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Ann Thorac Surg 2001;71:663-666
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Platelet PlA2 polymorphism enhances risk of neurocognitive decline after cardiopulmonary bypass

Joseph P. Mathew, MDc, Christine S. Rinder, MDa,b, J. Greg Howe, PhDa, Manuel Fontes, MDb, Jill Crouch, MHSa, Mark F. Newman, MDc, Barbara Phillips-Bute, PhDc, Brian R. Smith, MDa, the Multicenter Study of Perioperative Ischemia (McSPI) Research Group

a Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
b Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, USA
c Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

Accepted for publication August 28, 2000.

Address reprint requests to Dr. Rinder, Department of Anesthesiology, Yale School of Medicine, PO Box 208051, 333 Cedar St, New Haven, CT 06520-8051
e-mail: christine.rinder{at}yale.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Neurocognitive decline, often produced by atherosclerotic plaque embolization, remains a frequent complication of cardiopulmonary bypass. Plaque fragments may initiate local thrombosis, which, in turn, aggravates the embolic insult. Prothrombotic genetic factors may exacerbate this process. We investigated whether the PlA2 polymorphism of platelet GPIIIa, a prothrombotic risk factor in other cardiovascular settings, is associated with early neurocognitive decline after cardiopulmonary bypass.

Methods. Neurocognitive changes were evaluated by the Mini-Mental State Examination administered preoperatively and on postoperative day 4 and the PlA genotype determined in 70 patients undergoing cardiopulmonary bypass.

Results. Forty-nine patients were PlA1/A1, and 21 were PlA1/A2 or PlA2/A2. Fifty-two patients (74%) demonstrated post–cardiopulmonary bypass neurocognitive decline, of which 34 were PlA1/A1 and 18 were PlA1/A2 or PlA2/A2. Multivariate analysis revealed that the PlA2 genotype and baseline Mini-Mental State Examination were significantly associated with greater neurocognitive decline (decreased Mini-Mental State Examination scores, p = 0.036 and 0.024, respectively).

Conclusions. This study demonstrates a link between the PlA2 allele of platelet GPIIIa and more severe neurocognitive decline after cardiopulmonary bypass. Although the mechanism is unknown, it could represent exacerbation of platelet-dependent thrombotic processes associated with plaque embolism.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Neurologic complications, most commonly resulting from atherosclerotic plaque embolism [1], contribute significantly to the morbidity of cardiopulmonary bypass (CPB) surgical procedures. Major neurologic defects are found in 6% of patients who, in turn, experience a 10-fold greater mortality compared with neurologically intact patients undergoing CPB [2]. In addition to major deficits, up to 69% of patients exhibit subtle neurocognitive changes [3] that, although less catastrophic, can nevertheless be devastating to their quality of life.

The variability in CPB-induced neurologic dysfunction mandates the use of comprehensive standardized neuropsychologic tests for neurologic assessment [4]. The Mini-Mental State Examination (MMSE) is the most widely accepted psychometric test of cognitive performance [5] for assessing neurologic disease prevalence and tracking subtle neurocognitive decline in progressive disorders, eg, Alzheimer’s disease. Its ease of administration, high sensitivity to cognitive dysfunction, and correlation with functions central to activities of daily living make the MMSE suitable for evaluating early post-CPB neurobehavioral changes [5].

Alterations in platelet glycoprotein (GP) receptors may contribute to the pathophysiology of vascular events. PlA2, a polymorphism of the GPIIIa constituent of the platelet integrin receptor, GPIIb/IIIa, has been proposed as one risk factor for myocardial infarction [6]. Although still controversial [7], studies of PLA allelic frequencies in patients with coronary artery disease with and without coronary thrombosis [8] suggest that the PlA2 polymorphism may predispose to increased thrombogenicity. A recent study demonstrating increased PlA2 prevalence in young atherothrombotic stroke patients now suggests an enhanced risk for cerebrovascular thrombosis in PlA2 positive individuals [9]. We hypothesize that the cerebrovascular insult of CPB may be exacerbated by platelet-dependent factors, such as the PlA2 polymorphism. The current study examined whether the PlA2 polymorphism correlates with increased risk of early neurocognitive decline after CPB.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patient selection and conduct of cardiopulmonary bypass
After Human Investigation Committee approval and informed consent, 70 consecutive adults undergoing CPB at Yale-New Haven Hospital who were enrolled in the Multicenter Study of Perioperative Ischemia Research Group’s prospective study of post-CPB outcomes were studied. All patients underwent CPB using a membrane oxygenator, roller pumps, and cardiotomy suction. Transesophageal echocardiography examination was performed after anesthetic induction using a Hewlett-Packard Multiplane transesophageal echocardiography probe to grade aortic pathology [10].

Neuropsychological testing
The MMSE was chosen for this multicenter study because of its ease of administration, brief test duration, and reliability in different ethnic groups [5], making it suitable for a multicenter study of early neurocognitive changes. Although a battery of neurocognitive tests may give a more comprehensive assessment of the neural injury [11], the investigators elected to restrict the testing to facilitate comparisons between different centers. At Yale-New Haven Hospital, the MMSE was administered preoperatively and again on postoperative day 4 by the same individual to minimize any variability attributable to the test-giver, and to minimize any effects of sedation or perioperative medications. All MMSE changes (improvements and decrements) were analyzed, as early retesting may produce a training effect [11].

Determination of PlA genotypes
Blood drawn into tubes containing 5 mmol/L ethylenediaminetetraacetic acid was spotted onto sterile filter paper and dried [12]. Disks cut out of the blood spot were placed in polymerase chain reaction tubes with 20 µL of methanol. After drying overnight, two separate polymerase chain reaction reactions were performed for PlA1 and PlA2 as reported by Skogen and associates [13]. Amplification products were electrophoresed onto a 2:1 Nusieve:Seakem agarose (FMC Bioproducts, Rockland, ME) gel in TBE (Tris, Boric acid, EDTA [ethylenediaminetetracetic acid]) buffer. Primers for ß-actin were included as a control [14].

Platelet and leukocyte activation
Four blood samples were drawn into fixative (1% paraformaldehyde) (1) at the start of surgery, (2) before and (3) after aortic cross-clamp release, and (4) on arrival in the intensive care unit. Platelet and leukocyte activation were examined by flow cytometry exactly as previously reported [15] using monoclonal antibodies to CD62P and CD11b, respectively.

Statistics
Genotype was categorized by the presence or absence of the PlA2 allele as in previous studies [6, 8]. PlA1 homozygotes were compared by unpaired two-sided Student’s t test to PlA2 heterozygotes or homozygotes for characteristics identified as preoperative neurocognitive risk factors [16]. The change in MMSE scores from the preoperative to the postoperative test ({Delta}MMSE) was analyzed as a continuous variable. Multiple linear regression using SAS software (SAS Institute, Cary, NC) evaluated the effect of PlA2 and circulating activated platelets and leukocytes on the {Delta}MMSE, with baseline MMSE performance and age as covariates.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
The prevalence of preoperative risk factors for post-CPB cognitive decline was comparable for PlA1 homozygotes versus PlA1/A2 and PlA2/A2 patients (Table 1). Patients were largely white (93%), and the PlA genotype distribution, 49 PlA1/A1 (70%), 18 PlA1/A2 (26%), and 3 PlA2/A2 (4%) was comparable to previously reported studies [9].


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  		Table 1. Baseline Patient Demographics

 
Follow-up neurologic testing on postoperative day 4 determined that the average change in MMSE scores ({Delta}MMSE) was -3.8 ± 5.3 for all patients. Fifty-two patients (74%) demonstrated some degree of neurocognitive decline (range, -1 to -29). There was a significant univariate relationship between {Delta}MMSE and PlA2 genotype by multiple linear regression analysis (p = 0.029). Multivariate analysis similarly demonstrated that both PlA2 genotype and baseline MMSE were significantly associated with the {Delta}MMSE (p = 0.024 and 0.037, respectively); age was not predictive of {Delta}MMSE. Figure 1 shows all 70 patients separated into four quartiles on the basis of {Delta}MMSE and demonstrates the proportion of PlA1 homozygotes versus PlA2 heterozygotes and homozygotes in each quartile. First quartile patients demonstrated either no change in MMSE or slightly improved scores (range 0 to +6), as sometimes noted with repeat MMSE (training effect) [11]. {Delta}MMSE scores of second quartile patients were -1 to -3. PlA1/A2 and PlA2/A2 patients represented 17% and 24% of the first and second quartiles, respectively. {Delta}MMSE scores for third and fourth quartile patients were -4 to -5 and -6 to -29, respectively; 33% of third quartile and 45% of fourth quartile patients were PlA1/A2 and PlA2/A2, confirming progressive enrichment for the presence of PlA2 as the post-CPB {Delta}MMSE worsened.



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  		Fig 1. Association of PlA genotypes with the change in Mini-Mental State Examination scores from the preoperative to the postoperative test ({Delta}MMSE). Patients were divided into quartiles by {Delta}MMSE. For each quartile, PlA1/A1 are represented by the open bars, and PlA1/A2 and PlA2/A2 by solid bars. (Q1 = improved or unchanged MMSE [range, 0 to +6; n = 18]; Q2 = slightly worse {Delta}MMSE [range, -1 to -3; n = 17]; Q3 = moderately worse {Delta}MMSE [range, -4 to -5; n = 15]; Q4 = most severe {Delta}MMSE [range, -6 to -29; n = 20].)

 
The percentage of circulating activated platelets increased over the course of CPB as previously detailed [15]. Univariate analysis revealed a significant association between the change in platelet activation and {Delta}MMSE (p = 0.003); this association, however, was not statistically significant by multivariate analysis (p = 0.13). The changes in platelet activation over time are shown in Figure 2, expressed as a percentage of their baselines, with patients divided according to their PlA genotype. Both groups demonstrated a comparable activation response to the stimulus of CPB, and overall the two groups were not statistically different. On the first postoperative day, however, the percentage of circulating activated platelets in the PlA1 homozygotes approached baseline, whereas in the PlA1/A2 and PlA2/A2 patients, circulating activated platelets persisted, suggesting either an ongoing prothrombotic process or decreased clearance of the already activated platelets. Circulating monocytes and neutrophils demonstrated increased surface expression of the ß2 integrin, CD11b, over time, but these were not significantly associated with the {Delta}MMSE in either univariate or multivariate analysis (p > 0.1).



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  		Fig 2. Platelet activation during cardiopulmonary bypass in patients according to PlA genotype. The circulating activated platelets (CD62P+ platelets) expressed as a percentage of baseline value are shown at the following time points: baseline (BASE), immediately before cross-clamp release (pXCR), 5 minutes after cross-clamp release (aXCR), immediately postoperatively (PACU), and on the morning of the first postoperative day (POD#1). For each time point, PlA1/A1 patients are represented by the open bars, and PlA1/A2 and PlA2/A2 by solid bars.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Neurocognitive decline is frequent after CPB, with alterations present in nearly 70% of patients soon after the operation [3]. This pilot study demonstrated that patients who carry the PlA2 allele demonstrated more severe early neurocognitive decline compared with PlA1 homozygotes. Whether this allele predisposes to plaque embolization, thrombotic processes aggravating the initial injury, or other factors contributing to neurocognitive decline is uncertain. GPIIIa is the ß3 subunit common to the platelet fibrinogen receptor, GPIIb/IIIa ({alpha}IIbß3 integrin), and the platelet and endothelial vitronectin receptor ({alpha}vß3 integrin). The PlA2 polymorphism results from a Leu33->Pro substitution in the GPIIIa amino terminus [17], and a recent study [18] demonstrating a lower activation threshold for PlA2 platelets suggests one mechanism for the allele’s prothrombotic effects. In the present study, increased platelet activation correlated with a greater decline in neurocognitive outcome in the univariate analysis suggesting that this may represent part of the PlA2 association with adverse neurologic outcome, but this did not hold up in the multivariate analysis. The greater percentage of activated platelets on postoperative day 1 in the PlA2+ patients suggests that postoperative events and processes may account for part of the enhanced risk conferred by this polymorphism, and the postoperative period deserves critical attention in further follow-up studies.

Weiss and colleagues [6] first demonstrated a greater prevalence of the PlA2 allele in coronary thrombosis patients, and others [8, 19] have supported this finding. However, the association of PlA2 and non-CPB stroke risk remains uncertain, with Carter and coworkers [9] demonstrating increased PlA2 prevalence in stroke patients, whereas Carlsson and associates [20] found no allelic enrichment of PlA2 among patients with stroke. Larger patient numbers and restriction to patients with ischemic stroke by Carter and coworkers [9] may explain this discrepancy in findings.

Neurobehavioral change after cardiac surgical procedures represents a major complication of CPB, despite changes in the conduct of bypass aimed at reducing its frequency [21]. Pharmacologic interventions have been investigated, with some investigators asserting that CPB represents an ideal testing ground for neuroprotective agents given its high frequency of adverse outcomes and the ability to medicate prophylactically [22]. These and other similar studies have given investigators an appreciation of the subtlety and complexity of the neurologic changes produced by CPB, and a recent consensus conference published considerations that should be entertained when selecting neuropsychologic tests in this setting [11]. The Multicenter Study of Perioperative Ischemia Research Group investigators were cognizant of these recommendations, but were constrained by needs unique to a multicenter study design. The MMSE is somewhat restricted in its range, with greater sensitivity to moderate-to-severe cognitive impairment, particularly in the verbal domain [5]. However, the proven applicability of the MMSE in many nationalities, its 25-year track record in evaluating progressive neurocognitive decline stemming from multiple causes, the minimal training needed for the test-giver, and its brevity [5] made it the best choice for an international study of neurocognitive changes early after CPB. As demonstrated graphically in Figure 1, fully 25% of patients had no detectable worsening in their neurologic status by MMSE. Another 25% had only a modest change in MMSE scores, typical for the average change found over more than 28 months time in an epidemiological study of a population aged 75 years and older [23]. However, the next lower 25% of patients demonstrated even more severe changes, and the worst 25% showed a decline in scores in the range associated with major neurobehavioral deterioration in Alzheimer’s disease [24]. Follow-up testing at a later date will be performed to determine what proportion of these changes are transient.

Our study has demonstrated a link between the PlA2 allele and neurocognitive decline early after CPB, suggesting that the PlA2 polymorphism may exacerbate preexisting vascular pathologies. Larger studies will be needed to confirm this association and to determine whether PlA2 predicts a higher incidence of permanent neurocognitive deficits.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Joseph Mathew and Christine Rinder contributed equally and should be considered co-first authors. This study was supported by National Institutes of Health grant HL-47193 (B.R.S.) and a grant from the Ischemia Research and Education Foundation. Doctor C. Rinder is an American Heart Association Clinician-Scientist Award recipient.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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