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Ann Thorac Surg 2005;79:1545-1550
© 2005 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Aprotinin Inhibits Protease-Dependent Platelet Aggregation and Thrombosis

Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Accepted for publication November 10, 2004.

^_* Address reprint requests to Dr Sellke, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis Street, LMOB Suite 2A, Boston, MA 02215 (E-mail: fsellke{at}caregroup.harvard.edu).

	Abstract

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BACKGROUND: Hemostatic effects of the protease inhibitor aprotinin in cardiac surgery are well described, and recent evidence suggests an antithrombotic mechanism of aprotinin through inhibition of thrombin-mediated platelet activation. We hypothesized that aprotinin provides hemostasis while reducing vascular thrombosis by attenuating protease-dependent platelet function.

METHODS: Rabbits (3 to 4 kg) underwent carotid artery thrombosis induced by electrical current. Treatment animals (n = 8) received aprotinin by a 100,000-KIU bolus followed by a continuous infusion (25,000 KIU/h). Control animals (n = 8) received crystalloid solution. Thrombus weight and time to thrombotic occlusion were determined. Platelet aggregation was examined in response to protease-dependent (thrombin) and protease-independent (adenosine diphosphate, ADP) platelet agonists. Platelet thrombin protease-activated receptor (PAR) expression was analyzed by Western blot. Ear bleeding time and abdominal incisional bleeding were measured at baseline and serially.

RESULTS: Thrombus weight was decreased by aprotinin (6.1 ± 1.1 mg versus 10.8 ± 1.5 mg, aprotinin versus control, p < 0.05). Time to thrombotic occlusion was prolonged in the aprotinin group (17.4 ± 1.0 minutes versus 8.3 ± 1.3 minutes, p < 0.001). Rabbit platelet expression of thrombin PARs was demonstrated by Western blot analysis, and was not altered by aprotinin therapy. Platelet aggregation due to thrombin was decreased by aprotinin therapy (59.2% ± 3.0% versus 95.8% ± 1.5%, p < 0.001), whereas protease-independent, ADP-induced platelet aggregation was unchanged with aprotinin. Incisional bleeding was not different between groups. In the aprotinin group, bleeding time was unchanged at baseline and then reduced for the duration of the experiment (35.0 ± 4.7 seconds versus 76.8 ± 6.4 seconds, p < 0.05).

CONCLUSIONS: While providing hemostatic effects, aprotinin attenuates vascular thrombosis in part by inhibition of PAR activation, resulting in the prevention of thrombin-induced platelet aggregation.

	Introduction

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Postoperative bleeding in cardiac surgery often results from hemostatic defects associated with cardiopulmonary bypass (CPB), including platelet dysfunction, activation and consumption of coagulation factors, and increased fibrinolytic activity [1]. As a consequence, increased use of blood products and reexploration for hemorrhage are often necessary, with increased morbidity and mortality after cardiac surgery [2]. The use of the serine protease inhibitor, aprotinin, during CPB has been shown to reduce postoperative blood loss, lower transfusion requirements, decrease the frequency of reoperation for bleeding, and potentially improve operative mortality [3, 4]. In addition to the well-known hemostatic properties, antithrombotic effects have been described with the use of aprotinin [5]. The antithrombotic effect of aprotinin was suggested to involve blocking the proteolytic activation of the major thrombin receptor on platelets, the protease-activated receptor (PAR) that requires cleavage to transmit signals [6, 7]. In vitro experiments of human platelet aggregation have shown that aprotinin prevents protease-dependent platelet aggregation induced by thrombin, while protease-independent platelet aggregation in response to fibrinogen and adenosine diphosphate (ADP) is preserved. This inhibition of thrombin-induced platelet aggregation was demonstrated to be mediated by PAR1 that is expressed in human platelets [6]. In a recent clinical study of patients undergoing elective coronary artery bypass graft (CABG) procedures, aprotinin inhibited the proteolytic activation of PAR1 [8]. However, the role of aprotinin in preventing vascular thrombosis, potentially by blockade of PAR activation, has not been well described. We hypothesized that aprotinin provides hemostatic effects while reducing vascular thrombosis by attenuating protease-dependent platelet function.

	Material and Methods

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Animals
Animals were housed individually and provided with laboratory chow and water ad libitum. All experiments were approved by the Beth Israel Deaconess Medical Center Animal Care and Use Committee and the Harvard Medical Area Standing Committee on Animals (Institutional Animal Care and Use Committee) and conformed to the U.S. National Institutes of Health guidelines regulating the care and use of laboratory animals (NIH publication no. 5377-3 1996).

Surgical Procedure
New Zealand white rabbits (3 to 4 kg) were anesthetized with ketamine hydrochloride (15 mg/kg) and xylazine (15 mg/kg). The right marginal ear vein was cannulated for administration of intravenous fluids, and the right femoral vein was cannulated for intravenous access and venous blood sampling. The right femoral artery was cannulated for arterial blood sampling and intraarterial blood pressure monitoring using a catheter-tipped manometer (Millar Instruments, Houston, TX). Arterial blood pressure, heart rate, electrocardiogram, and oxygen saturation were monitored continuously throughout the experiment.

Experimental Protocol
Rabbits were divided randomly into two groups: treatment (n = 8) and control (n = 8). The treatment group received a dosing regimen of aprotinin (Bayer Pharmaceuticals Corporation, West Haven, CT) as follows: a loading dose of 100,000 KIU before the induction of anesthesia and the initiation of carotid artery thrombosis followed by a continuous infusion of 25,000 KIU/h. Time to thrombosis was monitored. After occlusion, the arterial thrombus was dissected from the carotid artery and weighed. During the experiment, template and incisional bleeding assays were performed at baseline and at 15, 30, 45, and 60 minutes after aprotinin administration.

Carotid Artery Thrombosis
The left common carotid artery was exposed in standard technique and an ultrasonic flow probe (Transonic Systems Inc, Ithaca, NY) was placed around the artery without constriction to continuously monitor carotid artery flow. Proximal to the flow probe, a 23-gauge electrode needle was inserted into the lumen of the carotid artery and secured into place with suture placement. Arterial blood pressure, heart rate, electrocardiogram, and carotid artery blood flow were monitored. Hemodynamic variables were acquired and analyzed using a digital measurement system (Sonometrics Corporation, London, Ontario, Canada). Thrombosis was initiated by application of anodal current (150 µA) until a 50% decrease in flow velocity was detected. The current was then stopped and the artery was allowed to occlude. The time to occlusion was monitored and recorded. After the carotid artery was occluded, the thrombosed arterial segment was dissected and thrombus weight measured [9–11].

Histologic Confirmation of Arterial Thrombosis
Thrombosed arterial segments were fixed in 10% formalin, embedded in paraffin, and sectioned (5 µm). The thrombosed arterial sections from both the control and treatment groups were stained with hematoxylin and eosin to confirm that thrombus formation was the cause of the cessation in arterial flow rather than only vasospasm.

In Vitro Platelet Aggregation Studies
Platelets were isolated from peripheral blood, which was drawn at baseline before the administration of systemic aprotinin or control solution. The blood was collected in a prewarmed syringe containing sodium citrate. Prostacyclin (1 µmol/L) was added and platelet-rich plasma was decanted off after an initial spin at 1,100 rpm for 10 minutes. Platelet-rich plasma was centrifuged at 2100 rpm for 12 minutes at room temperature and the resulting pellet gently resuspended at 2 x 10⁸ platelets per milliliter in platelet buffer solution (NaCl, 140 mmol/L; KCl, 5 mmol/L; MgCl₂, 0.4 mmol/L; NaHCO₃, 25 mmol/L; D-glucose, 5 mmol/L; 0.2% bovine serum albumin; and HEPES buffer, 20 mmol/L; pH 7.4). For the aggregation studies, 1 x 10⁸ platelets per milliliter were suspended in platelet buffer also containing CaCl₂ (1.2 mmol/L) and fibrinogen (100 µg/mL). Platelets were treated with aprotinin (50 or 100 KIU/mL) or control buffer followed by either thrombin (1 nmol/L) to determine protease-dependent aggregation or ADP (10 µmol/L) to measure protease-independent aggregation. Platelet aggregation was studied using a Bio/Data lumi-aggregometer (Bio/Data Corp, Horsham, PA) [6].

Platelet PAR Expression
PAR expression was measured in platelets from control and treatment animals by Western blot analysis. Platelets were isolated as described above from peripheral blood drawn from control and aprotinin-treated rabbits at the completion of the experiment (60 minutes after initiating aprotinin therapy). Platelet cell lysates were fractionated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membranes (Millipore, Billerica, MA) using a semidry transfer apparatus. Membranes were stained with Ponceau S and incubated with anti-PAR3 antibodies (Santa Cruz Biotechnology, Santa Cruz, CA) for immunoblotting. The membranes were then incubated with the appropriate secondary antibody conjugated to horseradish peroxidase. Peroxidase activity was visualized by means of an enhanced chemiluminescence substrate system (Amersham Piscataway, NJ) and radiography. Radiographs were digitized using a flatbed scanner and quantified using NIH Image software (National Institutes of Health, Bethesda, MD).

Bleeding Assays
Template bleeding was measured by using uniform incisions 10 mm long and 1 mm deep on the ventral surface of the ear using a Simplate device (bioMerieux, Inc, Durham, NC). Blood was blotted with filter paper every 15 seconds, avoiding direct contact with the incision. Bleeding time was defined as the time between the incision and the time at which blood did not stain the paper. An incisional bleeding assay was also performed. An incision 4 cm long and 0.25 cm deep was made in the anterior abdominal wall, including the superficial layer of abdominal wall musculature. A preweighed gauze sponge was placed in the incision for 5 minutes and the amount of blood absorbed was weighed. Both bleeding assays were performed at baseline and every 15 minutes for 1 hour after administration of aprotinin [9–11].

Data Collection and Statistical Analysis
Data are presented as mean ± SEM. Statistical analyses were performed using ANOVA or t test as appropriate. All data were recorded and entered into a computer database. Statistical significance was accepted at p < 0.05.

	Results

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Carotid Artery Thrombosis
Histologic analysis of all specimens in the control and treatment groups confirmed carotid artery thrombosis (Fig 1) and that the cessation of blood flow was not due to vasospasm only. Thrombus weight was less with aprotinin therapy than with controls (6.1 ± 1.1 mg versus 10.8 ± 1.5 mg, p < 0.05; Fig 2). Time to occlusion of carotid arterial flow was longer in the aprotinin group, consistent with a longer period of time before thrombotic occlusion (17.4 ± 1.0 minutes versus 8.3 ± 1.3 minutes, p < 0.001; Fig 3).

View larger version (59K): [in this window] [in a new window]   Fig 1. Representative images of hematoxylin and eosin-stained histologic cross-sections of carotid arteries showing thrombus (arrows) in control (left) and aprotinin-treated (right) specimens.

View larger version (12K): [in this window] [in a new window]   Fig 2. Thrombus weight was significantly reduced in the aprotinin group compared with controls (6.1 ± 1.1 mg versus 10.8 ± 1.5 mg, respectively; *p < 0.05 versus control).

View larger version (12K): [in this window] [in a new window]   Fig 3. Time to occlusion of carotid artery flow was greater in the aprotinin-treated group than in the control group (17.4 ± 1.0 minutes versus 8.3 ± 1.3 minutes, respectively; *p < 0.001 versus control).

View larger version (28K): [in this window] [in a new window]   Fig 4. Aprotinin treatment had no significant effect on protease-independent platelet aggregation in response to adenosine diphosphate (ADP).

View larger version (24K): [in this window] [in a new window]   Fig 5. Protease-dependent platelet aggregation in response to thrombin was reduced by aprotinin treatment compared with controls (63.7 ± 4.5% [aprotinin 50 KIU/mL] and 59.2 ± 3.0% [aprotinin 100 KIU/mL] versus 95.8 ± 1.5%, respectively; *p < 0.001 versus control).

View larger version (42K): [in this window] [in a new window]   Fig 6. Western blot analysis showed expression of protease-activated receptor-3 (PAR3) in rabbit platelets. No significant difference in PAR3 expression was observed between the control and treatment groups.

View larger version (22K): [in this window] [in a new window]   Fig 7. Blood loss as measured with the incisional bleeding assay showed a trend toward decreased bleeding in the aprotinin group compared with controls at 45 minutes (180.6 ± 26.7 mg versus 268.0 ± 27.3 mg, aprotinin versus control, p = 0.06) and 60 minutes (165.3 ± 23.3 mg versus 248.5 ± 44.9 mg, aprotinin versus control, p = 0.14). = control; = aprotinin.

View larger version (20K): [in this window] [in a new window]   Fig 8. Bleeding time was reduced in the aprotinin group compared with controls at 30 minutes (32.4 ± 7.3 seconds versus 97.5 ± 14.5 seconds, respectively), 45 minutes (31.0 ± 7.6 seconds versus 81.3 ± 9.7 seconds, respectively), and 60 minutes (35.0 ± 4.7 seconds versus 76.8 ± 6.4 seconds, respectively; *p < 0.05, **p < 0.01, and #p < 0.001 versus control). = control; = aprotinin.

	Comment

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Thrombin initiates its cellular effects primarily through PARs [12]. These receptors have a specific activation mechanism in which proteolytic cleavage exposes a tethered ligand that results in intramolecular activation of the receptor. Four PARs are known, and PAR1, PAR3, and PAR4 are activated by thrombin through proteolytic cleavage [7]. In our study, we found that rabbit platelets express a thrombin receptor from the PAR family, PAR3. Antibodies to PAR3 have been shown to inhibit thrombin-induced platelet aggregation in mice [13]. Moreover, PAR3 knockout mice were shown to be protected against thrombosis of mesenteric arterioles and pulmonary embolism [14]. In our rabbit model, we found that aprotinin prevented protease-dependent platelet aggregation (thrombin) without significant effects on protease-independent mechanisms of platelet aggregation (ADP). This mechanism of platelet inhibition likely contributed to the antithrombotic effect of aprotinin in our study shown as a decreased rate of thrombosis as well as reduced clot burden. In our model, the gene expression of PAR3 was unchanged with aprotinin therapy. This finding is consistent with aprotinin preventing the protease-dependent platelet aggregation at the level of PAR cleavage and activation rather than gene expression [6]. Thus, we have provided evidence to suggest that aprotinin reduces vascular thrombosis in our rabbit model of carotid artery injury, in part through a mechanism of inhibiting protease-dependent platelet aggregation.

Postoperative bleeding in patients undergoing CPB has been associated with increased fibrinolysis and platelet dysfunction [15]. Aprotinin has been demonstrated to prevent blood loss during cardiac surgery through antifibrinolytic effects and preservation of platelet function, through mechanisms including the maintenance of platelet glycoprotein receptor function [16, 17]. The platelet thrombin PAR has been shown to be involved in platelet dysfunction after CPB. In a study of 79 patients undergoing CABG with CPB, platelet aggregation mediated by the thrombin receptor was diminished after CPB. In addition, the reduction in platelet aggregation correlated with increased blood transfusion requirement [18]. Activation of the platelet PAR by thrombin generated during CPB is thought to desensitize the receptor, leading to platelet dysfunction [19]. Although platelets were not exposed to CPB in our model, activation of the coagulation pathway by the surgical wound and the induction of thrombosis with electrical current would result in the generation of thrombin. In our model, aprotinin potentially prevented desensitization of the platelet PAR by inhibiting thrombin-mediated platelet activation, thereby promoting hemostasis as was seen in the decreased bleeding time as well as the trend of diminished incisional bleeding. In addition, while aprotinin inhibits protease-dependent platelet activation, protease-independent platelet activation by fibrinogen and ADP is preserved [6]. Overall, aprotinin appears to be capable of dual roles: (1) having an antithrombotic effect by inhibiting protease-dependent platelet aggregation and (2) promoting hemostasis in surgical wounds by preventing excessive thrombin-mediated activation and desensitization of the platelet PAR as well as preventing fibrinolysis.

A few limitations of our study are worth mentioning. Our model was an animal model of arterial thrombosis, whereas the concern of graft thrombosis in coronary bypass patients has been described for vein grafts. Furthermore, several other factors that were not included in our model often are involved in cardiac surgical procedures that alter both platelet function and coagulation pathways, such as systemic heparinization and common medications such as aspirin and clopidogrel, as well as CPB as discussed above.

The preventive action of aprotinin in vascular thrombosis, potentially through platelet inhibition, may be an important underlying mechanism in physiologic responses attributed to aprotinin therapy such as the attenuation of platelet accumulation in reperfusion injury [20] or the reduction in the incidence of stroke after cardiac surgery in high-risk patients [21]. As we continue to understand the complex effects of the serine protease inhibitor aprotinin, including its antithrombotic effects demonstrated in this study, we will gain a better understanding of how to most effectively implement the beneficial aspects of this therapy. Further work with this agent may lead to a better understanding of the mechanisms involved in the prevention of blood loss, reperfusion injury, and vascular thrombosis, and the development of therapies to improve outcomes of cardiac surgical procedures.

	Acknowledgments

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Funding was provided by grants from the National Institutes of Health, National Institutes of Health R01 HL46716 (FWS) and National Institutes of Health NRSA 1F32 HL69651 (TAK), and the Bayer Corporation.

	References

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