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European Journal of Heart Failure 2002 4(4):461-467; doi:10.1016/S1388-9842(02)00026-0
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© 2002 European Society of Cardiology

Whole blood impedance aggregometry for the assessment of platelet function in patients with congestive heart failure (EPCOT Trial)

V.L. Serebruanya,*, M.E. McKenziea, A.F. Meistera, S.Y. Fuzaylova, P.A. Gurbela, D. Atarb, W.A. Gattisc and C.M. O'Connorc

a Sinai Hospital, Johns Hopkins University Baltimore, MD, USA
b Frederiksberg University Hospital, Frederiksberg Copenhagen, Denmark
c Duke Clinical Research Institute Durham, NC, USA

* Corresponding author. Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 West Belvedere Avenue, Schapiro Research Building – R 202; Baltimore, MD 21215, USA. Tel.: +1-410-601-5266; fax: +1-410-601-9061 E-mail address: heartdrug{at}aol.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Objective: Data from small studies have shown the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of the whole blood aggregometry (WBA) in a random outpatient CHF population.

Methods: Blood samples were obtained for measurement of whole blood aggregation, shear-induced closure time, platelet contractile force, expression of GP IIb/IIIa, and P-selectin in 100 consecutive patients with CHF.

Results: Substantial inter-individual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Surprisingly, aspirin use did not affect instrument readings as well. Whole blood aggregometry correlates well with the closure time (r2=0.587), and with GP IIb/IIIa expression (r2=0.435). Significant but less strong correlation has been observed for the WBA with platelet P-selectin expression (r2=0.295), and no correlation was present for the platelet contractile force measures (r2=0.030).

Conclusions: Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes, in their platelet characteristics, whole blood impedance aggregometry is indeed capable to serve as a valuable diagnostic tool, and may be successfully used as an established screening device in this population. Ability of the whole blood aggregometry to predict clinical outcomes, or for the monitoring of anti-platelet agents in CHF patients, will be evaluated in the ongoing clinical trials.

Key Words: Platelet function • Whole blood aggregometry • Congestive heart failure • Human

Received January 10, 2001; Revised December 10, 2001; Accepted January 21, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 
Congestive heart failure (CHF) is a major health problem among Americans, with an estimated prevalence of 4–5 million [1]. Despite major advances in treatment, including angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, mortality remains high [2]. In recent years evidence has been presented showing that patients who were receiving anticoagulant therapy in the setting of CHF had lower mortality rates than their non-anticoagulated counterparts [3]. The Studies of Left Ventricular Dysfunction (SOLVD) trial showed significantly reduced numbers of both cardiovascular related deaths as well as overall hospital admissions for patients with CHF on Warfarin [4]. As early as the 1970s, studies have suggested that platelet activity is increased in patients with CHF [5]. Many markers of platelet activation have been shown to be increased in these patients, including beta-thromboglobulin [6–8], P-selectin [9], PECAM-1 [10], and osteonectin [10]. Markers of thrombin activation and fibrinolysis, such as fibrinopeptide A [11], D-dimer, and thrombin-anti-thrombin III complexes, are also elevated in CHF [6,7,11]. Interestingly, studies have shown an elevation in several of the above markers regardless of whether the CHF was ischemic or non-ischemic in etiology [6,7,11]. The exact role of a possible pro-coagulant state in the development and progression of CHF is unknown at this time, and studies are ongoing.

Platelet activation may play an important role in the deterioration of the failing heart due to the development of microthrombi in the myocardium. Conventional platelet rich plasma aggregometry is still the ‘gold standard’ for the majority of clinical laboratories assessing platelet function. Platelet aggregation can be assessed with turbidimetric instruments or, more conveniently and faster, with whole blood impedance aggregometry (WBA) [12].

We sought to assess the diagnostic utility of WBA in selecting patients with the heightened platelet activity in the CHF population, and to compare impedance aggregometry measurements in autologous blood samples with closure time using the platelet function analyzer (PFA-100), surface receptor expression by flow cytometry, and platelet contractile force with the hemostatic analyzer.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Acknowledgments
 References
 
2.1. Study patients
The study was approved by the regional ethics committee and all subjects gave informed consent. One hundred consecutive outpatients were enrolled at the Duke University Heart Failure Clinic. Detailed patient's clinical characteristics are presented in Table 1. All had symptoms for at least 3 months, with no change in medication during the last month. Information on antecedent aspirin use was obtained as part of the study protocol. Aspirin use was defined as self-reported daily consumption of at least 81 mg of acetylsalicylic acid containing medication (coated or uncoated). Patients with decompensated heart failure or receiving an antithrombotic agent other than aspirin or Warfarin were excluded.


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  		Table 1 Clinical characteristics of the CHF patients

 
2.2. Samples
Blood was drawn between 08:00 h and 10:00 h in order to avoid any diurnal influence and sampled from an antecubital vein using a 19-gauge butterfly needle. The sample was transferred into vacuum filled tubes containing 3.8% sodium citrate (1:9 volume) after having discarded the first 1.5 ml of free running blood. Three Vacutainer tubes (7.0 ml) were collected for a total of 21 ml of whole blood–citrate mixture from each patient. To avoid possible observer bias, blood samples were coded and blinded. Sampling procedures and platelet studies were performed by phlebotomists unaware of the protocol. Whole blood aggregometry (Model 591/592, Chronolog Corporation, Harertown, PA, USA), as well as closure time by the PFA-100 (Dade Behring, Inc., Miami, FL, USA), whole blood flow cytometry (FACScan, Becton Dickinson, Inc., San Diego, CA, USA), and platelet contractile force by RM2 Instrument (Hemodyne, Inc., Richmond, VA, USA) were measured.

2.3. Whole blood impedance platelet aggregation
The Chronolog whole blood impedance aggregometer (Model 591/592) is a simple, compact instrument suitable for routine determinations of platelet aggregation in whole blood. The method was described in detail elsewhere [13]. Briefly, a 1:1 dilution with 0.5 ml of physiological saline and the specimen of whole blood is made in a sample cuvette and placed in the device reaction well. The electrode is inserted in the sample cuvette and the platelets in the blood sample adhere to two fine palladium wires on the electrode, forming uniform monolayers of platelets coating the wires. A small voltage difference is applied across the two wires, and the impedance caused by the platelets coating the wires is measured. In the absence of an aggregating agent or agonist, the interactions between the platelets and the electrodes stabilize, and the impedance between the two electrodes becomes constant, producing a baseline. When an agonist is added, platelets in the specimen are activated and begin to aggregate. The platelet coating on the palladium wires thickens over the next several minutes with a corresponding increase in electrical impedance between the electrode wires. This change in impedance is directly proportional to the extent of platelet aggregation and is indicated on the digital display in ohms after 6 min. Platelet aggregation was stimulated with 20 µmol ADP. Platelet aggregability was expressed as the change in electrical impedance and is expressed in ohms. Aggregation curves were recorded for 6 min and analyzed using AGGROLINK® software.

2.4. Closure time
The PFA-100TM is a high shear-inducing analyzer that simulates primary hemostasis after injury to a small vessel under flow conditions [14]. The device provides a constant negative pressure that aspirates a whole blood–citrate mixture. This mixture comes into contact with a collagen-coated membrane and then passes through an aperture. The time required to obtain occlusion of the aperture is digitally recorded. Precision testing is reported to show a coefficient of variation of <10% for within-day and between-day analyses on collagen/ADP cartridges and 5–14% for collagen/epinephrine cartridges [15]. Collagen/epinephrine cartridges are reported to show qualitative platelet defects, such as acetylsalicylic acid induced abnormalities, while collagen/ADP cartridges show thrombocytopathies but not qualitative platelet abnormalities.

2.5. Whole blood flow cytometry
This method was previously described in detail [16,17]. In brief, TBS buffer and fluorescein isothiocyanate (FITC) conjugated monoclonal antibodies to P-selectin (PharMingen, Inc, San Diego, CA, USA) and GP IIb/IIIa (DAKO, Inc, Carpenteria, CA, USA) were removed from the refrigerator and allowed to warm at room temperature. Amber tubes (1.25 ml) and Eppendorf tubes (1.5 ml) were marked and labeled appropriately. TBS buffer (450 µl) was pipetted into an Eppendorf tube, mixed with 50 µl of whole blood, and incubated with 5 µl of appropriate antibody at room temperature for 30 min. After incubation, 400 µl of 2% buffered para-formaldehyde was added. Samples were stored in the refrigerator at 4 °C until further analysis, which was done within 48 h using a FACScan flow cytometer. The data were collected in list mode files and then analyzed using CellQuest (1.3) software.

2.6. Platelet contractile force
The operating procedures for the hemostatic analyzer is described in detail elsewhere [18]. This instrument measures the force developed by platelets as they undergo cellular contraction and speed of clot formation in whole blood between a thermostated cup and parallel upper plate. Before gelation, the upper plate is centered above the cup and lowered into the clotting solution. As the clot forms, it attaches to the inner walls of the cup, and the bottom of the upper plate. A small portion of the upper clot surface, between the outer edge of the upper plate and the inner wall of the lower cup, is initially exposed to air. Evaporation is prevented by covering the air–clot interface with a thin layer of silicone oil. Once clotting is complete, platelets within the network pull fibrin strands inward, transmitting force through the network to the surfaces to which the clot is adherent. Force measurement is accomplished utilizing a force displacement transducer coupled to the upper plate and is expressed in kilodynes [19].

2.7. Statistical analyses
A post hoc comparison t-test and regression analysis were performed to identify specific correlation between the CHF clinical characteristics and WBA measures. A simple linear regression analysis was performed to identify the relation between the different platelet measurements in the same patient. An r2>0.200 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Acknowledgments
 References
 
After eight samples were excluded for quality concerns, 92 samples were analyzed. Table 2 represents the differences in the platelet measures dependent on the clinical characteristics of the patients with CHF. There were no statistically significant differences when patients were divided by the incidence of vascular events, emergency revascularization needs, or survival. Etiology of heart failure also appears to not be related to the WBA measures. Neither severity of heart failure nor aspirin use affected instrument readings. Figs. 1–4 represent individual plots of WBA's correlation with the closure time (Fig. 1), expression of GP IIb/IIIa (Fig. 2), surface P-selectin (Fig. 3), and platelet contractile force (Fig. 4). Whole blood aggregometry correlates well with the closure time, exhibiting a statistically high curve fit regression rate of (r2=0.587). WBA also correlates well with GP IIb/IIIa expression (r2=0.435). Significant correlation was observed for the WBA with platelet-bound P-selectin (r2=0.295), but no correlation with platelet contractile force measures (r2=0.030) was observed.


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  		Table 2 Effect of clinical characteristics of CHF patients on the platelet measures

 


Figure 1
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  		Fig. 1 Correlation between whole blood impedance platelet aggregability induced by 20 µM ADP with the shear induced closure time. r2>0.2 is usually considered significant in regression analysis.

 


Figure 2
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  		Fig. 2 Correlation between whole blood impedance platelet aggregability induced by 20 µM ADP with platelet expression of glycoprotein IIb/IIIa. r2>0.2 is usually considered significant in regression analysis.

 


Figure 3
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  		Fig. 3 Correlation between whole blood impedance platelet aggregability induced by 20 µM ADP with platelet bound P-selectin. r2>0.2 is usually considered significant in regression analysis.

 


Figure 4
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  		Fig. 4 Correlation between whole blood impedance platelet aggregability induced by 20 µM ADP with platelet contractile force. r2>0.2 is usually considered significant in regression analysis.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Acknowledgments
 References
 
The important role of platelets in patients with CHF has received increasing recognition in recent years. One attractive theory links CHF with acquired platelet dysfunction. Most researchers agree that platelet-related characteristics could affect both short- and long-term outcome in patients with CHF. Platelet activity is not currently measured in patients with CHF as a matter of routine. However, as more is learned about the role of heightened platelet function, and initial attempts are made to introduce anti-platelet therapy in this population, the ability to quantify platelet status becomes more clinically relevant.

The whole blood platelet impedance aggregometer (Model 591/592) is a relatively new but already established instrument for quantifying platelet activity. There are some data that WBA may serve as a valuable tool to detect patients with platelet dysfunction more efficiently and cost-effectively than conventional aggregometry, and have a potential use as a monitor the efficacy of aspirin treatment [20]. However, assessment of the WBA was not helpful for the identification of the aspirin users in our study. Prospective trials have to be conducted to demonstrate whether the WBA changes achieved under chronic aspirin intake could be suitably distinguished and have a positive predictive value for cardiovascular outcome.

The WBA has been reported to be a valuable tool for monitoring GP IIb/IIIa inhibitors during coronary interventions [21,22], and as a screening device for platelet function assessment in patients with acute myocardial infarction undergoing thrombolytic therapy [23]. Other investigators have reported that WBA was suitable for monitoring platelet function in patients undergoing heart surgery [24], and with diabetes [25]. The diagnostic utility of WBA has been observed in patients with myeloproliferative disorders [26], and for the early diagnosis of pre-eclampsia [27]. Finally, the instrument has also been reported to be a useful test to screen for abnormalities in primary hemostasis in the pediatric population [28].

We have found a strong correlation of the WBA with the closure time, GP IIb/IIIa expression, and platelet-bound P-selectin expression suggesting that WBA is a valuable method for the assessment of platelet function. However, there were no differences in the WBA dependent on the clinical characteristics of heart failure or aspirin use. There may be several explanations for this. First, platelet function may not be directly related to the severity of heart failure. It is entirely unknown whether platelet activity is associated with the outcome, prognosis, and deterioration of the failing myocardium. Second, considering that CHF patients commonly are treated with multiple medications (5.6 drugs average for each EPCOT participant), other pharmaceuticals may interfere with aspirin, reducing, or at least compromising, the antiplatelet effect. Finally, there are a variety of other confounding factors (e.g. biomarkers and hormones imbalance, coagulopathy, etc.) jeopardizing our ability to detect minor platelet abnormalities in these patients. Another possible reason that WBA in our study was not capable in detecting aspirin use is because 20 µM ADP has been used as an agonist. Indeed there are reports that collagen-induced WBA may serve better for determining anti-platelet effects of aspirin [29,30].

In conclusion, timely evaluation of platelet activity could contribute significantly to the safety and success of adjunctive anti-platelet strategies and/or prognosis in the CHF population. Despite the fact that patients with heart failure enrolled in the EPCOT trial exhibited marginal, sometimes oppositely directed changes in the platelet function, a strong correlation of WBA with the shear-induced closure time and with the platelet expression of GP IIb/IIIa and P-selectin prove that the whole blood impedance aggregometer is indeed a valuable platelet analyzer and may be successfully used for screening CHF patients. Ability of whole blood aggregometry to predict clinical outcomes or for the monitoring of anti-platelet agents in CHF patients will be evaluated in the ongoing clinical trials.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
References
 
This work was supported by HeartDrugTM Research, LLC (Wilmington, DE, USA), the Duke Clinical Research Institute (Durham, NC, USA), the Danish Medical Research Council (grant-nr. 22-01-0307 to D.A.), and the Danish Heart Foundation (grant-no. 00-2-3-46-22854 to D.A.). These data were presented in part at the XXIInd Congress of the European Society of Cardiology (Amsterdam, The Netherlands; August 26–30, 2000).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Acknowledgments
 References
 

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