
for patients without TE.
|
|
Hemostatic Indexes and the Presence of MES Showering
The generation of thrombin in vivo as reflected in plasma
prothrombin fragment F1.2 was found to be related in a highly
significant manner to the presence of MES showering in patients with
VADs in both statistical models (Table 2). The parameters predicted
by both models indicate a significant elevation in F1.2 (estimated to
be increased by 1.4 nmol/mL) in measurements in which MES were detected
relative to those without MES. A marker for circulating
inactivated thrombin, TAT, did not reach the criteria for
significance (P=0.08 in one model) but reflected a similar
trend toward a positive relation between coagulation activity and MES
signals.
|
Circulating Gran-plt conjugates were also found to be significantly related to the presence of MES in patients with VADs. Here there was an inverse relation in which the presence of MES was associated with a decrease in the percentage of circulating granulocytes harboring attached platelets. Both models demonstrated this effect to be significant.
Hemostatic Indexes and the Degree of MES Showering
In Tables 3 and 4 the relation between the degree of MES
showering and the measured hemostatic parameters are
presented for the 2 statistical models, respectively.
Prothrombin fragment F1.2 was found to be significantly higher for
light versus no MES showering in both statistical approaches. In Figure 2, F1.2 measurements made over the course
of VAD implantation are presented for the light and no MES
showering groups. The consistent elevation in F1.2 measurements
in which light MES showering was detected is apparent here. In one
model (Table 4), a significant difference between F1.2
measurements was also found between heavy versus no MES showering.
Circulating TAT approached significance in one of the models (Table 4), with a trend supporting a positive relation between
coagulation activity and light or heavy MES showering. No significant
differences were detected for heavy versus light MES showering for
either F1.2 or TAT.
|
|
|
) or no (
) MES
showering for the patient on the day that the blood sample was drawn.
Trend lines for the light (dotted line) and no (solid line) MES
showering groups reflect the medians for each group over time and
demonstrate the association of F1.2 elevations and MES showering.
The negative relation between circulating Gran-plt conjugates observed
in the earlier analysis also held for light versus no MES
showering in both models. No significant differences were detected for
heavy versus no or light MES showering. Other significant differences
found when grouping the data on the degree of MES showering were
detected using one of the two statistical models. Of note here were the
relations found between a lower PTT within the first 7 days of VAD
implantation and heavy MES showering (Table 3
).
Hemostatic Indexes in Patients With VADs Relative to Normal
Control Subjects
Comparing the measured hemostatic indexes from patients with VAD
with those from normal control blood donors in Table 5, it is seen that marked elevations
occurred in the VAD patient group with and without MES showering and in
the early implantation period (
5 days of device implantation) as well
as later measurements. Elevations in platelet activation (evidenced
by PF4 and ßTG and the percentage of circulating platelets
expressing p-selectin), coagulation (prothrombin fragment F1.2 and
TAT), fibrinolysis (D-dimer), and
leukocyte-platelet conjugates (Gran-plts) were present in the
implantation period after 5 days, regardless of the detection of MES
showering.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Reports in the literature present differing conclusions regarding an association between MES and TE in patients with VADs. Slater et al11 studied 8 patients with Thermo Cardiosystems HeartMate VADs and observed MES in 28% of their TCD measurements. They report a relatively low mean MES rate of 0.52±1.00 MES per 30-minute session for all of their TCD studies, and none of their patients examined with TCD exhibited clinically apparent TE. Moazami et al9 studied 14 patients with HeartMates and observed MES in 26% of their TCD measurements. They found an elevated rate of MES in one patient who had a thromboembolic neurological event (0.03 MES/min) relative to asymptomatic patients (0.016 MES/min). Nabavi et al10 studied 6 patients with Novacor VADs and observed MES in 84% of their TCD measurements. They observed a significant elevation in MES on days of clinically apparent thromboembolic events (18.5 MES per 30-minute session) versus days without events (4 MES per 30-minute session, P<0.001). We report here an elevation in MES after VAD implantation, observations of MES in 58% of our TCD measurements, and a trend toward increased MES rates in patients with clinically apparent thromboembolic neurological events. The percentage of MES-positive TCD measurements in our patients with Novacor VADs (18%) was comparable to the incidence of MES reported by Moazami et al and Slater et al for the HeartMate VADs and much lower than the 84% rate reported by Nabavi et al in their Novacor VAD patient group. Of note, Nabavi et al reported a higher incidence of thromboembolic neurological events in their 6 patients, with 67% having multiple TE, whereas we report TE in 6 of 12 patients with Novacors, all with single events.
MES are frequently observed in prosthetic heart valve patients, although the relation between MES, hemostatic alterations, and thromboembolic neurological events remains poorly defined. Braekken et al22 found elevated MES rates up to 5 years after implantation in a group of bileaflet mechanical valve patients with a history of cerebrovascular symptoms (1 MES/min) when compared with patients who remained asymptomatic (0.02 MES/min, P=0.04), whereas Georgiadis et al6 23 and Sliwka and Georgiadis7 report no significant differences between patients with and those without TE. Sturzenegger et al8 found significantly elevated ßTG compared with normal control subjects in a group of 5 patients with mechanical prosthetic heart valves with a history of recurrent TE and suggested that MES are composed in part of activated platelets. However, that study did not find elevations in TAT, fibrinopeptide A, or D-dimer versus normal control subjects. Georgiadis et al measured plasma D-dimer, antithrombin III, and TAT simultaneously with TCD in a group of 100 patients with prosthetic heart valves and did not find significant relations between MES and their measured hematologic parameters.24 They report that the incidence of MES was significantly elevated in patients with mechanical valves compared with patients with bioprosthetic prosthetic heart valves and suggest that observed MES were not the result of thrombotic material but platelet aggregates or gaseous material. In a recent study, Sliwka and Georgiadis7 report significantly elevated MES counts (MES/h) in patients with mechanical valves versus patients with bioprosthetic heart valves and suggest that MES in patients with bioprosthetic valve are caused by formed material resulting from blood-biomaterial interactions.
Cavitation microbubbles are hypothesized to be responsible for observed elevations in MES rates in patients with mechanical heart valves.7 25 Hyperbaric oxygenation has been reported to result in decreased MES rates, believed to be the result of displacement of less soluble nitrogen with more soluble oxygen in the blood, thus reducing the rate of cavitation by gaseous nitrogen.26 27 On the other hand, the extremely small size and short duration of cavitation bubbles and observations of cavitation in vitro at supernormal as opposed to physiological pressure loading suggest that cavitation is not the sole source for MES in vivo.25 28 Shu et al28 report that TCD was unable to detect gaseous cavitation microbubbles in vitro under known cavitation generating conditions and suggest that this was due to cavitation bubbles being too small, too few, or of too short a duration. It is interesting to speculate that our observed differences in MES rates between the Thoratec VAD and BiVAD (mechanical valves) and the Novacor system (bioprosthetic valves) may be due at least in part to cavitation effects. However, our observed trends of elevated thrombin generation with increasing MES rates suggest a thrombotic origin for MES.
Prosthetic heart valve implantation is similar to VAD implantation in that patient blood contacts artificial surfaces and disturbed flow fields for an extended implant period. However, VAD implantation results in much more extensive blood-biomaterial contact than prosthetic heart valve implantation. The expected alterations in coagulation, fibrinolysis, and cellular activation after VAD implantation have been described for several devices. Spanier et al14 report elevated thrombin generation and fibrinolysis in HeartMate VAD patients, indicated by elevated plasma levels of TAT, F1.2, and D-dimer. Livingston et al29 found higher levels of thrombin generation (F1.2, TAT), platelet activation (PF4, ßTG), and fibrinolysis (D-dimer) in patients with HeartMates immediately after surgery when compared with patients with non-VAD bypass. A previous study by our group found significant increases in thrombin generation (TAT), monocyte-tissue factor expression, and circulating levels of monocyte-platelet and granulocyte platelet conjugates compared with normal control subjects for the duration of device support in a group of 17 patients with Novacor VADs and 13 with Thoratec VADs (5 BiVADs).15 These previous studies provide a foundation for hypothesizing that hemostatic alterations associated with VAD implantation may provide a thrombotic source for emboli subsequently detected as MES.
We have suggested in prior studies that thrombotic deposition may preferentially occur early in the implantation period within the VAD and that this deposition may decrease over time as fibrinolytic pathways dominate.30 The relation that was found in one of the statistical models between heavy MES showering and lower PTT in the first week of implantation would support this model. The INR after the first week of implantation was not found to be different among any MES-based groupings. With regard to the use of anticoagulation monitoring, it is worthwhile to note that elevations in F1.2 and TAT in all patients with VADs and the relation between F1.2 and MES appeared in the face of a relatively aggressive anticoagulation regimen.
We have shown that MES are related to VAD implantation and remain significantly elevated for at least the first 4 weeks of VAD support. Although we did not find a direct and significant statistical relation between thromboembolic neurological events and MES, the trend in MES data suggests that there may be an important role for MES in mediating TE in patients with VADs. It is possible that the mechanisms responsible for generating the small asymptomatic emboli detected as MES may not be related to the generation of larger emboli that precipitate clinical thromboembolism. Further, cavitation may be partly responsible for MES, particularly in patients supported by devices with mechanical valves. However, the hematologic indexes suggest that subclinical coagulation may be an important mediator in the formation of MES. Whereas the utility of TCD in predicting increased risk for stroke in VAD patients remains debatable, TCD in conjunction with sensitive assays of coagulation, fibrinolysis, and cellular activation may provide a methodology for identifying potential thrombotic mechanisms that result in MES. Additional studies into the possible relation between MES and stroke and between hematologic alterations and MES are warranted, as identification of patients or time periods of increased risk for stroke would greatly improve patient treatment and quality of life.
|
Acknowledgments |
|---|
This study was supported by a grant-in-aid (W.R.W.) from the American Heart Association. The authors would like to thank Stephen Winowich, Carla Nastala, and Eileen Stanford of the University of Pittsburgh Medical Center Artificial Heart Program for their clinical support in this study.
Received August 27, 1999; accepted September 20, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Barbut D, Hinton RB, Szatrowski TP, Hartman GS, Bruefach M, Williams-Russo P, Charlson ME, Gold JP. Cerebral emboli detected during bypass surgery are associated with clamp removal. Stroke. 1994;25:2398–2402.[Abstract]
2.
Barbut D, Yao FS, Hager DN, Kavanaugh P, Trifiletti
RR, Gold JP. Comparison of transcranial Doppler
ultrasonography and transesophageal
echocardiography to monitor emboli during
coronary artery bypass surgery. Stroke. 1996;27:87–90.
3.
Clark RE, Brillman J, Davis DA, Lovell MR, Price TRP,
Magovern GJ. Microemboli during coronary artery bypass grafting
genesis and effect on outcome. J Thorac Cardiovasc
Surg. 1995;109:249–258.
4.
Levi CR, O’Malley HM, Roberts AK, Hoare MC, Royle JP,
Chan A, Beiles BC, Chambers BR, Bladin CF, Donnan GA.
Transcranial Doppler detected cerebral microembolism
following carotid endarterectomy. Brain. 1997;120:621–629.
5.
Spencer M. Transcranial doppler monitoring
and causes of stroke from carotid endarterectomy.
Stroke. 1997;28:685–691.
6. Georgiadis D, Kaps M, Berg J, Mackay TG, Dapper F, Wheatley DJ, Lees KR. Transcranial Doppler detection of microemboli in prosthetic heart valve patients: dependency upon valve type. Eur J Cardiothorac Surg. 1996;10:253–258.[Abstract]
7.
Sliwka U, Georgiadis D. Clinical correlations of
Doppler microembolic signals in patients with
prosthetic cardiac valves. Stroke. 1998;29:140–143.
8.
Sturzenegger M, Beer JH, Rihs F. Monitoring combined
antithrombotic treatments in patients with prosthetic heart
valves using transcranial Doppler and coagulation
markers. Stroke. 1995;26:63–69.
9. Moazami N, Roberts K, Argenziano M, Catanese K, Mohr JP, Rose EA, Oz MC. Asymptomatic microembolism in patients with long-term ventricular assist support. ASAIO J. 1997;43:177–180.[Medline] [Order article via Infotrieve]
10.
Nabavi DG, Georgiadis D, Mumme T, Schmid C, Mackay TG,
Scheld HH, Ringelstein EB. Clinical relevance of intracranial
microembolic signals in patients with left
ventricular assist devices. Stroke. 1996;27:891–896.
11. Slater JP, Roes EA, Levin HR, Frazier OH, Roberts JK, Weinberg AD, Oz MC. Low thromboembolic risk without anticoagulation using advanced-design left ventricular assist devices. Ann Thorac Surg. 1996;32:1321–1328.
12. Roberts JK, Mohr JP, Moazami N, Oz MC. Microembolic signals in patients with left ventricular assist devices. Stroke. 1996;27:1915–1916. Letter.
13. Himmelreich G, Ullmann H, Riess H, Rosch R, Loebe M, Schiessler A, Hetzer R. 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] [Order article via Infotrieve]
14.
Spanier T, Oz MC, Levin HR, Weinberg AD, Stamatis K,
Stern D, Rose E, Schmidt AM. Activation of coagulation and fibrinolytic
pathways in patients with left ventricular assist devices.
J Thorac Cardiovasc Surg. 1996;112:1090–1097.
15.
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.
16. Wagner WR, Johnson PC. Therapeutic techniques for reducing thrombosis after cardiovascular implants. In: Klitzman B, ed. Problems in General Surgery. Philadelphia, Pa: JB Lippincott Co; 1994;11:241–264.
17.
Consensus Committee of the Ninth International Cerebral
Hemodynamic Symposium. Basic identification criteria of
Doppler microembolic signals. Stroke. 1995;26:1123.
18. Contant G, Gouault-Heilmann M, Martinoli JL. Heparin inactivation during blood storage: its prevention by blood collection in citric acid, theophylline, adenosine, dipyrimidole-c.t.a.d. mixture. Thromb Res. 1983;31:365–374.[Medline] [Order article via Infotrieve]
19. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38:963–974.[Medline] [Order article via Infotrieve]
20.
Liang K-Y, Zeger SL. Longitudinal data analysis
using generalized linear models. Biometrika.. 1986;73:13–22.
21. Groemping U. GEE: An SAS Macro for Longitudinal Data Analysis. Universitaet Dortmund, Germany: Fachbereich Statistik; 1994.
22.
Braekken KS, Russell D, Brucher R, Svennevig J.
Incidence and frequency of cerebral embolic signals in patients with a
similar bileaflet mechanical valve. Stroke. 1995;26:1225–1230.
23. Georgiadis D, Grosset DG, Kelman AW, Faichney A, Lees KR. Prevalence and characteristics of intracranial microembolic signals in patients with different types of prosthetic cardiac valves. Stroke. 1994;25:587–592.[Abstract]
24. Georgiadis D, Mallinson A, Grosset DG, Lees KR. Coagulation activity and emboli counts in patients with prosthetic cardiac valves. Stroke. 1994;25:1121–1214.
25. Graf T, Fischer H, Reul H, Rau G. Cavitation potential of mechanical heart valve prostheses. Int J Artif Organs. 1991;14:169–174.[Medline] [Order article via Infotrieve]
26.
Kaps M, Hansen J, Weiher M, Tiffert K, Kayser I, Droste
DW. Clinically silent microemboli in patients with artificial
prosthetic aortic valves are predominantly gaseous and not
solid. Stroke. 1997;28:322–325.
27.
Georgiadis D, Wenzel A, Lehmann D, Lindner A, Zerkowski
HR, Zierz S, Spencer MP. Influence of oxygen ventilation on Doppler
microembolic signals in patients with artificial heart
valves. Stroke. 1997;28:2189–2194.
28. Shu MCS, Gross JM, Johnson KM. Can cavitation bubbles generated by mechanical heart valves be detected by transcranial Doppler? J Heart Valve Dis. 1995;4:542–552.[Medline] [Order article via Infotrieve]
29. Livingston ER, Fisher CA, Bibidakis EJ, Pathak AS, Todd BA, Furukawa S, McCluren JB, Addonizio VP, Jeenanandam V. Increased activation of the coagulation and fibrinolytic systems leads to hemorrhagic complications during left ventricular assist implantation. Circulation. 1996;94(suppl II):II-227–II-234.
30.
Wagner WR, Johnson PC, Kormos RL, Griffith BP.
Evaluation of bioprosthetic valve-associated thrombus in
ventricular assist device patients. Circulation. 1993;88:2023–2029.
This article has been cited by other articles:
 |
|
 |
|
  R. John, F. Kamdar, K. Liao, M. Colvin-Adams, L. Miller, L. Joyce, and A. Boyle Low thromboembolic risk for patients with the Heartmate II left ventricular assist device. J. Thorac. Cardiovasc. Surg., November 1, 2008; 136(5): 1318 - 1323. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dittrich and E. B. Ringelstein Occurrence and Clinical Impact of Microembolic Signals During or After Cardiosurgical Procedures Stroke, February 1, 2008; 39(2): 503 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Joshi, L. S. Magder, Z. Kon, S. Kallam, M. Kwon, R. Sangrampurkar, R. Pierson, and R. Poston Association between prothrombin activation fragment (F1.2), cerebral ischemia (S-100{beta}) and international normalized ratio (INR) in patients with ventricular assisted devices Interactive CardioVascular and Thoracic Surgery, June 1, 2007; 6(3): 323 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D. Doblar Intraoperative Transcranial Ultrasonic Monitoring for Cardiac and Vascular Surgery Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2004; 8(2): 127 - 145. [Abstract] [PDF]
|
|
|
|
 |
|
 T. A. Snyder, M. J. Watach, K. N. Litwak, and W. R. Wagner Platelet activation, aggregation, and life span in calves implanted with axial flow ventricular assist devices Ann. Thorac. Surg., June 1, 2002; 73(6): 1933 - 1938. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||