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Ann Thorac Surg 1996;62:1404-1411
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Nafamostat Mesilate Reduces Blood–Foreign Surface Reactions Similar to Biocompatible Materials

Division of Cardiac Surgery, Cardiovascular Center, Owari Prefectural Hospital, and Department of Thoracic Surgery, Nagoya University, School of Medicine, Aichi, Japan

Accepted for publication June 15, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Nafamostat mesilate (FUT-175) is a synthetic serine protease inhibitor that inactivates coagulation, fibrinolysis, and platelet aggregation. Nafamostat mesilate may suppress the blood–foreign surface reaction similar to biocompatible materials by blocking factor XIIa.

Methods. We performed an in vitro study of cardiopulmonary bypass (CPB) with fresh human blood among the following three groups: standard CPB sets (C), biocompatible CPB sets (B), and standard CPB sets with FUT-175 (10 mg/L) (F). A clinical study using these same CPB groups also was performed in 45 patients undergoing aortocoronary bypass operations (15 patients each). We injected FUT-175 at 40 mg/h during CPB.

Results. In the in vitro study, both groups B and F showed significantly lower levels of coagulation factors, thrombin-antithrombin III complex, fibrinopeptide A, ß-thromboglobulin, complement C3a, granulocyte elastase, and free hemoglobin than group C at the conclusion of the study. Thrombin-antithrombin III complex and free hemoglobin in group F also were lower than in group B. The platelet count remained at a higher level in group F than in the other groups. Separation of bradykinin was suppressed most significantly in group F. In the clinical study, group F also showed significantly lower levels of 2-plasmin inhibitor plasmin complex and C3a than both groups C and B. There were minimal levels of free hemoglobin in group F.

Conclusions. Nafamostat mesilate may contribute major beneficial effects toward conservation of blood during CPB and prevention of coagulopathy after CPB.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
During cardiac operations, blood is exposed to the artificial surface of extracorporeal circuits. This exposure results in activation of coagulation, fibrinolysis, and platelet aggregation [1–3]. Consumption of coagulation factors, excessive fibrinolysis [4, 5], and a transient impairment of platelet function [6, 7] may lead to abnormal bleeding after cardiac operations. Biocompatible materials such as a heparin-coated extracorporeal circuit have been used to reduce the activation of humoral cascade systems. Nafamostat mesilate (FUT-175); 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate) is a synthetic serine protease inhibitor developed by Torii & Co, Ltd (Tokyo, Japan). Nafamostat mesilate is an inactivator of coagulation fibrinolysis, and platelet aggregation with potent inhibitory activity against thrombin, coagulation factors in active form (XIIa, Xa), kallikrein, plasmin, and complement factors (C1r, C1s) [8, 9]. Inhibitory activity against factor XIIa reduces the activated contact phase in coagulation; therefore, FUT-175 may decrease the activation of humoral cascade systems similar to a biocompatible cardiopulmonary bypass (CPB) circuit. We performed an in vitro study of CPB with fresh human blood to estimate the inactivation capacity of FUT-175.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In Vitro Study
PREPARATION OF THE CARDIOPULMONARY BYPASS CIRCUIT.
An in vitro study of CPB was performed on eight sets of three different circuit groups: control (C), biocompatible (B), and FUT-175 (F). The CPB circuit of groups C and F was composed of a nonheparin-coated oxygenator (Bentley Univox; Baxter Healthcare Corp, Irvine, CA), an arterial filter (William Harvey H-625; Bard, Billerica, MA), a cardiotomy reservoir (William Harvey H-4720; Bard), and a vinyl chloride CPB tube. Group B was treated with a heparin-coated (Duraflo II) oxygenator (Bentley Univox gold; Baxter Healthcare Corp), an arterial filter (William Harvey H-640; Bard), a cardiotomy reservoir (William Harvey H-4700; Bard), and a bionate tube, which is a biocompatible material recently developed in Toyobo, Japan. Each CPB set was primed with 500 mL of electrolyte solution and 500 mL of fresh blood voluntarily donated from 4 people on our medical staff. The donors had the same blood type and were checked previously to ensure no cross reaction. The blood was mixed with anticoagulant CPD solution and divided into three equal volumes. Ten milligrams of FUT-175, which had been dissolved in a 5% glucose solution (1 mg/mL), was added to the priming solution of group F. We injected 1,000 IU of bovine lung heparin chloride and 1.4 g of NaHCO₃ just before the initiation of CPB. Anticoagulant CPD solution was neutralized with CaCl₂, 0.55 g. Additional heparin chloride was administered when the activated clotting time (ACT) fell below 400 seconds. This procedure may influence complement, granulocyte, and platelet activation; however, it should avoid any difference of priming conditions among groups. We performed CPB by using a rotary pump (Mera, Tokyo, Japan) with a perfusion rate of 3.0 L/min for 4 hours. Blood temperature was maintained at approximately 30°C with a heat exchanger.

MEASUREMENTS.
Activation of coagulation, fibrinolysis, and platelets was estimated by measuring specific blood markers. To estimate a contact factor, we measured blood concentrations of the active form of factor XII (XIIa) and bradykinin using enzyme-linked immunosorbent assay. Factor XII activity also was measured. To estimate a coagulation factor, we measured blood concentrations of thrombin-antithrombin III complex (TAT), fibrinopeptide A (FPA), and fibrinogen. As a marker for fibrinolysis, 2-plasmin inhibitor plasmin complex (PIC) concentrations were measured. Blood concentrations of 2-plasmin inhibitor, plasminogen activator inhibitor-1, and plasminogen also were measured. For estimation of platelet activation, we assessed the platelet count and blood concentrations of ß-thromboglobulin (ß-TG) and thromboxane B2. Blood concentrations of complement (C3a, C4a), free hemoglobin, and granulocyte elastase also were measured. Hemocytogram and blood concentrations of factor XIIa and bradykinin were measured at 5 minutes, 15 minutes, 1 hour, 2 hours, and 4 hours after the initiation of CPB and in each sample of donated blood. The ACT was measured with Hemochron 400 (Technidyne, NJ). Other measurements were performed at the initiation and conclusion of CPB. Plasma was separated from sampled blood by centrifugation at 1,000 g for 10 min at 4°C immediately after collection, then stored at -80°C until analysis. At the end of the study, an arterial filter and the extracorporeal tubing were washed with saline and preserved with glutaraldehyde solution, and were observed by a scanning electron microscope (Hitachi S-2500; Hitachi, Co Ltd, Tokyo, Japan).

Clinical Study
Forty-five patients who had provided informed consent and were scheduled for elective coronary artery bypass operations were randomly assigned to receive FUT-175 (n = 15), to use biocompatible CPB circuits (n = 15), or to serve as controls (n = 15). The operations were performed by the same team of surgeons and anesthetists. Anesthesia was standardized to include intermittent positive pressure ventilation with nitrous oxide and oxygen and was maintained with high-dose fentanyl. The operations were performed through a midline sternotomy. Bovine lung heparin chloride (300 IU/kg) was injected before cannulation of the aorta and right atrium. Additional heparin chloride was administered when the ACT fell below 400 seconds. In each group, the same CPB circuits were used as in the in vitro study, and the circuits were primed with 1,500 mL of electrolyte solution. Bypass flows of 2.5 L•min^-1•m^-2 were obtained with a minimally occlusive roller pump. No systemic cooling was used during CPB. Myocardial preservation during aortic occlusion was maintained with oxygenated cold blood cardioplegia without topical cooling. After weaning from bypass, the residual heparin was reversed with protamine sulfate (1 mg/100 IU total heparin administered). In group F, FUT-175 was dissolved in a 5% glucose solution (1 mg/mL) and was infused through a central venous catheter at the rate of 40 mg/h, beginning with the administration of heparin and continuing until the end of CPB. The cell-saving discard suction apparatus was used in each case throughout the procedure. Blood samples were taken serially from a peripheral arterial line at the beginning of CPB, 1 hour after CPB, and at the end of CPB. The same blood markers as in the in vitro study were measured.

Plasma was separated from the heparin-treated blood samples by centrifugation at 1,000 g for 10 minutes at 4°C immediately after collection, then stored at -80°C until analysis. Duplicate measurements were performed on each sample. Differences among groups were evaluated by the nonpaired t test or one-way analysis of variance and post hoc tests; p value less than 0.05 was considered significant. The results were expressed as mean ± standard deviation.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In Vitro Study
ACTIVATED CLOTTING TIME.
In group C, the ACT was approximately 400 seconds during the study, and additional heparin was administered in 3 sets when the ACT fell below this level (500 IU each). In group B, the ACT was approximately 1,000 seconds, and no additional heparin was administered. The ACT was greater than 1,500 seconds at all points in group F. No visible clot formation occurred in CPB circuits in any group.

CONTACT PHASE OF COAGULATION.
Blood concentrations of bradykinin were not detected in any donated blood (less than 9.6 pg/mL). Blood concentrations of bradykinin increased promptly after the initiation of CPB and decreased gradually in groups B and C. On the other hand, bradykinin increased gradually in group F (Fig 1). Blood concentrations of factor XIIa increased slightly during the study in all groups. There were no significant differences in factor XIIa levels among the three groups. Activity of factor XII also showed no significant changes during the study in any group (Table 1).

View larger version (53K): [in this window] [in a new window]   Fig 1. . Blood concentrations of bradykinin during the in vitro study. The x axis indicates time since the beginning of the in vitro study. *p < 0.05, **p < 0.01 between groups F and B or C. (CPB = cardiopulmonary bypass.)

FIBRINOLYSIS.
Concentrations of PIC did not increase significantly during the study in any group, and there were no significant differences among groups. Plasminogen concentrations decreased slightly in all groups; however, there were no significant differences among groups. Concentrations of 2-plasmin inhibitor decreased only in group C, showing a significant difference from groups B and F. Blood concentrations of plasminogen activator inhibitor-1 increased in all groups; however, group C showed higher levels than the other groups.

PLATELET COUNT.
Initial platelet count in the donated blood, which was calculated theoretically, was 98,000 ± 2,500/µL. The platelet count decreased rapidly after initiation of CPB and remained at approximately 10,000/µL after 30 minutes in group C. In group B, the platelet count decreased slowly after CPB initiation and remained at about 30,000/µL. Platelet count decreased minimally in group F and remained at 50,000/µL during the study period. The platelet count in group F remained higher than in group C throughout the study (p < 0.01) and was also higher than in group B in the first 30 minutes after the initiation of CPB (Fig 2).

View larger version (59K): [in this window] [in a new window]   Fig 2. . Platelet count during the in vitro study. The x axis indicates time since the beginning of the in vitro study. *p < 0.05, **p < 0.01 between groups F and B or C. (CPB = cardiopulmonary bypass.)

Concentrations of thromboxane B2 also were increased in each group; however, there were no significant differences among groups.

OTHER INDICES.
Blood concentrations of both complement components (C3a, C4a) increased significantly during the study, with a sixfold and fourfold increase, respectively, in group C. On the other hand, C3a and C4a increased only twofold in groups B and F. Concentrations of C3a in group C showed significantly higher levels than in group B or F; however, there was no significant difference among the groups for C4a (see Table 1).

Free hemoglobin increased during the study in all groups. At the end of the study, free hemoglobin concentrations were significantly lower in group F than in group B or C (see Table 1).

Blood concentrations of granulocyte elastase increased eightfold in group C. Granulocyte elastase also increased slightly in groups B and F, but significantly less than in group C (see Table 1).

ELECTRON MICROSCOPY.
In group C, several red blood cells, platelets, and leukocytes adhered to fibrin fibers on the inner surface of the extracorporeal tubing. There were only a few red blood cells on the inner surface in group F, and few red cells were observed on the bionate tube in group B (Fig 3). Scanning electron micrographs of the arterial filter in group C showed red blood cells, leukocytes, and platelets forming aggregates and clusters, with multiformed pseudopodia. On the other hand, few red blood cells adhered to the arterial filter with occasional fibrin fibers in group F, and only a few red blood cells were observed on the heparin-coated arterial filter in group B (Fig 4).

View larger version (209K): [in this window] [in a new window]   Fig 3. . Scanning electron micrographs of the inner surface of the extracorporeal tubing. (A) The vinyl chloride tube in the control group. (B) The bionate tube in the biocompatible group. (C) The vinyl chloride tube with FUT-175 (10 mg/L). (All x1,000 before 33% reduction.)

View larger version (246K): [in this window] [in a new window]   Fig 4. . Scanning electron micrographs of the arterial filter. (A) The noncoated arterial filter in the control group. (B) The heparin-coated arterial filter in the biocompatible group. (C) The noncoated arterial filter with FUT-175 (10 mg/L). (All x1,000 before 33% reduction.)

PLATELET COUNT.
The platelet count decreased slowly during CPB in each group and showed no significant differences at the end of CPB among the three groups. Concentrations of ß-TG increased threefold in group C and twofold in groups B and F. Levels of ß-TG were slightly higher in group C; however, there were no significant differences among the groups at the end of CPB. Concentrations of thromboxane B2 were increased slightly in all groups, but there were no significant differences among the groups at the end of CPB (see Table 3).

OTHER INDICES.
Blood concentrations of both complement components (C3a, C4a) increased significantly during CPB, with a fivefold and threefold increase, respectively, in group C. Both C3a and C4a increased only twofold in groups B and F. Concentrations of C3a in group F were significantly lower than in group C or B; however, there were no significant differences among the groups in C4a levels (see Table 3).

Free hemoglobin increased during the study in all groups. At the end of CPB, free hemoglobin concentrations were significantly lower in group F than in group C (see Table 3).

Blood concentrations of granulocyte elastase increased severalfold during CPB in each group. Granulocyte elastase in group F showed the lowest value at the end of CPB; however, there were no significant differences among the groups.

Activity of coagulation factor XII also showed no significant differences among the groups at the end of CPB.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
During extracorporeal circulation, blood–foreign surface reaction on the inner surface of the CPB circuit activates the contact phase of coagulation. The contact phase of coagulation is composed of factors XII and XI, prekallikrein, and high molecular weight kininogen. Factor XII, which is activated on the foreign surface first, leads to the activation of prekallikrein to kallikrein, which activates factor XII. The active form of factor XII (XIIa) activates factor XI, which then activates the humoral coagulation cascade [10]. Kallikrein leads to the production of bradykinin from high molecular weight kininogen and accelerates the conversion of prourokinase to urokinase. Urokinase then activates fibrinolysis. Kallikrein also accelerates the aggregation and degranulation of white blood cells. Factor XIIa activates C1r enzymatically, which accelerates the classic pathway of the complement system. Kallikrein also activates factor B of the alternative pathway of the complement system. Therefore, acceleration of the contact phase causes activation of fibrinolysis, the complement system, the kinin system, and white blood cells.

Inactivation of factor XII is the primary method to suppress the contact phase of coagulation and subsequent phenomena. There are two different ways to suppress factor XII. One is to use biocompatible materials on the foreign surface. It has been reported that heparin-coated CPB circuits reduce the blood–foreign surface reaction [11, 12]. Another way to suppress factor XII is to use a drug that specifically inactivates factor XII.

FUT-175 is a synthetic protease-inhibiting agent that has potent inhibitory activity with respect to thrombin, coagulation factors in the active form (XIIa, Xa), kallikrein, plasmin, complement factor (C1r, C1s), and trypsin. FUT-175 has a high affinity for these proteases, with Ki values of approximately 10^-7 to 10^-8 mol/L [13]. Because FUT-175 inhibits activation of factor XII, it should reduce blood–foreign surface reactions. Biocompatible materials have been developed recently to reduce blood–foreign surface reactions on extracorporeal circuits. However, FUT-175 can also block blood–foreign surface reactions on conventional extracorporeal circuits. Therefore, FUT-175 should diminish cellular adhesion to the inner surface of extracorporeal circuits as well as do biocompatible materials.

In the in vitro study, activation of coagulation was inhibited most strongly in the group using FUT-175. Platelet count in the FUT-175 group remained higher than in the group using biocompatible materials. Degranulation of platelets and granulocytes was diminished by FUT-175 as strongly as by biocompatible materials. The classic pathway of complement also was suppressed equally by FUT-175 and biocompatible materials. At the concentrations used in the in vitro study, FUT-175 functioned similarly to the biocompatible materials and also inhibited activation of the humoral cascade systems and prevented platelet aggregation as a serine protease inhibitor. In addition, FUT-175 showed lower free hemoglobin levels than did biocompatible materials; FUT-175 may act as an antihemolytic agent. However, fibrinolysis showed no significant difference between these groups in the in vitro study. Production of bradykinin was suppressed particularly by FUT-175. As biocompatible materials show no suppression of bradykinin release, FUT-175 may suppress bradykinin production directly.

Our results in the in vitro study are slightly different from those reported by Sundaram and colleagues [14]. They reported that FUT-175 significantly reduced the release of ß-TG, neutrophil elastase, and FPA and completely inhibited the formation of complexes of C1 inhibitor with kallikrein and factor XIIa; however, platelet counts did not differ in the simulated extracorporeal circulation. In our results, FUT-175 significantly reduced FPA, TAT, and C3a and preserved platelet counts. The FUT-175 concentration in their report was 4,200 ng/mL, which is similar to that in our in vitro study. They used closed circuits of CPB sets, whereas we used open circuits; this difference may have caused a discrepancy between their results and ours [14].

The FUT-175 group showed significant differences from the control group only in C3a, PIC, and free hemoglobin in the clinical study. However, FUT-175 suppressed fibrinolysis and the classic pathway of complement more strongly than did biocompatible materials. Thus, FUT-175 may have suppressed fibrinolysis directly as a protease inhibitor in the clinical study. However, fibrinolysis was not activated in the in vitro study, even in the control group. This discrepancy may be caused by the condition with or without a human body. Wachtfogel and colleagues [15] reported that PIC levels were not significantly increased either in an in vitro study and or a clinical study. However, our clinical study showed a significant increase of PIC levels during CPB, which has been confirmed by our previous study [16]. In our clinical study, biocompatible materials showed a significant difference from the control group only in C3a concentrations. Suppression of the classic complement pathway should have been caused mainly by suppression of the contact phase in both groups B and F. There may be many other factors that affect activation of coagulation, fibrinolysis, platelets, white blood cells, the complement system, and the kinin system in the clinical study. These factors create a discrepancy between the clinical and the in vitro studies.

Hydrolysis of FUT-175 occurs mainly in the blood and liver, followed by glucuronic acid conjugation [17]. Elimination of FUT-175 from the bloodstream is rapid, with a half-life of several minutes. In our clinical study, FUT-175 concentrations were approximately 2,000 ng/mL in a hypothermic phase when FUT-175 was injected continuously at a rate of 40 mg/h [16]. In the in vitro study, FUT-175 was used at the 10 mg/1,000 mL priming volume. Concentrations of FUT-175 were approximately 10,000 ng/mL (10^-5 mol/L) at the beginning of the study. Elimination of FUT-175 is minimal, and its concentrations could be maintained at a stable level in the in vitro study. Therefore, FUT-175 concentrations in the in vitro study should be slightly higher than in the clinical study. In the in vitro study, the ACT was more than twice as high in group B and three times as high in group F, even using the same dosage of heparin. Released heparin from Duraflo II heparin coating prolonged the ACT in group B, and FUT-175 prolonged the ACT directly in group F.

Aprotinin is another protease inhibitor that is widely used in cardiac operations. It has been reported that aprotinin significantly reduces both blood loss and blood transfusion requirements in patients undergoing cardiac operations. Aprotinin also reduced thrombin generation and fibrinolytic activity in clinical studies [18, 19]. In the present clinical study, FUT-175 reduced plasmin generation significantly and suppressed thrombin generation slightly; however, there was no significant reduction of blood loss. We used a low dose of FUT-175, the same dose as used for hemodialysis, in this study. Although FUT-175 has been used successfully in hemodialysis as an anticoagulant, its use in CPB remains experimental. Future investigations with FUT-175 are necessary to confirm its efficacy at various dosages, primarily related to its role in cardiac operations.

In conclusion, FUT-175 prevents coagulation, fibrinolysis, platelet activation, complement production, hemolysis, and granulocyte activation by reducing blood–foreign surface reactions to suppress the contact phase of coagulation, or by functioning directly as a serine protease inhibitor. Thus, FUT-175 should contribute major beneficial effects toward conservation of blood during CPB and prevention of coagulopathy after CPB.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Usui, 2-903 Umegaoka, Tenpaku-ku, Nagoya 468, Japan.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Akihiko Usui Mitsuya Murase Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Usui, A. Articles by Murase, M. Search for Related Content PubMed PubMed Citation Articles by Usui, A. Articles by Murase, M.