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Ann Thorac Surg 1995;59:149-153
© 1995 The Society of Thoracic Surgeons

Iloprost and Echistatin Protect Platelets During Simulated Extracorporeal Circulation

Alvise Bernabei, MD, Nicolas Gikakis, Maria Anna Kowalska, PhD, Stefan Niewiarowski, MD, PhD, L. Henry Edmunds, Jr, MD

Division of Cardiothoracic Surgery, Harrison Department of Surgery, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Accepted for publication July 28, 1994.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Temporary, reversible inhibition of platelets during cardiopulmonary bypass is an attractive strategy to protect platelets and normalize postoperative bleeding times. Iloprost, an analogue of prostacyclin, and the disintegrins reversibly inhibit platelets by different mechanisms. We tested the hypothesis that reduced doses of iloprost and either echistatin, a natural disintegrin, or RO43-5054, a peptidomimetic, in combination provide better platelet protection than any drug alone during simulated extracorporeal circulation. Thirty-five recirculation studies using fresh, heparinized human blood in an extracorporeal perfusion circuit that contained a 0.45-m2 spiral coil membrane oxygenator were performed. Iloprost, but neither echistatin nor RO43-5054, increased platelet cyclic adenosine monophosphate. Combinations of iloprost and either fibrinogen receptor antagonist at reduced doses submaximally increased platelet cyclic adenosine monophosphate. Platelet adhesion and release of beta-thromboglobulin antigen was completely inhibited by combinations of the two classes of drugs, but only partially inhibited by each drug alone. Combinations of drugs also completely inhibited platelet aggregation to adenosine diphosphate; these platelets retained full sensitivity to adenosine diphosphate after 90 minutes of recirculation when drugs were removed by gel filtration. We conclude that combinations of iloprost and a fibrinogen receptor antagonist at doses that are unlikely to produce clinical side effects completely inhibit platelet activation and preserve platelet function during in vitro extracorporeal circulation.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Cardiopulmonary bypass (CPB) increases postoperative bleeding time by reducing platelet numbers and function [1, 2]. During CPB, platelets adhere to surfaces of the perfusion circuit [3], aggregate, release, fragment [4], and are diluted by the priming volume. Temporary inhibition of platelets during the period of CPB is an attractive strategy to reduce platelet emboli and to preserve platelet numbers and function so that bleeding times are not increased after CPB ends.

Dipyridamole, prostanoids, and disintegrins reversibly inhibit platelets [5–7] and both dipyridamole and prostanoids have been used clinically to preserve platelet numbers and function. ipyridamole is a weak platelet inhibitor [5], has a long half-life in plasma, and although used successfully in one study [7], has not progressed to general use. The prostanoids are effective in animals [8] and patients [9, 10], but in man are potent vasodilators and must be used with a vasoconstrictor to maintain systemic blood pressure [10]. The disintegrins, a class of RGD (arg-gly-asp) containing proteins from viper venoms [11–14], reversibly inhibit fibrinogen binding to platelet GPIIb/IIIa receptors and are effective in protecting platelets during extracorporeal circulation in vitro [14] and in vivo [15]. The potency and mechanism of action of synthetic peptidomimetics are similar to disintegrins [11, 16]. A recent study describes platelet protection during cardiopulmonary bypass in dogs using a synthetic RGD peptidomimetic, RO44-9883 [17].

The prostanoids and disintegrins inhibit platelets by different mechanisms [12, 18]. This fact raised the possibility that a combination of subthreshold doses of these two different inhibitors may better protect platelets without producing undesirable side effects. In this study, we tested this hypothesis during simulated CPB using a combination of iloprost and either echistatin, a natural peptide, or a peptidomimetic, RO43-5054 (Roche Pharmaceuticals, Berne, Switzerland).


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Perfusion circuits with a total surface area of 0.45 m2 were assembled from silicone rubber tubing (1/4-inch ID, 1.8 m; Dow Corning Corp, Midland, MI), polycarbonate connectors, a polyvinyl chloride venous reservoir bag (Gish Biomedical Inc, Santa Ana, CA), and a 0.4-m2 spiral coil membrane oxygenator (model 0400-2A; Avecor Corp, Minneapolis, MN). Circuits were used once and discarded. Adenosine diphosphate (ADP) and prostaglandin E1 were purchased from Sigma Chemical Co, St. Louis, MO. Iloprost was obtained from Berlex Laboratories, Cedar Knolls, NJ. RO43-5054 [16] was a gift of Roche Pharmaceuticals, Berne, Switzerland. Echistatin was isolated from snake venom (Echis carinatus; Sigma Chemical Co, St. Louis, MO) by methods developed in our laboratory [16] using two-step reverse-phase high performance liquid chromatography.

Three hundred milliliters of human blood was obtained from healthy fasting donors after abstinence from all medication for at least 2 weeks. Informed written consent was obtained from all donors and protocols for the study were approved by the Institutional Review Board of the University of Pennsylvania.

Blood and gas compartments of the circuit were flushed with 100% carbon dioxide for 15 minutes and evacuated before priming the perfusion circuit with blood. Blood was recirculated for 90 minutes at 0.3 L/min by a calibrated, barely occlusive roller pump (Sarns Inc, Ann Arbor, MI). Blood temperature was maintained at 37°C by immersing the reservoir bag in a constant temperature water bath. The oxygenator was ventilated with a mixture of 95% O2 and 5% CO2 at a rate of 0.7 L/min.

In control experiments (n = 10), blood was drawn directly into a reservoir bag containing porcine intestinal heparin (5 U/mL blood), Elkins-Sinn Inc, Cherry Hill, NJ) and dextrose (2.25 mg/mL blood). In each of three experimental groups (n = 5), the reservoir bag also contained sufficient drug to produce the following concentrations after priming: iloprost (1 nmol/L); RO43-5054 (50 nmol/L); echistatin (60 nmol/L); iloprost (1 nmol/L) and RO43-5054 (50 nmol/L); or iloprost (1 nmol/L) and echistatin (60 nmol/L). A total of 35 studies were performed. These concentrations of platelet inhibitors were chosen to produce partial platelet inhibition after determination of the drug concentration required to produce 50% inhibition of platelet-rich plasma (IC 50) after stimulation with ADP. For the drugs used in this study, the IC 50 concentrations were as follows: iloprost, 10 nmol/L; echistatin, 112 nmol/L; RO43-5054, 82 nmol/L.

Serial blood samples were taken from the circuit at 5, 15, 45, and 90 minutes of recirculation. An initial control sample was taken directly from the donor's vein. The zero minute and a standing control sample incubated at 37°C but not recirculated were taken from the venous reservoir before connection to the circuit. Blood samples were drawn into polypropylene tubes containing 1 mL acid-dextrose-citrate solution for each 9 mL of blood. Samples were centrifuged at 150 g for 10 minutes and then at 13,600 g for 5 minutes to produce platelet-rich plasma and platelet poor plasma. Gel-filtered platelets were prepared from platelet-rich plasma on Sepharose 2B columns (Pharmacia, Uppsala, Sweden) with a modification of the procedure described by Tangen and associates [19]. Columns were equilibrated with calcium-free Tyrodes buffer containing 0.1% dextrose and 0.35% bovine serum albumin. Fibrinogen (Kabi, Stockholm, Sweden) was added to the gel-filtered platelets and allowed to equilibrate before adding ADP.

Whole blood platelet counts were performed with Unopette Microcollection System (Becton-Dickinson, Rutherford, NJ) in a hemocytometer under phase microscopy. Platelet count taken from the reservoir before recirculation (zero time) was the 100% standard. Platelet counts in platelet-rich plasma and gel-filtered plasma were performed with a Coulter Counter (Coulter Electronics, Hialeah, FL). Platelet aggregation studies in platelet-rich plasma and gel-filtered platelets adjusted to 150,000 platelets/µL were performed with an aggregometer (Chrono-log, Havertown, PA). Threshold doses of ADP (ie, the lowest dose of agonist able to produce irreversible aggregation of a least 60% after 5 minutes) were determined on donor samples. Subsequent samples were tested at the threshold ADP concentration and results were expressed in arbitrary light transmission units. Beta-thromboglobulin antigen (BTG) was determined by radioimmunoassay [20]. Samples taken from the reservoir bag for BTG assay were mixed with ACD-prostaglandin E1 solution.

Cyclic adenosine monophosphate (AMP) was measured in platelets in the presence of iloprost and both fibrinogen receptor antagonists separately and in combination by the method of Saloman [21].

The effect of the platelet inhibitors on the number of platelets remaining in the circulation (percent of control), BTG levels and platelet response to ADP at serial times during recirculation were compared statistically by two-way analysis of variance (inhibitor by time). Because the analysis of variance F tests demonstrated significant (p < 0.05) differences, Sheffé's multifactorial analysis of the serial time points between groups were compared to determine differences between means.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Table 1Go shows that iloprost and forskolin raise the level of cyclic AMP in platelets, whereas echistatin and RO43-5054 do not have an effect. Neither fibrinogen antagonist alters platelet response to iloprost and forskolin, as evidenced by measurements of cyclic AMP concentrations. In contrast, epinephrine inhibited an increase in cyclic AMP induced by forskolin and iloprost.


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  		Table 1. . Effect of Agonists on Intracellular Cyclic Adenosine Monophosphate Formationa
 
Changes in platelet count during simulated extracorporeal circulation reflect platelet adhesion to and detachment from the synthetic surfaces of the perfusion circuit. Figure 1Go presents the results of all groups. The percentages of circulating platelets for all five experimental groups differ significantly (p < 0.05) from control at 5 and 15 minutes. RO43-5054 is not significantly different from control at 45 minutes, but the other groups are. Only the two combination drugs completely prevent adhesion and differ significantly from control at 90 minutes. The combination of iloprost and echistatin is significantly different from RO43-5054 at all time points and from echistatin at 5 minutes.



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  		Fig 1. . Mean platelet count expressed as percent of measured counts in reservoir samples at zero time before recirculation. Error bars represent standard errors of the mean in all figures. {circ} = control; • = iloprost; {blacktriangledown} = RO43-5054; {triangledown} = echistatin; {blacksquare} = RO43-5054 and iloprost; {square} = echistatin and iloprost. At 5 and 15 minutes all drugs significantly inhibited the expected decrease in platelet count (p < 0.05). At 45 minutes, inhibition was significant for all compounds except RO43-5054. At the end of recirculation (ie, 90 minutes) only samples containing combinations of drugs significantly differed from control samples.

 
In the absence of platelet inhibition, plasma BTG, a marker of platelet alpha granule release, progressively increases during recirculation (Fig 2Go). Iloprost (1 nmol/L) largely suppresses BTG release, but the two fibrinogen receptor antagonists only partially inhibit release. However, at 5 minutes only the combination groups significantly (p < 0.05) differ from control; iloprost alone does not. After 5 minutes all groups significantly differ from control but not from each other.



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  		Fig 2. . Concentration of beta thromboglobulin (BTG) antigen in plasma during simulated extracorporeal circulation. See Fig 1Go for explanation of symbols. After 5 minutes, all experimental groups significantly (p < 0.05) differed from control but not from each other. At 5 minutes, only samples that contained a combination of drugs significantly differed from control samples.

 
Figure 3Go shows platelet aggregability with ADP during simulated extracorporeal circulation. As compared with blood obtained directly from the donor, samples of blood withdrawn at the beginning of recirculation contained platelets that were more responsive to ADP. In standing control samples, platelet sensitivity to ADP gradually decreased without recirculation to a mean of 89.2% LTU. Platelet aggregability was inhibited slightly by iloprost, echistatin, and RO43-5054 tested separately. However, a significant inhibition of ADP-induced platelet aggregation was produced by combinations of iloprost and echistatin or of iloprost and RO43-5054.



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  		Fig 3. . Inhibition of adenosine diphosphate–induced platelet aggregation during recirculation expressed as a percentage of light transmission units (LTV). See Figure 1Go for explanation of symbols. At 90 minutes, platelet aggregation in standing control samples averaged 89.2% LTU.

 
Gel-filtered platelets prepared from blood and subjected to 90 minutes recirculation showed decreased sensitivity to ADP as compared with platelets obtained from samples before recirculation (Fig 4Go). Interestingly, gel-filtered platelets obtained from blood samples and recirculated for 90 minutes in the presence of combinations of iloprost and echistatin or iloprost and RO43-5054 had the same sensitivity to ADP as platelets obtained from blood before recirculation. Control experiments demonstrated that 125I-echistatin added to plasma was completely removed from platelets during gel filtration (data not shown).



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  		Fig 4. . Adenosine diphosphate–induced aggregation of gel-filtered platelets at zero and 90 minutes for control and for platelets exposed to combination drugs. Mean and standard errors are given. (Control = solid bar; Iloprost and echistatin = open bar; Iloprost and RO43-5054 = hatched bar.) Both combinations completely protected platelet function during 90 minutes of recirculation and values differ significantly (*p < 0.03) from the control value. (LTU = light transmission units)

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The mechanisms by which prostanoids and disintegrins reversibly inhibit platelet function differ. Prostanoids increase platelet cyclic AMP levels [18], which in turn inhibit signal transduction of all platelet agonists, including ADP and thrombin. This block in signal transduction inhibits exposure of glycoprotein GPIIb/IIIa (fibrinogen) receptors on the platelet surface. Williams and colleagues [22] demonstrated that two disintegrins, albolabrin and elegantin, do not alter cytosolic Ca2+ and cyclic AMP levels in platelets. The current study (Table 1Go) shows that echistatin and RO 43-5054 do not raise cyclic AMP concentrations in platelets. Disintegrins and RGD peptidomimetics block binding of fibrinogen to the GPIIb/IIIa receptors [11] that are required to bind platelets to fibrinogen-coated surfaces such as the extracorporeal perfusion circuit [23]. Disintegrins do not interfere with thrombin-induced platelet aggregation and release [14], but do inhibit BTG release that comes after platelet aggregation to ADP and platelet interaction with surfaces during simulated extracorporeal circulation [14]. It is possible that disintegrins only inhibit intracellular signaling that results from the binding of fibrinogen to GPIIb/IIIa receptors.

Iloprost appears to be a stronger inhibitor of BTG release than either echistatin or RO 43-5054 in these experiments. However, iloprost and echistatin are equally effective in preventing platelet adhesion to synthetic materials. These results may be related to differences in the two drugs with respect to thrombin receptors on the platelet surface. Thrombin is formed during both clinical and simulated extracorporeal circulation [24, 25]; its effect on platelets is not blocked by echistatin [14] but is inhibited by iloprost [26].

These studies indicate synergistic inhibition of platelets by combinations of the two classes of drugs. Combinations completely inhibit platelet adhesion and BTG release and fully preserve platelet sensitivity to ADP. In the doses used, each drug alone only partially inhibits platelet adhesion and BTG release.

Iloprost is a potent analogue of prostacyclin and has a half-life in plasma of approximately 30 minutes [26]. The inhibitory effect of the drug does not outlast its presence in plasma [27]. Kappa and colleagues [10] achieved satisfactory platelet inhibition during clinical CPB with plasma concentrations between 1,758 ± 329 and 2,053 ± 576 pg/mL. At these concentrations, iloprost must be given with continuous infusions of phenylephrine to maintain systemic blood pressure during cardiopulmonary bypass [10]. This constraint has restricted use of the drug to patients with heparin-induced thrombocytopenia and thrombosis [10]. If used synergistically with a disintegrin, a plasma level of 1 nmol/L equals 350 pg/mL-approximately one-sixth the dose used by Kappa and co-workers [10]-and is not expected to produce troublesome or dangerous hypotension.

Disintegrins protected platelets during simulated extracorporeal circulation in vitro [14] and in vivo in a sheep model [15]. The half-life of disintegrins in hamster and mice blood is approximately 20 to 40 minutes [28, 29]; therefore, disintegrins must be infused during cardiopulmonary bypass. Although disintegrins cause profound thrombocytopenia in baboons [30], this effect has not been observed in other species. More recently Cartreux and associates [17] protected platelets by infusions of an RGD peptidomimetic, RO44-9883, during cardiopulmonary bypass in dogs, but also observed prolonged bleeding times after bypass for up to 3 hours.

The administration of low doses of iloprost and disintegrins together may be advantageous because platelets are more completely protected and drug side effects are reduced. Disintegrins and RGD peptidomimetics, in contrast to prostacyclin and iloprost, do not protect platelets against thrombin, which can degranulate platelets and reduce hemostatic function. Simultaneous administration of disintegrins or RGD peptidomimetics can reduce iloprost doses and prevent vasodilatation and hypotension. Addition of small doses of iloprost can decrease the dose of disintegrins needed to prevent platelet adhesion to surfaces and hasten the return of normal post-bypass bleeding times. Recently Peerlinck and colleagues [31] found that low doses of the RGD peptidomimetic MK-383 inhibit platelet aggregation, but only mildly increase bleeding times in humans. At higher doses of MK-383, both platelet aggregation and bleeding time are more markedly abnormal. Further studies in patients are needed to evaluate the efficacy of platelet protection, time to normalize bleeding times, and side effects of low doses of iloprost and RGD peptidomimetics in combination.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This research was supported by HL 47186 and 47456 from the National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, MD. We thank Dr Beat Steiner (F Hoffmann La Roche, Basel, Switzerland) for the generous gift of RO43-5054, and Dr Barrie Ashby (Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA) for his help in assaying cyclic AMP in platelets. Technical assistance of Ms Lee Silver is gratefully acknowledged.


   Footnotes
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 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Edmunds, Division of Cardiothoracic Surgery, Hospital of the University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104.


   References
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 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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