Ann Thorac Surg 2004;77:644-650
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass
Yuichiro Kaminishi, MDa,
Yuji Hiramatsu, MD, PhD*b,
Yasunori Watanabe, MD, PhDc,
Yukihiro Yoshimura, MDb,
Yuzuru Sakakibara, MD, PhDb
a Division of Cardiovascular Surgery, Jichi Medical School, Tochigi, Japan
b Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan
c Department of Cardiovascular Surgery, Hitachi General Hospital, Hitachi, Japan
Accepted for publication August 1, 2003.
* Address reprint requests to Dr Hiramatsu, Department of Cardiovascular Surgery, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan.
e-mail: yuji3{at}md.tsukuba.ac.jp
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Abstract
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BACKGROUND: The pharmacological inhibition of blood-foreign surface interactions is an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate (a broad-spectrum synthetic protease inhibitor) and minimal-dose aprotinin on blood-surface interactions in clinical cardiopulmonary bypass.
METHODS: Eighteen patients undergoing coronary surgery were divided into three groups: (1) the control group (heparin, 4 mg/kg; n = 6), (2) the nafamostat mesilate group (heparin plus nafamostat, 0.2 mg/kg bolus followed by 2.0 mg/kg/h during cardiopulmonary bypass; n = 6), and (3) the aprotinin group (heparin plus aprotinin, 2.0 x 104 KIU/kg; n = 6). Platelet count, platelet aggregation, ß-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, 
2-plasmin inhibitor-plasmin complex, D-dimer, neutrophil elastase, and interleukin-6 were measured before, during, and after bypass. Bleeding times and blood loss were recorded.
RESULTS: There were no significant differences between groups in platelet count, ß-thromboglobulin, plasminogen activator inhibitor-1, interleukin-6, bleeding times, or blood loss. Platelet aggregation was better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1.2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The 2-plasmin inhibitor-plasmin complex and D-dimer were significantly lower with either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat.
CONCLUSIONS: Nafamostat mesilate fails to reduce thrombin formation and neutrophil elastase release, whereas minimal-dose aprotinin inhibits both. Neither nafamostat nor aprotinin inhibits platelet activation. Nafamostat reduces fibrinolysis during cardiopulmonary bypass, although its effect is not as potent as aprotinin.
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Introduction
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Activation of blood protease systems increases the risk of bleeding, along with the thrombotic and inflammatory complications associated with cardiopulmonary bypass (CPB) [1]. Pharmacological inhibition of blood-foreign surface interaction using specific inhibitors is an attractive strategy for reducing this morbidity [2]. Heparin has deficiencies as an anticoagulant because it inhibits coagulation only at the end of the cascade [3]. The "blood anesthesia" strategy envisions inhibiting the initial reaction of blood elements to temporarily shut down the amplification cascades that lead to clotting and inflammatory reaction during CPB [4]. Despite great efforts, no better alternative to heparin has been available to maintain blood fluidity [2, 5–7]. Nafamostat mesilate (NM) (Futhan, 6'-amidino-2-naphthyl-p-guanidinobenzoate dimethane sulfonate, Mr = 540 [Torii, Tokyo, Japan]) is a synthetic serine protease inhibitor with a specificity similar to trypsin [8]. The NM has a potent and short-lived inhibitory activity on thrombin, XIIa, Xa, kallikrein, plasmin, complement factors C1r and C1s, and trypsin, and has a high affinity for these proteases with Ki values of approximately 10-7 to 10-8 mol/L [8]. The NM almost completely inhibits either the formation or activity of XIIa and kallikrein, two of the key enzymes of the contact system, and has the ability to interact with platelets to reduce aggregation [9]. It has been used for pancreatitis, disseminated intravascular coagulation, hemodialysis, and cardiopulmonary bypass with reports of reduction in postoperative bleeding [10–13]. During in vitro CPB, NM inhibited neutrophil elastase release [9]. Although its inhibitory effects on complement are controversial [5, 12], NM has been looked at as one of the most promising protease inhibitors.
We evaluated the effects of NM on blood-foreign surface interactions, thrombin formation, fibrinolysis, platelet activation, and inflammatory response during clinical CPB as compared with the effects of aprotinin (Trasylol [Bayer AG, Leverkusen, Germany]). The purpose and meaning of this study is to clarify the efficacy of NM as a blood anesthetic in CPB by comparing the effects of the commonly used protease inhibitor, aprotinin. Aprotinin inhibits plasmin, kallikrein, platelet activation, and the kallikrein-induced activation of neutrophils [14], and has been widely applied to cardiac surgery in order to reduce blood loss [15–17]. A minimal-dose is the common regimen of aprotinin in Japan, because that dose is the upper limit of most standard medical insurance coverages. It has been reported that minimal-dose aprotinin is as effective as low-dose aprotinin in the inhibition of fibrinolysis and the reduction of blood loss [18, 19]. Although both drugs are thought to be promising for the control of blood-foreign surface interactions, no study has ever compared NM and aprotinin. Based on the available clinical and in vitro data, we hypothesized that NM inhibits thrombin formation, platelet activation and inflammatory reactions induced by CPB, as well as or better than minimal-dose aprotinin.
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Patients and methods
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The study involved 19 consecutive patients who underwent elective coronary artery bypass on CPB at the Hitachi General Hospital, Ibaraki, Japan. Complete data sets were obtained for 18 patients. All patients gave their informed consent and the research was performed based on the guidelines of the internal review board. Patients were randomly divided into three groups: (1) the control group (heparin, 4 mg/kg) with 6 patients, (2) the NM group (heparin, 4 mg/kg plus NM, 0.2 mg/kg bolus injection followed by 2.0 mg/kg/h during CPB) with 6 patients, and (3) the aprotinin group (heparin, 4 mg/kg plus aprotinin, 2.0 x 104 KIU/kg) with 6 patients. The NM was dissolved in 5% glucose solution and the initial dose (0.2 mg/kg) was given more than 10 minutes before starting CPB. Subsequently, NM was continuously administered until CPB was terminated. Aprotinin was infused more than 10 minutes before skin incision. In all groups, heparin was injected before cannulation and additional heparin was given when the activated clotting time fell below 480 seconds. In the NM and aprotinin groups, a quarter of the initial heparin dose was added every hour, even if the activated clotting time was more than 480 seconds.
A membrane oxygenator (D903 [Dideco, Modena, Italy]) primed with electrolyte solution was used and the bypass flow was kept at 2.5 L/min/m2 by a roller pump. Venous temperature during CPB was maintained at about 28°C. During aortic cross-clamping, oxygenated cold blood cardioplegia was administered through the aortic root every 30 minutes.
Blood samples were obtained for analysis before heparin administration (baseline), at 60 minutes of CPB, at 30 minutes after protamine administration (protamine), on admission to the intensive care unit (ICU), and at 12 hours after surgery (12 hours). Samples were obtained with 3.8% sodium citrate (for platelet aggregation, thrombin-antithrombin complex, prothrombin fragment F1.2, 2-plasmin inhibitor-plasmin complex, plasminogen activator inhibitor-1 and D-dimer, 9:1 by volume), 1% ethylenediamine-tetraacetic acid-2Na (for neutrophil elastase and interleukin-6, 9:1 by volume) or 3.8% sodium citrate plus dipyridamole (for ß-thromboglobulin, 9:1 by volume). Samples for hematocrit and platelet count were collected in ethylenediamine-tetraacetic acid-2Na tubes.
The hematocrit value and platelet counts were analyzed using a cell counter (SE-ALPHA, [SYSMEX, Kobe, Japan]). Platelet counts were expressed as a percentage of the baseline values. Blood for platelet aggregation was centrifuged at 150 g for 10 minutes to prepare platelet-rich plasma and then at 15,000 g to prepare platelet-poor plasma. Platelet aggregation to adenosine diphosphate was assessed with an aggregometer (HEMA TRACER 601 [Tokyo Koden, Tokyo, Japan]) with the use of 150,000 platelets/µL. Threshold doses of adenosine diphosphate were determined as the lowest doses of agonist needed to produce a biphasic aggregation of more than 60% after 5 minutes in the baseline samples. Threshold doses of adenosine diphosphate were then used to measure the aggregation as a percentage of light transmittance in subsequent samples.
The ß-thromboglobulin levels were measured with the use of an enzyme-linked immunosorbent assay kit from Roche (Basel, Switzerland). Prothrombin fragment F1.2 levels were measured with an enzyme-linked immunosorbent assay kit from Hoechst (Frankfurt, Germany). Thrombin-antithrombin complex levels were measured with an enzyme-linked immunosorbent assay kit from SRL (Tokyo, Japan). The 2-plasmin inhibitor-plasmin complex and plasminogen activator inhibitor-1 levels were measured with the use of a latex photometric immunoassay kit from Dia-Iatron (Tokyo, Japan). D-dimer levels were measured with an enzyme-linked immunosorbent assay kit from Fuji-rebio (Tokyo, Japan). Neutrophil elastase levels were measured with an enzyme-linked immunosorbent assay kit from Sanwa Chemical (Tokyo, Japan). Interleukin-6 levels were measured with a chemiluminescent enzyme immunoassay kit from Fuji-rebio (Tokyo, Japan). Bleeding times were measured in duplicate on the forearm at the time points: baseline, ICU, and 4 hours after surgery, by means of a blood pressure cuff inflated to 40 mm Hg. Simplate II (Organon Teknika, Durham, NC) lancet was used to create reproducible incisions. Postoperative chest drainage was recorded for 24 hours.
Statistics
All values are expressed as mean ± standard error of the mean. One-way analysis of variance as compared with the baseline value was used for comparison within the groups. Comparison of two groups over time was performed by analysis of variance with repeated measures. The sequential rejective Bonferroni test was used to correct for multiple comparisons [20].
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Results
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There were no significant differences among the three groups with the number of grafts, CPB time, cross-clamp time, rectal temperature, or postoperative drainage (Table 1).
All patients tolerated the surgery without complications related to this study.
Changes in measured blood and plasma constituents are depicted in Table 2.
Dilution of all formed blood elements was corrected using the hematocrit. Platelet counts decreased significantly in all groups from 69.4% to 71.3% (p < 0.001) of the baseline at the time point of ICU and remained at less than 82.8% at 12 hours. No consistent differences between groups were observed. Platelet aggregation to adenosine diphosphate decreased significantly at the time point of CPB in the control and NM groups, and at protamine in the aprotinin group. At 12 hours, better aggregability was observed in both the aprotinin group (p = 0.023) and NM group (p = 0.023) compared with the control group. The ß-thromboglobulin levels increased significantly during CPB and returned to the baseline levels by 12 hours after surgery in all groups without consistent differences between the groups. Baseline values of bleeding times were about 4.5 minutes in all groups. Bleeding times were prolonged as 11 to 13 minutes at ICU and remained at about 8 minutes after 4 hours in all groups. There were no differences between the groups over time (data not shown in Table 2).
Thrombin-antithrombin complex levels increased significantly after CPB in all groups. Thrombin-antithrombin complex levels were lower in the aprotinin group compared with the control group at the time points of CPB (p = 0.036), protamine (p = 0.030), and ICU (p = 0.028). The NM did not inhibit the thrombin-antithrombin complex level increase, and an even higher value of thrombin-antithrombin complex level was observed at the CPB point compared with the control group (Fig 1).
The changes of prothrombin fragment F1.2 were similar to the thrombin-antithrombin complex changes. Aprotinin attenuated the increase of prothrombin fragment F1.2 compared with the control group at CPB (p = 0.014), protamine (p = 0.035), and ICU (p = 0.007), whereas NM did not (Fig 2).
The NM and aprotinin significantly inhibited the 2-plasmin inhibitor-plasmin complex formation at the time point of ICU (p = 0.034 for NM; p = 0.024 for aprotinin, compared with the control) (Fig 3).
D-dimer levels were consistently lower in the aprotinin compared with the control group. A small but significant reduction of D-dimer by NM (p = 0.041, compared with the control group) was observed at ICU (Fig 4).
There were no significant differences between the three groups in 2-plasmin inhibitor-plasmin complex overtime.
Neutrophil elastase levels at protamine were reduced by aprotinin (p = 0.049) but not by NM (Fig 5).
There were no significant differences between the groups in interleukin-6 for the duration of the study.
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Comment
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We expected that complete inhibition of the two major active proteins of the contact pathway by NM would reduce both thrombin and fibrin formation by inhibiting factor Xa through the intrinsic pathway. Because the contact pathway proteins are important in controlling the whole body inflammatory response as mediated by neutrophils and other vasoactive substances [9], we also expected that this strong contact pathway inhibitor would reduce inflammatory mediators, probably more efficaciously than does aprotinin. During CPB, activation of the contact system initiates subsequent activation of neutrophils and the neutrophil elastase release through kallikrein [21, 22]. Theoretically, the strong inhibition of XIIa and kallikrein by NM should shut down the release of elastase by neutrophils. It has been reported that NM inhibits the protease involved in the release of cytokines from cytokine-producing cells [23]. On the other hand, the effects of aprotinin on the inflammatory response have been thought to be limited because its inhibiting dose for kallikrein is about 100 times greater than that for plasmin [5]. Very high-dose aprotinin may attenuate some of the inflammatory response, but the minimal-dose should not be potent enough to make a significant impact on the inflammatory mediators.
However, the failure of NM to reduce thrombin formation and inflammatory mediators negated our hypothesis. The present NM regimen failed to reduce thrombin formation, platelet activation, and inflammatory reactions, whereas even minimal-dose aprotinin showed significant inhibition of thrombin formation, fibrinolysis, and neutrophil elastase release. The NM only had a significant impact on the control of fibrinolysis as shown in the 2-plasmin inhibitor-plasmin complex and D-dimer changes, but the effects were not as strong as those with aprotinin. One possible reason for these results is that the extrinsic coagulation pathway has a certain influence on thrombin formation and the subsequent fibrin formation, and NM does not modulate the extrinsic pathway. Monocyte tissue factor expression in pericardial wound blood has been observed in clinical CPB [24], and therefore the activation of Xa through the extrinsic pathway may not be shut down, even in the presence of NM. Even in the in vitro CPB, the expression of monocyte tissue factor and pro-coagulant activity is observed; although this monocyte activation begins only after 2 hours of recirculation [25]. In this study, pericardial blood was basically washed but occasionally returned directly to a filtered reservoir; therefore the influence of the extrinsic pathway on each case could not be even. We may need to further our clinical investigations with and without returning the wound blood to verify the effects of the extrinsic pathway.
Postoperative blood loss was not reduced by NM in our study. This result differs from those reported by Murase and colleagues [11] and Sato and colleages [26]. Murase and colleagues [11] reported that NM inhibited fibrinolysis and preserved platelet counts and function, and reduced postoperative blood loss [11]. Our NM dose (2.0 mg/kg/h) was at least 2 times higher than that in their study (40 mg/h), but our study did not reproduce the findings. The lesser impact of NM on platelet counts and function and on fibrinolysis in our study could be the reason for this difference. However, postoperative blood loss is usually minimal in coronary surgery. Therefore it is difficult to lessen the minimized bleeding unless the drug has a huge impact on platelets or fibrinolysis, or both. The fact that NM did not modulate even the platelet counts or platelet aggregability is a surprise, because the drug has shown significant effects on platelet counts and aggregation in previous in vitro studies [9, 10] and our preliminary studies in a simulated CPB.
Thus, there must be a dose issue. Hydrolysis of NM occurs mainly in the blood and liver, followed by glucuronic acid conjugation [27]. Elimination of NM from the blood is rapid, with a half-life of 8 minutes. In deciding on the NM dose in the present study (2.0 mg/kg/h), we followed most previous clinical studies [10–13], which confirmed the efficacy of NM with the doses between 40 and 100 mg/h (or 2.0 mg/kg/h). As Usui and colleagues [10] mentioned, plasma concentrations of NM may differ greatly between in vitro and in vivo studies because the elimination of NM is minimal and therefore NM concentrations could be kept at a stable and higher level in vitro. They found five times greater concentrations of NM in their in vitro study compared with those in vivo. Unfortunately, we did not monitor the NM concentration in the present study or in the preliminary in vitro study. Much higher doses may be necessary to see the potential efficacy of NM in clinical situations. We should conclude that the present regimen of NM (at 2.0 mg/kg/h) does not reach the therapeutic range in clinical CPB.
Clearly, this study lacks statistical power with a small sample size, which may lead to some noise and conceal true changes. It should be pointed out that the biochemical assays and the drugs used in this study are expensive, and that the protocol was only permitted in minimal sample sizes because NM is not officially approved for clinical CPB. In addition, NM is not a novel drug and most previous clinical CPB studies were carried out in the mid-1990s. Although most studies mainly focused on the reduction of postoperative bleeding, several studies evaluated and confirmed its efficiency as a blood-foreign surface inhibitor in CPB showing the inhibition of thrombin formation, fibrinolysis, platelet activation, or complement activation. However, these results with limited markers did not provide concrete information for the efficacy of the drug because no study made comparison with other protease inhibitors. At least the results have not convinced cardiac surgeons that NM should replace aprotinin as the protease inhibitor of choice for CPB. Therefore, the most important meaning of this re-investigation of NM is to measure and clarify the efficacy of NM as a potential blood anesthetic in CPB by revealing the differences with the effects of well-known protease inhibitor, aprotinin, using carefully chosen markers. Despite the negative results of NM on thrombin formation, neutrophil elastase release and platelet activation in our study, we believe that these results provide important information to investigators who are interested in blood anesthesia. Comparison with aprotinin clarified the potentiality of NM on blood-foreign surface interactions more concretely than ever.
The results obtained in this study and the available clinical and in vitro data show the need for further investigations of NM as a blood anesthetic for CPB before we discard this safe drug. We would now like to go on to elucidate its potential impact on the inhibition of platelets, the contact system and neutrophil activation, and sequestration in the in vitro studies. Clinical investigations are necessary to confirm its efficacy at various higher dosages, with and without returning the wound blood to verify the influence of the extrinsic pathway. Among many available protease inhibitors, NM is still one of the most potent and promising inhibitors of the contact system, and it has great potential as a blood anesthetic for CPB.
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Acknowledgments
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This work was supported by The University of Tsukuba Research Project in 2001. The authors wish to thank Avi Landau for language direction and Dr Shiro Hinotsu for statistical assistance.
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Top
Abstract
Introduction
p less than 0.05 by two-way analysis of variance with Bonferroni correction between the NM group or the aprotinin group and the control group. 
p less than 0.05 by two-way analysis of variance with Bonferroni correction between the NM group and the aprotinin group. (ICU = intensive care unit.)
