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Ann Thorac Surg 1998;66:373-381
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Integrilin prevents prolonged bleeding times after cardiopulmonary bypass¹

^a Harrison Surgical Research Laboratories, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
^b Sol Sherry Thrombosis Research Center, Department of Medicine, Temple University, Philadelphia, Pennsylvania, USA
^c COR Therapeutics Inc, San Francisco, CA, USA

Address reprint requests to Dr Edmunds, Department of Surgery, Hospital of University of Pennsylvania, 6 Silverstein, 3400 Spruce St, Philadelphia, PA 19104-4283
e-mail: (hedmunds{at}mail.med.upenn.edu)

Presented at the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 26, 1998.

	Abstract

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Cardiopulmonary bypass reduces platelet number and function, increases postoperative bleeding time, and is the major, unsolved cause of nonsurgical bleeding after open heart operations. Temporary inhibition of platelet function during cardiopulmonary bypass (platelet anesthesia) protects platelets and reduces postoperative bleeding time and bleeding.

Methods. Integrilin, a short-acting, reversible platelet glycoprotein IIb/IIIa inhibitor was studied in 28 baboons that had 60 minutes of normothermic cardiopulmonary bypass using peripheral cannulas. A control group, two groups that received different doses of Integrilin, and a group that received a combination of Integrilin and low-dose Iloprost were studied. Blood samples for platelet count, aggregation to adenosine diphosphate, ß-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, and fibrinopeptide A were obtained at seven time points. Template bleeding times were measured before and at five intervals after cardiopulmonary bypass.

Results. Both doses of Integrilin and the combination of Integrilin and Iloprost significantly protected platelet number, inhibited the response to adenosine diphosphate, and reduced postoperative bleeding times, but they did not reduce ß-thromboglobulin release except in the high-dose Integrilin group. Thrombin formation and activity were qualitatively, but not significantly, reduced in all treatment groups. Bleeding times were not significantly different from baseline at the time protamine was given in the combination group and 60 minutes after protamine administration in all treatment groups.

Conclusions. Integrilin alone or in combination with Iloprost significantly reduces platelet activation during cardiopulmonary bypass and produces normal or near-normal bleeding times at the time protamine is given.

	Introduction

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Open heart operation dilutes and activates platelets to adhere to biomaterial surfaces [1], to form aggregates [2] and microparticles [3], and to synthesize and release a variety of chemical mediators [2, 4, 5]. By the end of cardiopulmonary bypass (CPB) platelet count and function are reduced [2, 4, 5] and bleeding time is prolonged [4]. Loss of platelet numbers and function is the most important, unsolved, nonsurgical cause of postoperative bleeding after open heart surgery [4].

Platelets are activated to express membrane receptors and to release chemical mediators in both the perfusion circuit and the wound [4, 6]. Because thrombin is the most likely agonist [7], suppression of thrombin formation, which is not yet possible, is necessary for preventing platelet activation by more compatible biomaterials. An alternative approach is to inhibit platelets during CPB and to reverse the inhibitor shortly after CPB ends. This concept of platelet anesthesia has been tried with a variety of reversible platelet inhibitors [4, 8–10], but because of serious side effects or delayed restoration of function no inhibitor has achieved the goal of a normal bleeding time at the time heparin is reversed by protamine.

Integrilin (eptifibatide; COR Therapeutics, Inc, San Francisco, CA) is a synthetic, disulfide-linked cyclic heptapeptide with a modified KGD sequence that has high affinity and specificity for the platelet glycoprotein IIb/IIIa integrin [11]. Integrilin inhibits platelet aggregation and adhesion. The drug has high potency, rapid onset of action, and a short half-life in plasma [11, 12]. We tested the ability of Integrilin to provide platelet anesthesia alone or with the prostacyclin analogue Iloprost (Berlex Laboratories, Cedar Knolls, NJ), during CPB in baboons.

	Material and methods

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Preliminary studies
Initial bolus and subsequent infusion doses of Integrilin and Iloprost required to inhibit platelets for 1 hour were determined by measuring platelet count, platelet aggregation to adenosine diphosphate (ADP), and forearm template bleeding times in duplicate in 12 anesthetized baboons in which arterial and central venous blood pressures, thermodilution cardiac outputs, and electrocardiographic measurements were monitored. Blood volume was estimated as 0.08 x body weight. Blood samples and bleeding times were taken at seven sampling times simulating a CPB experiment.

The IC₅₀ for ADP (20 µmol/L)-induced platelet aggregation in baboon blood is 570 nmol/L Integrilin and is very similar in baboons and man for ADP and other agonists [11, 12]. Integrilin is cleared somewhat more quickly in baboons. Using these data and results of in vitro tests, we studied two Integrilin protocols in vivo. In 4 baboons a bolus dose of 250 µg of Integrilin per kilogram, a second bolus of 150 µg/kg 20 minutes later followed by an infusion of 6 µg/kg per minute for 45 minutes and 3 µg/kg per minute for 15 minutes was tested. In 5 animals a bolus dose of 250 µg/kg followed by infusion of 3 µg/kg per minute for 30 minutes; 2 µg/kg per minute for 15 minutes, and none for the last 15 minutes was studied in CPB simulations.

In vitro studies of Iloprost showed that concentrations of 0.15 and 0.20 ng/mL failed to inhibit baboon platelets stimulated by thrombin, but 0.25 ng/mL provided complete inhibition. This concentration in human blood was also inhibitory in a previous in vitro study [13]. In 3 baboons a bolus of 1.4 ng/kg followed by an infusion of 0.4 ng/kg per minute for 45 minutes plus 150 µg of Integrilin kg followed by an infusion of 4 µg/kg per minute for 30 minutes was tested.

The high-dose Integrilin protocol completely suppressed platelet aggregation at the simulated end of CPB and produced a bleeding time of 10.7 ± 2.9 minutes at the time protamine would have been given (15 minutes after CPB) in the simulated study. Platelet aggregation at the end of CPB was 86.8% ± 4.6% with the low-dose Integrilin protocol; bleeding time was 8.4 ± 0.9 minutes at the time protamine would have been given. With the combination protocol platelet aggregation was 81.5% ± 7.0% of baseline at end of CPB; bleeding time was 4.0 ± 0.5 minutes at the time for protamine.

Experimental study
Juvenile baboons (Papio annubis) quarantined for at least 6 weeks and weighing 13 to 20 kg were used. For each study, the baboon was placed in a squeeze cage, sedated with 10 mg/kg ketamine hydrochloride intramuscularly, and induced with 5 mg/kg thiopental sodium intravenously. The animal was intubated, and general anesthesia was maintained with inhalational isofluorane. The right or left neck and both groins were prepared and draped appropriately for a sterile cutdown and cannulation of vessels. Hemodynamic monitoring was accomplished using an arterial line with a 22-G catheter placed in the femoral artery, and a 5-F Swan-Ganz catheter was placed through a femoral vein. After anticoagulation a 10 to 14F BioMedicus (Medtronic, Inc, Eden Prairie, MN) wire-wrapped, polyurethane catheter was introduced into the jugular vein and advanced into the right atrium. A similar, but shorter 8F arterial catheter for reinfusion was inserted into the femoral artery. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals published by National Institutes of Health (NIH publication 86-23, revised 1985). This study was approved by the Institutional Animal Care and Utilization Committee of the University of Pennsylvania.

The bypass circuit consisted of silicone rubber tubing (Dow Corning Inc, Midland, MI), two polyurethane, wire-wrapped cannulas (Medtronic Inc, Eden Prairie, MN), a bubble oxygenator (Bentley 5, Pediatric; Baxter Healthcare, Inc, Irvine, CA) [14], an arterial line filter (Intersept Pediatric; Medtronic, Inc, Anaheim, CA), and roller pump (model 13400; Sarns Inc, Ann Arbor, MI). After porcine sodium heparin anticoagulation treatment (300 U/kg; Elkins-Sinn, Inc, Cherry Hill, NJ) a 12F polyurethane catheter was introduced into the jugular vein and advanced into the right atrium. A similar but shorter 8F arterial catheter was inserted into the femoral artery for reinfusion. This system allowed the priming volume to be reduced to 500 mL of Normosol (Abbott Laboratories, North Chicago, IL). Normothermic bypass was begun at 50 mL/kg per minute or approximately half the normal cardiac output. The heart continued to eject and supply approximately half of the circulation. Perfusion was maintained for 60 minutes at which time the CPB was terminated.

Based on preliminary dosage studies (see below) animals were divided into the following 4 groups: group 1, (n = 7); control; group 2, (n = 7) bolus injection of Integrilin (200 µg/kg) before starting CPB and an infusion of 4 µg/kg per minute (Model 55-1111 and 2400-003; Harvard Apparatus, South Natick, MA) for 30 minutes after starting CPB; group 3 (n = 7) a 200 µg/kg bolus of Integrilin at the time of heparin before starting CPB followed by an infusion of 6 µg/kg per minute for 30 minutes after CPB started; and group 4, (n = 7) Integrilin bolus of 200 µg/kg followed by an infusion of 4 µg/kg per minute for 30 minutes after CPB began plus an infusion of Iloprost at 2 ng/kg per minute for 15 minutes beginning at the time of heparin followed by an infusion at 0.5 ng/kg per minute (slightly higher than that used in the preliminary study) for an additional 45 minutes. The Iloprost infusion was stopped 15 minutes before CPB ended.

Seven blood samples (15 to 20 mL) were obtained at baseline before heparin and platelet inhibitors; 2 minutes after heparin, bolus doses of platelet inhibitors, and beginning infusions before CPB; 5 minutes after starting CPB; and 55 minutes after starting CPB. Protamine (3 mg/kg; Elkins-Sinn, Inc, Cherry Hill, NJ) was given 15 minutes after the end of CPB; blood samples and bleeding times were obtained 10 minutes later and 30, 60, 120, and 180 minutes after the 10-minute collection.

Blood samples were assayed for hematocrit, platelet count, white blood cell count, platelet aggregation to ADP, ß-thromboglobulin release, prothrombin fragment F1.2, fibrinopeptide A, and thrombin-antithrombin complex. Dilution of formed blood elements and plasma markers was corrected with hematocrit.

Blood samples were obtained from animals in groups 3 and 4 at each sampling time for measurement of plasma concentrations of Integrilin.

Heart rate by electrocardiogram, and systemic arterial, central venous, and pulmonary arterial pressures were continuously monitored (Hewlett Packard 78534C; Hewlett Packard, Palo Alto, CA). Intermittent thermodilution cardiac outputs were measured before and after CPB (Oximetrix 3 SO₂/CO computer; Abbott Labs, North Chicago, IL).

Measurements
Platelets were counted by phase microscopy or by Coulter counter (model STKR; Coulter Electronics Inc, Hileah, FL) in triplicate. For platelet studies, blood (8 mL) was anticoagulated with 1 mg D-PHE-PRO-ARG–chloromethyl-ketone [15]. Platelet-rich plasma was obtained by centrifuging whole blood at 150 g for 10 minutes. Platelet-poor plasma was prepared by centrifugation at 13,600 g for 5 minutes. Platelet count of platelet-rich plasma was adjusted to 150,000 per µL by dilution with platelet-poor plasma for aggregation to ADP using a Payton aggregometer (model 440; Chrono-Log, Inc, Havertown, PA). The concentration of ADP required to produce complete second wave aggregation was measured; complete second wave aggregation was assumed when light transmission was 62.5% or greater within 5 minutes. The concentration of ADP required to obtain full aggregation of the baseline sample was determined, and the percent aggregation was normalized to 100%. In subsequent samples the percent aggregation observed at that ADP concentration was proportionally normalized to the baseline value.

For plasma ß-thromboglobulin analysis blood was withdrawn into centrifugation tubes containing 10% (by volume) of 3.8% acid citrate dextrose, and prostaglandin E1 solution at 0°C. ß-thromboglobulin was measured by radioimmunoassay [16].

Template bleeding times were measured in duplicate on the forearm at baseline and at 5 time points after protamine administration using a blood pressure cuff inflated to 40 mm Hg. The Simplate II (Organon; Teknika Corporation, Durham, NC) lancet was used to create reproducible skin incisions for determination of bleeding time.

Plasma levels of F1.2 (Behring Diagnostics, Inc, Westwood, MA), fibrinopeptide A (American Bioproducts, Parsipanny, NJ), and thrombin-antithrombin complex (Behring Diagnostics, Inc) were measured by enzyme-linked immunosorbent assay using commercial assay kits.

A reversed-phase high-performance liquid chromatographic method of solid phase-extracted plasma samples was used by COR Therapeutics Inc to measure concentrations of Integrilin at 7 time points in animals in groups 3 and 4.

Statistical analysis
Data points represent the mean ± standard error of the mean. Four-way, factorial analysis of variance for repeated measures with the Bonferroni adjustment (SPSS for Windows 7.5; SPSS, Inc, Chicago, IL) was used for statistical analysis of group and time effects. When group effects were significant (p < 0.05), two-way analysis of variance between control and each experimental group (separately) was used to establish significant differences. The unpaired t statistic was used for specific comparisons at specific time points between groups when the two-way analysis of variance group (with Bonferroni adjustment) effect was significant. The paired Student’s t test with Bonferroni correction was used for analysis of differences within groups when the time effect was significant by multivariate analysis of variance and one-way analysis of variance. Differences were considered statistically significant at a p value less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
No consistent differences between groups were observed in cardiac output, heart rate, and arterial, central venous, or pulmonary arterial pressures, and all values remained within normal ranges at all time points (data not shown).

Both group and time effects for changes in platelet count were significant (Table 1), and each group that received Integrilin had significantly higher platelet counts than control animals (Fig 1). Similarly, the drug significantly suppressed platelet aggregation in response to ADP at the start of CPB (Fig 2), and suppression in groups 3 and 4 remained significantly greater than in the control group at the end of CPB (Table 1). At the time protamine was given there were no significant differences between groups in platelet function. ß-thromboglobulin level was significantly less in the high-dose Integrilin group (group 3) than in control animals at the end of CPB (Fig 3; Table 1). The addition of Iloprost to low-dose Integrilin (group 4) did not augment inhibition of alpha granule release.

View larger version (22K): [in this window] [in a new window]   Fig 1. Hematocrit-corrected platelet counts before, during, and after cardiopulmonary bypass for 4 groups. Platelet counts are standardized as a percentage of baseline (Base) for each time point. Filled circles indicate control group (group 1); open squares indicate low-dose Integrilin (group 2); open circles indicate high-dose Integrilin (group 3); and filled squares indicate combination (group 4). Values are the mean ± standard error of the mean. (End = 55 minutes after starting cardiopulmonary bypass; Hep = 2 minutes after heparin, bolus doses of platelet inhibitors, and beginning of infusions before cardiopulmonary bypass; Prot = 25 minutes after end of cardiopulmonary bypass; Start = 5 minutes after starting cardiopulmonary bypass; 30, 60, 120, and 180 = number of minutes after the Prot time point.)

View larger version (20K): [in this window] [in a new window]   Fig 2. Platelet aggregation to adenosine diphosphate before, during, and after cardiopulmonary bypass. Data points are standardized as a percentage of baseline (Base) for each time point of the group. Symbols and abbreviations are as in Fig 1.

View larger version (20K): [in this window] [in a new window]   Fig 3. Hematocrit corrected ß-thromboglobulin release before, during and after cardiopulmonary bypass for four groups. Symbols and abbreviations are as in Fig 1. Baseline measurements are subtracted from all subsequent measurements.

View larger version (49K): [in this window] [in a new window]   Fig 4. Template bleeding times before, during, and after cardiopulmonary bypass. Gray bars indicate control group (group 1); white bars indicate low-dose Integrilin group (group 2); hatched bars indicate high-dose Integrilin group (group 3); and black bars indicate combination group (group 4). Values are the mean ± standard error of the mean. Abbreviations are as in Figure 1.

After bolus doses of Integrilin equilibrated with the priming volume, plasma concentrations of the drug reflected the infusion rate. At the end of CPB Integrilin concentrations were too low to inhibit platelets because the IC₅₀ of the drug is 570 nmol/L.

	Comment

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Previous studies have validated the concept of platelet anesthesia as a means to prevent loss of platelet number and function during CPB and open heart operations [8–10]. Because platelets are activated both in the wound [6] and the perfusion circuit, the inhibitor must prevent adhesion, aggregation, and release of granule contents and be quickly reversible. Because antidotes to platelet inhibitors are not known, reversibility is achieved by rapid clearance of the drug from blood. The half life of Integrilin in human volunteers is approximately 60 to 90 minutes (COR Therapeutics Inc) and as shown in this study is capable of preserving platelet number and function and restoring template bleeding time to baseline values at the time protamine is given after CPB.

We hypothesized that the synergistic effect of a combination of low-dose Iloprost and Integrilin would provide more complete inhibition of platelet function and granule release than either drug alone [13], would avoid vasodilatation associated with platelet inhibitory doses of prostanoids [9], and would allow more rapid restoration of platelet function and baseline bleeding time. No support for this hypothesis was obtained at the doses used in this study, but the results of this study do not negate this possibility for other synergistic, rapidly cleared platelet inhibitor doses or combinations.

Recently, Byzova and Plow [17] reported that prothrombin binds to platelet glycoprotein IIb/IIIa receptors and that this binding accelerates thrombin formation. They further demonstrated that the chimeric monoclonal antibody, mAB 7E3, which binds to platelet glycoprotein IIb/IIIa receptors, interferes with prothrombin binding and partially inhibits thrombin generation by approximately 25% to 30% [17]. Van ‘t Veer and colleagues [18] also found that glycoprotein IIb/IIIa receptor antagonists also decrease thrombin generation by the tissue factor pathway. We did not observe significant reductions in thrombin formation or activity in this study, but all markers of thrombin formation and activity were qualitatively less in all treatment groups than those in the control group at the end of CPB. In a previous study using a nonpeptide, RGD mimetic, platelet glycoprotein IIb/IIIa inhibitor, tirofiban (Aggrastat; Merck, Inc, Fort Washington, PA), similar but statistically significant reductions in F1.2 and thrombin-antithrombin complex but not fibrinopeptide A were observed at the end of CPB when drug administration was started 60 minutes before and continued during CPB in baboons [19]. The small number of studies, differences in dosage schedules, and relative resistance of baboon platelets, compared with human platelets [20], to agonists probably negate any differences between these two studies with respect to thrombin generation and activity. However, if confirmed for nonpeptide inhibitors, because glycoprotein IIb/IIIa receptor antagonists interfere with prothrombin binding to platelets and also impair factor X activation by the extrinsic coagulation pathway [17], these drugs may significantly reduce thrombin formation and activity during open heart operations. If this hypothesis is proved, significant reductions in bleeding and embolic complications associated with open heart surgery can be anticipated.

Although Integrilin has a short half-life in blood, dosing remains the greatest obstacle to clinical use. For most first-time valvular or myocardial revascularization operations, blood loss is minimal and transfusions are not required. However, with more extensive operations or reoperations bleeding is sometimes a major problem, and more rapid restoration of platelet function and normal bleeding times can be expected to significantly reduce postoperative blood loss and transfusion requirements. Extensive clinical experience with Integrilin during cardiologic interventions verifies the safety and efficacy of the drug [21]. This study provides data that the drug is also safe and efficacious when used with CPB and supports instigation of a clinical trial.

	Acknowledgments

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Sun Woo Park, Bradford Richardson, Ramin Malekan, David R. Phillips, and Charles Homcy for their contributions to this study.

Supported by grant HL 47186 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. COR Therapeutics provided drugs and financial support.

	Footnotes

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 
¹ With the exception of Mr Hollenbach, no author was paid by COR Therapeutics and none own COR Therapeutics stock or stock options or have a remunerative role of any kind with the company. COR Therapeutics provided the drug and some financial support as acknowledged but did not edit any content or data in this article.

	References

Top Footnotes Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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