Ann Thorac Surg 2006;81:1644-1649
© 2006 The Society of Thoracic Surgeons
Original article: Cardiovascular
Transcerebral Platelet Activation After Aortic Cross-Clamp Release is Linked to Neurocognitive Decline
Joseph P. Mathew, MD
a
,
Henry M. Rinder, MD
b
,
c
,
*
,
Brian R. Smith, MD
b
,
c
,
Mark F. Newman, MD
a
,
Christine S. Rinder, MD
b
,
d
a Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
b Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
c Department of Internal Medicine (Hematology), Yale University School of Medicine, New Haven, Connecticut, USA
d Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, USA
Accepted for publication December 20, 2005.
* Address correspondence to Dr Rinder, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, PO Box 208051, New Haven, CT 06520-8051 (Email: christine.rinder{at}yale.edu).
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Abstract
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BACKGROUND: Neurocognitive decline after cardiac surgery requiring cardiopulmonary bypass (CPB) may be caused in part by highly prothrombotic atheroemboli to the brain; the source of these emboli is likely the ascending aorta and aortic arch. We examined transcerebral platelet activation gradients using simultaneous measurements in arterial and jugular venous blood and then compared gradients with post-CPB-associated neurocognitive injury.
METHODS: Eighty-one patients undergoing elective coronary artery bypass graft surgery requiring CPB were studied. Neurocognitive function was measured preoperatively and again at 6 weeks postoperatively. Paired arterial and jugular venous blood samples were drawn before surgery, immediately before and after aortic cross-clamp removal (an event previously linked to embolic showers), and at the end of the operation. Transcerebral platelet activation gradients (venous minus arterial values) were compared in patients with and without cognitive deficit.
RESULTS: Immediately after aortic cross-clamp removal, there was a significant increase in the transcerebral platelet activation gradient (increased % P-selectin-positive platelets during transcerebral passage) in the subset of patients who subsequently developed post-CPB cognitive deficit; this platelet activation gradient did not occur in patients without cognitive injury. In contrast, there was no transcerebral gradient of platelet activation in CPB patients as an entirety, nor was there a gradient at all other time points in the patient subset who went on to have cognitive deficit develop. This fleeting gradient of transcerebral platelet activation after cross-clamp removal was also significantly correlated with the overall change in cognitive injury score.
CONCLUSIONS: Transient intracerebral platelet activation after removal of the aortic cross-clamp is associated with post-CPB neurocognitive injury.
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Introduction
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Neurocognitive injury contributes significantly to the morbidity of surgical procedures requiring cardiopulmonary bypass (CPB) [1]. Although advances in anesthesia and surgery have improved overall outcome [2], the incidence of neurologic injury has changed little in recent decades [3]. The cause of CPB-associated cerebral injury is multifactorial, but embolic events account for more than 60% of associated strokes [4]. The majority of strokes are detected early postoperatively. Evidence suggests that aortic manipulation, particularly the application or removal of the aortic cross-clamp [5–7], may dislodge atheromatous, highly prothrombotic [8] material from the ascending aorta, which embolizes to the brain and other organs.
Although overt stroke is relatively rare post-CPB, neurocognitive deficits are considerably more frequent [1], often resulting in long-term neurocognitive decline, which can be critically assessed as early as 6 weeks postoperatively [3]. Given the major role of platelets in nonsurgical cerebrovascular events [9], we chose to examine a possible role for platelet activation in post-CPB cerebral injury. Three markers of platelet activation were chosen for their varying specificity for platelet activation. The first marker was the platelet surface P-selectin expression, which is an immediate marker of platelet activation that subsequently binds the activated platelet to circulating leukocytes [10–12]. This marker is particularly useful in the CPB setting because P-selectin-positive platelets rapidly appear and can be expressed as a percentage of the total platelet population, making it unchanged by hemodilution [13]. A second, slower to appear, cellular marker of platelet activation is an increase in the percentage of monocyte-platelet and polymorphonuclear leukocytes-platelet conjugates as a result of platelet P-selectin expression. Finally, regulated upon activation normal T cell expressed presumed secreted (RANTES), is a chemokine that is released by activated platelets into plasma; RANTES in plasma indicates the cumulative degree of platelet secretion and functions to foster adhesion of monocytes to activated endothelial cells [14, 15].
These platelet activation markers were measured in simultaneously-drawn arterial and jugular venous blood samples so that the platelet activation in the jugular venous sample minus the arterial platelet activation (ie, the transcerebral activation gradient) would reflect platelet activation occurring in the cerebral bed of patients undergoing CPB. For platelet surface P-selectin expression and leukocyte-platelet conjugate formation, blood sampling was timed to bracket the aortic cross-clamp removal, an event that has been linked to cerebral emboli by transcranial Doppler evaluation [5]. Samples for plasma RANTES measurements were collected only at the end of CPB to keep the total volume of blood sampling within acceptable limits. We then correlated these studies with neurocognitive testing to determine whether a transcerebral platelet activation gradient at specific times during CPB surgery was associated with postoperative cognitive decline.
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Material and Methods
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Patient Selection and Conduct of CPB
After approval by the Institutional Review Board for Human Investigation (original approval date, March 4, 1999, and most recently, January 31, 2005) and after informed consent, 121 adults undergoing elective coronary artery bypass grafting requiring CPB at Duke University Medical Center were consecutively enrolled. Patients with symptomatic cerebrovascular disease, uncontrolled hypertension, alcoholism, psychiatric illness, renal failure, active liver disease, or less than a seventh grade education were excluded. Each patient had a radial artery catheter placed, and a 16G 5.25-inch catheter (Angiocath [Becton Dickinson, Sandy, UT]) was inserted into the right internal jugular vein. Anesthesia was induced with midazolam, fentanyl, and isoflurane, and CPB was hypothermic (30°C to 32°C) with perfusion maintained at pump flow rates of 2 to 2.4 L/min–1/m2.
Blood Sampling
Simultaneous radial arterial and jugular venous whole blood samples were drawn at baseline (prior to anesthesia induction), and immediately prior to aortic cross-clamp release (XCR), 5 minutes after aortic XCR, and at the end of surgery. Blood was immediately fixed in 1% paraformaldehyde in phosphate-buffered saline. Preliminary studies had shown no difference in all platelet activation markers between radial artery and aortic arch blood samples. To limit the volume of blood drawn, paired blood samples for RANTES measurement were drawn at only a single time point into 5-mM ethylene diamine tetra-acetic acid, and plasma was prepared and frozen. The end of surgery time point was selected for RANTES, because we anticipated that the degree of transcerebral platelet activation would peak at that time. Assays for RANTES and P-selectin are not known to be influenced by the temperature at which the sample is drawn.
Reagents and Flow Cytometry
Platelet P-selectin expression was measured using fluorochrome-conjugated monoclonal antibodies, with the platelet-specific monoclonal antibodies (ie, anti-CD41a [glycoprotein IIb/IIIa] and anti-CD62P [P-selectin]), both purchased from Pharmingen (San Diego, CA). Whole blood samples were fixed, washed, and labeled with monoclonal antibodies as previously described [16]. The percentage of P-selectin+ platelets was determined by labeling with fluorescein isothiocyanate-anti-CD41a and phycoerythrin-anti-CD62P [12]. Leukocyte-platelet binding, an additional cellular marker of platelet activation, [12, 16] was determined by labeling samples with fluorescein isothiocyanate-anti-CD45 (Pharmingen), phycoerythrin-anti-CD41a, and phycoerythrin-Cy5-anti-CD14 [17] (Beckman Coulter, Miami, FL). Samples were analyzed on a FACScan flow cytometer (Becton-Dickinson, Mountain View, CA).
RANTES Assay
Plasma was assayed for RANTES by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN).
All laboratory assays were performed by investigators blinded to the neurocognitive data.
Cognitive Function Testing
Cognitive function was assessed the day before surgery and 6 weeks postoperatively by investigators blinded to the laboratory data. This postoperative time point has been shown to reflect later neurocognitive outcomes [3]. The cognitive test battery included five instruments, resulting in 10 measures, consistent with the consensus statement on neurobehavioral outcomes assessment after CPB [18]. The five instruments were the short story module of the Randt Memory Test [19], the Digit Span subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Test [20], the modified Visual Reproduction Test from the Wechsler Memory Scale [21], the Digit Symbol Subtest of the WAIS-R [20], and the Trail Making Test (part B) [22]. Consolidation and factor analysis of the individual test scores was performed as previously described [3] to yield a numerical value (without units). Means and standard deviations were calculated from the baseline scores for each relevant factor as previously described in detail [3].
Statistical Methods
As previously described [3], cognitive assessment produced four standardized factor scores representing independent, equally weighted cognitive function domains with the score change calculated by subtracting the baseline from the postoperative score. Two summary measures were calculated to represent cognitive function. First, cognitive deficit (CD), a binary outcome, was defined as a decline of 
1 standard deviation in performance on at least one of the four domains. Second, cognitive index (CI), was the sum of the four domain scores with the change in CI calculated by subtracting the baseline from the postoperative value. Patients were grouped into those who demonstrated a CD and those who did not, and these groups were compared for demographics and measured laboratory variables using SigmaStat software (SPSS, Chicago, IL) as follows: all variables were first tested for normalcy; continuous variables were examined using the Student's t test or the nonparametric Mann-Whitney U rank sum test; binary variables were compared by a 
2 test or the nonparametric Fisher's exact test. For evaluation of the change in CI and its relationship to continuous variables, the Spearman correlation for nonparametric variables was used. Analysis of variance repeated measures were used to evaluate the overall peri-CPB course of platelet P-selectin expression between groups.
For group statistics, values are reported as mean ± standard deviation. Variables measured at multiple time points are reported as mean ± standard error of the mean. For transcerebral changes in RANTES or the percentage of activated P-selectin+ platelets, or the percentage of leukocyte-platelet conjugates, the value in the arterial sample was subtracted from the corresponding jugular sample.
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Results
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Neurocognitive Testing
Eighty-five of the 121 patients (70%) returned for neurocognitive testing 6 weeks after surgery. Of the 36 patients not retested, 2 patients died, poor health prevented 6 from returning, and 28 were unwilling to return or were lost to follow-up. Four returning patients who were unable to complete the full battery of tests were excluded, leaving 81 patients for final analysis. Twenty-four of these 81 patients (30%) demonstrated a cognitive deficit (CD, binary outcome variable). Table 1
lists the demographics of patients with and without a CD. The two groups were not significantly different in their preoperative cardiac function or the conduct of their surgery, nor was there a difference in the percentage receiving preoperative aspirin. In the 81 patients as a whole, the continuous outcome variable (ie, the change in CI), increased slightly on average (mean change, +0.13; range, –0.68 to +0.78), as is typical for retesting during the 6-week interval [23].
Jugular-Arterial Platelet Activation Gradient and Neurocognitive Injury
The transcerebral gradient was defined by the jugular minus the arterial value for all laboratory assays. The platelet activation gradient, defined as the jugular-arterial difference in % P-selectin+ platelets, did not differ between cognitive groups as a whole (p = 0.07), and was comparable at all times in patients with (n = 24) and without a CD (n = 57), except at the time point 5 minutes after aortic XCR (Fig 1). At that time, patients who went on to have a CD develop had a positive and significantly greater transcerebral platelet activation gradient than patients without a CD (p = 0.04). We then compared the continuous neurocognitive measure (ie, the change in CI), with this jugular-arterial platelet activation (P-selectin) gradient at all four time points. Once again, only the after aortic XCR point showed a significant correlation (inverse) with the platelet activation gradient (p = 0.005; r = –0.3) (Table 2). Circulating monocyte-platelet and polymorphonuclear leukocytes-platelet conjugates were similarly measured as an additional cellular platelet activation marker. In patients with and without a CD, the transcerebral monocyte-platelet and polymorphonuclear leukocytes-platelet gradients were not significantly different (Fig 2A and B, respectively). Similarly, the change in CI was not correlated with either of the leukocyte-platelet gradients at any point (Table 2). Jugular and arterial plasma samples collected only at the end of surgery were assayed for the chemokine, RANTES, which is released into plasma by activated platelets and correlates to some extent with the amount of platelet release [12]. Jugular RANTES levels were significantly higher than arterial RANTES levels (3486 ± 2088 vs 2993 ± 1761, respectively; p <0.01), but this end CPB jugular-arterial RANTES gradient was not significantly different between patients with and without a CD (p = 0.63), nor did the transcerebral RANTES gradient correlate with the change in CI at this time point (Table 2).
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Fig 1. Jugular-arterial (J-A) platelet activation gradient in patients with and without cognitive deficit. The gradient of P-selectin+ platelets was compared in 24 cognitive deficit (CD) patients versus 57 patients with no CD at the following time points: baseline (BASE), immediately before aortic cross-clamp release (aXCR), 5 minutes after aortic XCR (5min pXCR), and at the end of surgery (endOR). At the 5 minutes after XCR time point, patients with a CD had a significantly greater J-A platelet activation gradient (*p = 0.048).
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Table 2. Spearman Correlation Coefficients (p Values in Parentheses) for the Correlation of the Change in Cognitive Index with Transcerebral Cellular Gradients at Each Sampling Time Point
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Fig 2. Jugular-arterial (JUG-ART) gradient for leukocyte-platelet conjugates in patients with and without cognitive deficit (CD). The gradient of (A) monocytes with bound platelets and (B) neutrophils (polymorphonuclear leukocytes) with bound platelets was compared in patients with and without CD at the times identified in Fig 1. The leukocyte-platelet conjugate gradient did not differ between patient groups at any time point (p > 0.05) for both (A) monocyte-platelet and (B) polymorphonuclear leukocytes-platelet. (BASE = baseline; aXCR = immediately before aortic cross-clamp release; 5min pXCR = 5 minutes after aortic XCR; endOR = at the end of surgery.)
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Anesthesia Effect
As is evident in Figure 1, transcerebral platelet activation decreased significantly in all patients (p < 0.001) from baseline to the point just prior to XCR, an interval that includes the anesthesia induction, surgery, and the majority of CPB time; this was apparent in our interim analysis of the first 61 subjects. To determine whether anesthesia induction might be partly responsible for this decrease, paired samples for transcerebral platelet activation (P-selectin) were drawn 15 minutes after anesthesia induction in the final 60 patients. The transcerebral platelet activation gradient at this point averaged 4.8% ± 1.8% (mean ± standard error of the mean) significantly lower (p = 0.002) than the baseline gradient (9.7% ± 1.2%), which suggests some effect of anesthesia on platelet activation across the cerebrovascular bed.
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Comment
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This investigation measured platelet activation in paired jugular venous and radial arterial blood samples timed to coincide with specific operative events during coronary artery bypass grafting surgery requiring CPB. We compared this transcerebral activation gradient with neurocognitive testing 6 weeks post-CPB. After aortic XCR, patients who subsequently showed neurocognitive decline (by both dichotomous and continuous measures) demonstrated an increased transcerebral gradient of P-selectin+ platelets, an immediate marker of activation-induced platelet 
-granule release. Platelet P-selectin expression did not differ between groups during CPB as a whole. In a separate patient study, we have previously shown an indirect link between platelet activation and post-CPB cognitive decline [24]. In that study, the platelet polymorphism PlA2, which is associated with increased platelet activation and coronary thrombosis risk [25, 26], was a significant risk factor for post-CPB neurocognitive decline. Additional indirect evidence for a platelet role in post-CPB cognitive decline is the finding in large population studies that early post-CPB resumption of aspirin confers significant protection from subsequent cerebrovascular injury [27].
The link between platelet activation and cerebral ischemia is well-established in nonoperative settings [28]. Although those studies sampled blood after symptoms were manifest, all have suggested a correlation between platelet activation and cerebral injury [29, 30]. Previous work by our laboratory has similarly shown a transcoronary platelet activation gradient in patients with acute coronary syndromes [31], but the current study is the first to prospectively correlate transcerebral platelet activation with subsequently detected cerebral injury. In addition to confirming an association between platelet activation and post-CPB neurocognitive decline, this study also gives insight into the timing and transient appearance of the activation insult. The increase in the platelet activation gradient after XCR is particularly striking because the same patient subset sampled 5 minutes earlier, just prior to release, displayed no activation gradient, and the P-selectin gradient disappeared by the end of surgery.
The cause of post-CPB neurocognitive decline includes intraoperative embolism of air or atheromatous material, hypotension, or hypertension [32], and postoperative atrial fibrillation [33]. The evidence is growing that a significant proportion of perioperative cerebral events can be attributed to atheromatous embolism. Brain pathology in patients dying within 24 hours of CPB [33], as well as a review of significant post-CPB cerebral injury [4], has suggested that embolism causes the majority of cerebrovascular events. The source of these emboli is not certain, but increased atheromatous disease in the ascending aorta is associated with increased transcranial Doppler-detected cerebral emboli during CPB [7]. Moreover, procedures involving the greatest aortic manipulation (eg, a fully occlusive aortic cross-clamp) are also associated with greater post-CPB neurocognitive decline when compared with the less invasive, tangential (side-biting) clamp [6], and aortic cross-clamp removal is known to be a particularly high-risk time point for embolism [5].
P-selectin expression on the activated platelet surface binds platelets to monocytes and neutrophils [10, 11], forming leukocyte-platelet conjugates in the circulation after exposure to CPB [34] and in other settings of chronic platelet activation [34]. In clinical conditions associated with low-grade but persistent platelet activation, leukocyte- platelet conjugates may be more sensitive in detecting platelet activation [35, 36]. However, in vitro experiments have demonstrated that immediately after an initial platelet-activating event, the first detectable change is a transient increase in the expression of P-selectin on free platelets [16]. The binding of these P-selectin+ platelets to leukocytes in whole blood occurs more gradually during a period of as much as 15 minutes. Our data suggest that the activation stimulus in the cerebral circulation is extremely brief and limited in duration enough that there was insufficient time for activated platelets to bind leukocytes, possibly explaining why the transcerebral leukocyte-platelet conjugate gradient was insensitive to subsequent neurocognitive injury.
The RANTES levels, drawn only at the end of surgery, were significantly increased across the cerebral bed, suggestive of cumulative local platelet secretion. However, the RANTES gradient did not correlate with neurocognitive outcome. It is possible that if the plasma samples had been drawn at the earlier time point (ie, after XCR), the RANTES gradient would also have been associated with postoperative neurologic injury. Moreover, the slight temperature difference between points and the ability to bind locally to endothelial cells [14] might alter its plasma concentrations such that circulating levels were not an accurate reflection of the degree of platelet release and secretion.
Whether the intracerebral platelet activation demonstrated in this preliminary study actively contributes to the associated cerebral injury, or is simply a marker of cerebrovascular tissue injury, is unknown. Still, the significant association of transcerebral platelet activation is highly relevant to the pathophysiology of XCR with neurocognitive injury. Activated platelets have an important role in murine and primate [37] middle cerebral artery occlusion models, in which inhibition of platelet microaggregates by IIbß3 blockade reduced neurologic injury. Alternatively, platelet products released upon activation may aggravate neuronal injury after thrombotic occlusion [38]. Thromboxane A2 and serotonin, potent vasoconstrictors released upon platelet activation, may contribute to local cerebral vasospasm and associated tissue injury [39]. Accordingly, it is possible that a platelet inhibitor might ameliorate (but not abrogate) the injury caused by cerebral emboli peri-CPB. Furthermore, the short time frame of transcerebral platelet activation demonstrated in the current article suggests that a short-acting agent prior to XCR could be an appropriate choice for such an investigation.
An unexpected observation in this study was the relatively high baseline platelet activation gradient that subsequently decreased after anesthesia induction; this study was not designed to assess an effect of anesthesia, and no solid conclusions should be drawn. Whether this transcerebral gradient is specific to the coronary artery bypass grafting patient population or the preoperative setting, or both, is unknown.
In summary, there is a significant association between intraoperative transcerebral platelet activation and neurocognitive decline, which is detected 6 weeks after cardiac surgery requiring cardiopulmonary bypass. These data provide further evidence to support aortic cross-clamp removal as a high-risk cerebrovascular event.
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Acknowledgments
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This study was supported by a Grant-in-Aid from the American Heart Association (Midatlantic Affiliate grant no. 9951185U), and the National Institutes of Health (grant no. HL-47193).
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Abstract
Introduction
