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Ann Thorac Surg 2004;77:869-874
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Clinical significance of PlA polymorphism of platelet GP IIb/IIIa receptors during long-term VAD support

Evgenij V. Potapov, MDa*, Stanislav Ignatenko, MDa, Boris A. Nasseri, MDa, Matthias Loebe, MD, PhDd, Cornelia Harkea, Martin Bettmann, MDa, Anke Doller, MDb,c, Vera Regitz-Zagrosek, MD, PhDb,c, Roland Hetzer, MD, PhDa

a Departments of Cardiothoracic and Vascular Surgery, Berlin, Germany
b Cardiovascular Disease in Women, Deutsches Herzzentrum Berlin, Germany
c Charité, Campus Virchow Klinikum, Humboldt University, Berlin, Germany
d Michael E. DeBakey Department of Surgery, Division of Transplantation and Assist Devices, Baylor College of Medicine, Houston, Texas, USA

Accepted for publication August 19, 2003.

* Address reprint requests to Dr Potapov, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
e-mail: potapov{at}dhzb.de


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Although bleeding and thromboembolism remain major complications after implantation of ventricular assist devices (VADs), no standard anticoagulation protocols are available. Genetic polymorphism of platelet glycoprotein IIb/IIIa may contribute to the development of complications. The present study demonstrates a relationship between the PlA genotype and postoperative complications in patients implanted with pulsatile and axial flow VADs.

METHODS: The PlA genotype was determined in 41 consecutive patients treated with a VAD who received anticoagulation with phenprocoumon and aspirin. Pulsatile Novacor (Novacor Corp, Oakland, CA) and Berlin Heart VADs (Berlin Heart, Berlin, Germany) were implanted in 28 patients and the axial flow MicroMed DeBakey VAD (MicroMed Technology, Inc, Houston, TX) in 13. The relationship between the PlA genotype, the anticoagulation regime, and bleeding and thromboembolic events was analyzed.

RESULTS: There were no differences between patients with the A1A1 and A1A2 genotype regarding demographic characteristics, weight, or infection episodes. The international normalized ratio (INR), platelet activation tests, and doses of aspirin and dipyridamol before events were similar in both groups. Patients with the A1A1 genotype developed more bleeding complications (39% vs 0%, p = 0.021), while patients with the A1A2 genotype showed a tendency toward more thromboembolic events (13% vs 30%, p = 0.33). With regard to different types of VAD, patients with the axial flow DeBakey VAD and the A1A1 genotype developed significantly more bleeding complications (70% vs 0%, p = 0.033).

CONCLUSIONS: In patients with a long-term VAD determination of PlA polymorphism and subsequent adjustment of the anticoagulation regime may lead to a reduction of bleeding and thromboembolic complications.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
The implantation of a ventricular assist device (VAD) is an established procedure for patients with end stage heart failure. Due to the continuing shortage of donor organs [1], an increased number of patients on a VAD required support for months or years. Recently, different types of VADs have been used for long-term support. During long-term VAD therapy one of the important issues is balanced anticoagulation. Despite new data concerning coagulatory processes during long-term VAD support [2] and the use of extended control tests such as the international normalized ratio (INR), the thrombocyte aggregation test (TAT), and the thrombelastogram (TEG), thromboembolic and bleeding complications remain major limitations for long-term VAD support and for the VAD as a definitive therapy [3].

Currently, sophisticated anticoagulation strategies tailored for different types of VAD are used in different centers [2, 4, 5], but as yet no standard anticoagulation protocols have been developed [4, 6]. For patients on the HeartMate (Thoratec Corp., Pleasanton, CA) left (L)VAD, only acetylsalicylic acid is suggested for long-term anticoagulation to minimize the rate of thromboembolic events, while patients on the Novacor (Novacor Corp, Oakland, CA) left ventricular assist system (LVAS), Berlin Heart (Berlin Heart, Berlin, Germany), and Thoratec (Thoratec Laboratories Corp, Pleasanton, CA) should be treated additionally with phenprocoumon and platelet aggregation inhibitors. In patients with an axial flow VAD, the anticoagulation protocol mostly includes phenprocoumon, acetylsalicylic acid, and dipyridamol [2, 4, 7, 8].

Platelet activation plays a central role in arterial thrombosis [9]. Platelet activation by various agonists renders the major platelet integrin, von Willebrand factor, vitronectin, and glycoprotein (GP) IIb/IIIa (a functional adhesion receptor for binding fibrinogen) a final pathway for platelet aggregation.

The GP IIb/IIIa receptor is polymorphic and the PlA alloantigen, coding for GP IIb/IIIa, has two antigenic determinants, A1 and A2, located in a 17 to 23 kD fragment of GP IIIa. The genes for GP IIb and IIIa are contained within a single 260 kb segment in the q21 to 23 band of chromosome 17. The distribution in the German population is 70.2% for A1A1, 27.2% for A1A2, and 2.6% for A2A2[10].

We hypothesized that genetic polymorphism of platelet GP IIb/IIIa may contribute to the development of thromboembolic and bleeding complications during long-term VAD support.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 Acknowledgments
 References
 
Study population
Between 1999 and 2002, 41 patients more than 16 years old on VAD support and receiving phenprocoumon and acetylsalicylic acid, were included in the study. All patients gave written consent and the study protocol was approved by the institutional ethics committee. The study population included 13 patients implanted with the MicroMed DeBakey VAD (MicroMed Technology, Inc, Houston, TX) with Carmeda coating, 11 patients with the Novacor LVAS N100, and 17 with the Berlin Heart VAD with Carmeda coating.

Determination of PlA genotypes
Genotyping was performed after the follow-up was completed. A 10 mL venous blood sample was taken in a tube containing ethylenediamine tetraacetic acid (EDTA) and stored at -70°C for subsequent DNA extraction. The DNA was isolated as described by Miller and colleagues [11]. Platelet antigen genotypes were determined by allele-specific restriction enzyme analysis [12, 13]. Briefly, a 268 base pair sequence containing exon 3 of the GP IIIa gene was amplified by polymerase chain reaction (PCR) using specific primers: the sense primer 5'-TTCTGATTGCTGGACTTCTCTT and the reverse primer 5'-TCTCTCCCCATGGCAAAGAGT [10]. Polymerase chain reaction was carried out in a 25-µL volume containing 60 ng genomic DNA, 10 pmol of each primer, 50 mmol/L KCl, 10 mmol/L TRIS-HCl (pH 8.3), 1.5 mmol/L MgCl2M, 200 µmol/L of each dNTP and 0.5 U Taq DNA polymerase (Invitrogen, Karlsruhe, Germany). Samples were processed in a GenAmp PCR System 9600 (Perkin Elmer Cetus). After an initial 5-minute denaturation at 94°C, 35 temperature cycles were carried out consisting of 30 seconds at 94°C, 30 seconds at 54°C, and 30 seconds at 72°C, followed by a final extension step of 10 minutes at 72°C. Polymerase chain reaction efficiency was checked on a 2% agarose gel for 20 minutes at 120 V. Five µL of the amplified product were digested with 10 U MspI (MBI Fermentas, St. Leon Rot, Germany) in a final volume of 20 µL at 37°C overnight, in accordance with the relevant manufacturer's recommendations. Fragments were separated on a 10% polyacrylamid gel (49/1 acrylamid/bisacrylamid) containing 0.5x TBE for 120 minutes at 120 V. Restriction profiles were visualized by silver staining [14].

Definitions of events during follow-up
During follow-up, the following were defined as severe bleeding events: primary cerebral bleeding, late pocket bleeding requiring transfusion of packed red blood cells, late pericardial tamponade requiring surgery, or hemothorax requiring insertion of a chest tube. Secondary cerebral bleeding due to a thromboembolic event or lysis for pump thrombosis were excluded from the analysis.

As thromboembolic events, were defined: pump thrombosis, pump stop due to thrombosis (in patients with the DeBakey VAD), transitory ischemic attack, transient or persistent neurologic deficit, as well as clinically evident thromboembolic events in peripheral arteries. Thromboembolic events occurring after changes in the anticoagulation regime due to bleeding events were excluded from the analysis.

Anticoagulation regime
Anticoagulation in all patients in the late postoperative period was performed using oral administration of phenprocoumon, acetylsalicylic acid, and dipyridamol. The target INR in all patients before analyzed events was 3.5 and the target suppression of platelet activation (TAT) with arachidonic acid was 30%. Doses of acetylsalicylic acid and dipyridamol, measured INR, and the actual results of TAT immediately before an event were analyzed. If the patient suffered from the event after discharge, the last INR and TAT results before discharge were used for analysis. Due to incomplete data, and in some patients a long time period between the last TEG and the event, the TEG results were not included in the study.

Infection episodes
Infection requiring rehospitalization and IV use of antibiotics, such as pneumonia, pocket infection, or sepsis, were analyzed.

Analysis of complications
The complications were analyzed with regard to the PlA genotype. An additional analysis was performed with the patients divided into two subgroups depending on the type of assist device: continuous flow VAD (Micromed DeBakey VAD, n = 13) and pulsatile flow VAD (Novacor LVAS and BerlinHeart VAD, n = 28).

Statistical analysis
Statistical analysis was performed using SPSS 11.0 (SPSS Inc., Chicago, IL). Quantitative data are presented as means and standard deviation or 95% confidence intervals, qualitative data as numbers and percent. The Pearson {chi}2 [2] test was used to test for group differences for qualitative data. Univariate logistic regression was performed to analyze the impact of different factors on the occurrence of bleeding or thromboembolic events. A multivariate analysis could not be performed because of the small number of events. Freedom from bleeding was calculated using Kaplan-Meier estimates. To test for differences between the two genotypes a log rank test was used. A reference value of p of less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 Acknowledgments
 References
 
The patients were divided into two groups: carriers of the A1A1 genotype (n = 31) and carriers of the A1A2 genotype (n = 10). There were no carriers of the A2A2 genotype in the study population.

There were no significant differences between the groups with regard to demographic data, body weight, infection episodes, or follow-up time (Table 1). The genotype distribution in the study population, as well as in the subgroups (axial flow VAD and pulsatile flow VAD), was in Hardy-Weinberg equilibrium. There were no differences between patients with different genotypes with regard to acetylsalicylic acid and dipyridamol doses before the event or between patients with A1A1 and A1A2 genotypes in the subgroups (Fig 1). There were no differences between patients with different genotypes with regard to INR (Fig 2) or TAT results (data not shown) before the event or if patients with A1A1 and A1A2 genotypes were compared in the subgroups.


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  		Table 1. Demographic Characteristics of Patients With Different Genotype

 


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  		Fig 1. Mean acetylsalicylic acid and dipyridamol doses in patients with A1A1 and A1A2 genotypes in the study population, in patients with the Micromed DeBakey VAD and in patients with a pulsatile VAD before event. The vertical bars represent 95% confidence interval (CI). No significant differences were noted between patients with different genotypes. (BH= Berlin Heart; VAD = ventricular assist device.)

 


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  		Fig 2. Mean INR in patients with A1A1 and A1A2 genotypes in the study population, in patients with the Micromed DeBakey VAD and in patients with a pulsatile VAD before event. The vertical bars represent 95% confidence interval (CI). No significant differences were noted between patients with different genotypes. (BH = Berlin Heart; INR = international normalized ratio; VAD = ventricular assist device.)

 
Patients with the A1A1 genotype presented significantly more bleeding complications than patients with the A1A2 genotype (39% vs 0%, p = 0.021), while patients with the A1A1 genotype presented a tendency toward less thromboembolic complications than patients with the A1A2 genotype (13% vs 30%, p = 0.33). The Kaplan-Meier analysis for all patients showed significant differences between patients with different genotypes (p = 0.011) and is presented in Figure 3. The analysis in subgroups showed that patients with the axial flow VAD and A1A1 genotype presented significantly more bleeding complications than patients with the axial flow VAD and A1A2 genotype (70% vs 0%, p = 0.033), while the rate of thromboembolic events was similar (20% vs 0%, p = 0.4). Patients with a pulsatile VAD and the A1A1 genotype showed a tendency towards more bleeding complications than patients with a pulsatile VAD and the A1A2 genotype (24% vs 0%, p = 0.29), while the A1A1 patients showed a tendency towards a lower rate of thromboembolic events (10% vs 43%, p = 0.08).



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  		Fig 3. Kaplan-Meier analysis of freedom of bleeding events in all patients. There were significantly more bleeding events in patients with the A1A1 genotype (p = 0.011).

 
The results of the univariate analysis for bleeding events are presented in Table 2. The univariate analysis showed no significant risk factors for thromboembolic events (data not shown). A multivariate analysis was not performed due to the small number of patients and events.


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  		Table 2. Results of the Univariate Analysis for Bleeding Event

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
Acknowledgments
 References
 
The study showed a significant association of the PlA A1A1 genotype with bleeding and a trend towards association of A1A2 with thromboembolic events during long-term mechanical circulatory support.

Contact between blood components and the artificial surfaces of the VAD leads to alterations in the physiologic balance between procoagulatory and anticoagulatory pathways with an increased tendency toward bleeding in the early postoperative period and toward thromboembolism in the late postoperative period [15–17]. The platelet activation follows adhesion, which can be stimulated by contact with the artificial surfaces of the VAD [2].

The pathogenesis of thrombosis is influenced by the genetic profile that drives the synthesis of plasma proteins or the expression of the receptors for agonists and adhesive proteins, both in platelets and endothelial cells. The GP IIb/IIIa complex plays a pivotal role in mediating platelet aggregation. The activation of platelets is associated with changes in the conformation of the GP IIb/IIIa complex, which becomes a functional complex for fibrinogen, von Willebrand factor, and other related adhesive proteins [9, 18, 19]. Consequently, the presence of structural polymorphism in such proteins could affect the role of these molecules in the hemostasis process. An association between the polymorphism of the GP IIb/IIIa and the occurrence of acute coronary thrombosis has been reported [20, 21]. Some studies demonstrated an elevated rate of restenosis after stenting of coronary arteries [22] in carriers of the A2 allele, more thromboembolic events and more extensive complicated lesions of the coronary arteries [23], and an association with coronary artery disease in low risk patients [24]. A prolonged bleeding time was shown in carriers of the A1A1 genotype [25].

Senti and colleagues showed a higher fibrinogen concentration in subjects with the A1A1 genotype [26], while Undas and colleagues found that A2 carriers exhibit higher consumption rates for fibrinogen and prothrombin 27]. These findings are in accord with our results, which show more bleeding complications in VAD patients with the A1A1 genotype and a trend towards more thromboembolic complications in VAD patients with the A1A2 genotype.

The different effect of acetylsalicylic acid in patients with different PlA genotypes may substantially contribute to the differences between groups in postoperative complications. It has been found that the A1A1 subjects are more sensitive to acetylsalicylic acid [27]. In the A1 homozygotes, acetylsalicylic acid ingestion resulted in reductions in the velocity of thrombin formation, prothrombin consumption, and fibrinogen removal, while the presence of the A2 allele is associated with an impaired antithrombotic action of acetylsalicylic acid. Acetylsalicylic acid ingestion in these individuals did not result in reductions in the velocity of thrombin formation, prothrombin consumption, or fibrinogen removal [27]. Although there were no significant differences between groups in doses of acetylsalicylic acid and the level of suppression of platelet aggregation, there were significant differences between patients with the A1A1 and A1A2 genotype with regard to postoperative events.

The results of the univariate analysis showed that the high daily doses of acetylsalicylic acid ( > 300 mg) may increase the risk of bleeding complications (Table 2) without decreasing the risk of thromboembolic events. The thrombin-lowering action of acetylsalicylic acid in the range between 75 and 300 mg daily, given for 7 days, is not dose dependent [28]. It has been shown in large clinical studies that the antithromboembolic effect of acetylsalicylic acid does not increase with doses more than 300 to 350 mg daily, while an incidence of bleeding complications is dose related and increases with increased doses of acetylsalicylic acid [29–33]. A large meta-analysis showed that doses of 75 to 150 mg daily were at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain [34].

Interestingly, despite the different design and different impact of axial and pulsatile VADs on platelets [2], it seems that the type of VAD showed no significant impact on thromboembolic events in the study. The not significantly increased risk for bleeding in patients in the present study (OR 3.14, p = 0.113 with wide ranges between 0.8 and 13) may suggest some impact of the type of device; however, the fact that the patients with axial flow pumps received more acetylsalicylic acid (Fig 1) should be taken into account as a confounding variable.

The coagulatory system, as part of the inflammatory system, is influenced by the clinical status of the patient, which also contributes to the development of thromboembolic complications [15, 35, 36]. However, in the present study there were no differences between groups for infection episodes.

Since the presence of the A2 allele in the study population is approximately 25%, which is similar to the findings reported from a number of large studies [24, 37], it is important to take the present findings into consideration in creating a tailored anticoagulation therapy in patients supported with a VAD. In these patients, determination of PlA polymorphism and corresponding adjustment of platelet inhibitor doses may lead to a reduction of bleeding and thromboembolic complications. Further, high doses of aspirin should be avoided in all VAD patients, while additional use of clopidogrel in patients with the A1A2 genotype should be discussed.

Limitations of the study
The present study uncovered the relationship between PlA polymorphism and postoperative complications in patients on VADs and treated with phenprocoumon, acetylsalicylic acid, and dipyridamol. The small number of patients, the main limitation of the study, means that it is not sufficiently powered to avoid type II errors. This fact also precludes a multivariate analysis to substantiate the observations made by univariate analysis and taking into account confounding variables. More definitive statements could only be based on a study with significantly more patients enrolled, and consequently, a large prospective study to evaluate the impact of different anticoagulation strategies in patients with different genotypes is necessary.

Conclusion
The study showed a significant association of the PlA A1A1 genotype with bleeding and of A1A2 with thromboembolic complications during long-term follow-up in patients implanted with a VAD. In VAD patients, determination of PlA polymorphism and corresponding adjustment of platelet inhibitor doses may reduce bleeding and thromboembolic complications.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
References
 
We are grateful to Julia Stein for statistical advice and Anne Gale for editorial assistance.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 

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