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Ann Thorac Surg 1995;59:106-111
© 1995 The Society of Thoracic Surgeons

Effect of Aprotinin on Activated Clotting Time, Whole Blood and Plasma Heparin Measurements

Departments of Anesthesiology, Internal Medicine, Pathology, and Surgery, Washington University School of Medicine, and Departments of Internal Medicine and Pathology, St. Louis University School of Medicine, St. Louis, Missouri

Accepted for publication September 7, 1994.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Twenty cardiac surgical patients requiring cardiopulmonary bypass were enrolled in this study designed to evaluate the effect of aprotinin on activated clotting time (kaolin and celite), whole blood, and laboratory-based plasma (anti-Xa) heparin measurements. Whole blood heparin measurements were not different (p = 0.98) between aprotinin-treated (3.2 ± 2.8 U/mL) and control (3.2 ± 3.0 U/mL) specimens. Plasma anti-Xa heparin measurements were also not different (p = 0.95) between aprotinin-treated (2.7 ± 2.5 U/mL) and control (2.8 ± 2.5 U/mL) specimens. The relationship between whole blood (plasma equivalent) and plasma heparin measurements was similar (p = 0.1) in the presence (slope, 1.04; r² = 0.89) or absence (slope, 1.11; r² = 0.89) of aprotinin. In contrast to weak correlations between celite (r = 0.50) or kaolin (r = 0.53) activated clotting time values, whole blood heparin measurements correlated well (r = 0.93) with plasma heparin measurements during cardiopulmonary bypass in the presence of aprotinin. These findings indicate that whole blood heparin measurements are unaffected by aprotinin and correlate well with plasma anti-Xa heparin measurements even in the presence of aprotinin. Therefore, the automated protamine titration assay can be used to monitor accurately heparin concentrations in patients receiving aprotinin.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
U se of aprotinin reduces bleeding and blood product use significantly in cardiac surgical patients [1]. Although reports have suggested that aprotinin may be a heparin-sparing agent [2] and may have anticoagulant properties [3], other reports reveal that prolonged celite activated clotting time (ACT) values may reflect aprotinin's ability to inhibit ACT activators in vitro [4–6]. Thrombotic complications have been reported with the use of aprotinin when heparin administration was based on celite ACT protocols [7, 8]. Although the exact incidence and mechanism for aprotinin-mediated procoagulation is unknown, currently it is recommended to use aprotinin with careful maintenance of adequate anticoagulation, either by using fixed-dose heparin schedules based on weight and duration of cardiopulmonary bypass (CPB) or with anticoagulation monitoring using an assay unaffected by aprotinin [9].

An on-site hemostasis management system can provide both ACT and whole blood heparin concentration measurements [10]. Whole blood heparin measurements using this automated protamine titration method correlate extremely well with plasma anti-Xa heparin measurements before and during extracorporeal circulation in contrast with ACT measurements [11]. Previous evidence suggests that aprotinin may affect the extrinsic pathway [12], whereas other reports indicate that whole blood heparin measurements are unaffected by aprotinin [6]. Because this whole blood heparin assay uses a thromboplastin reagent to activate the extrinsic pathway, any potential effects of aprotonin on this assay are important. Therefore, this study was designed to assess the effect of aprotinin on the determination of heparin concentration using on-site ACT assays, whole blood protamine titration, and laboratory-based anti-Xa assays.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Twenty adult patients scheduled for cardiac operation or lung transplantation requiring CPB were enrolled in this study. Informed consent was obtained from all patients enrolled in this Institutional Human Studies Committee-approved protocol. Exclusion criteria included emergency procedures. All patients were anesthetized with an opioid-based technique; the anesthetic was supplemented with inhalational anesthetic agents, muscle relaxants, and benzodiazepines. Extracorporeal circulation was accomplished with a Bio-Medicus Au: need city & state of manufacturercentrifugal pump (Medtronic-Biomedicus Inc, Eden Prairie, MN), a Monolyth Au: need city & state of manufacturermembrane oxygenator (Sorin Biomedical Inc, Arcadia, CO), and systemic hypothermia maintained at 28°C during cardioplegia. The CPB system was routinely primed with 1.5 L of Plasmalyte solutionAu: need city & state of manufacturer, 50 mEq of sodium bicarbonate (NaHCO₃), 25 g of mannitol, and 5,000 units of porcine heparin. In patients receiving aprotinin (Miles Inc, West Haven, CT), administration of this antiproteolytic agent was based on the previously described full-dose regimen [1]. After a negative test dose (1 mL), a loading dose of 280 mg (2 x 10⁶ KIU) was infused over 20 to 30 minutes followed by a 70-mg/h infusion, and 200 mg was added to the CPB prime solution.

Systemic anticoagulation for CPB was accomplished with porcine heparin. A total dose of 250 or 300 U/kg body weight of unfractionated heparin was administered before initiation of CPB. Anticoagulation for CPB was monitored with on-site, whole blood heparin and ACT measurements using the Hepcon instrument (Medtronic Hemotec, Englewood, CO); further doses of heparin were administered as needed to maintain a pre-CPB reference heparin concentration and an ACT of 480 or more seconds. The reference heparin concentration was based on the whole blood heparin concentration measured 10 minutes after administration of heparin and before initiation of CPB. After rewarming the patient to 37°C, extracorporeal circulation was discontinued and heparin was neutralized with protamine. The protamine dose was determined based on the most recent whole blood heparin measurement before discontinuation of CPB (1.3 mg of protamine per milligram of residual heparin).

Phase I Study
To assess the accuracy of on-site, ACT, and whole blood heparin measurements in relation to plasma heparin measurements before and after initiation of CPB, the study was divided into two phases. Phase I was designed to evaluate correlations before CPB and was carried out with blood speciments from 10 patients who had not received heparin for CPB. In this phase, blood specimens were obtained either (1) before heparin administration to assess the effect of aprotinin on heparin concentration measurements in vitro or (2) after heparin administration to examine the in vitro effect of aprotinin on celite ACT. Blood specimens obtained before heparin administration were divided into five aliquots and inserted into vials containing different amounts of heparin yielding final heparin concentrations of 0, 0.7, 1.4, 2.7, 4.9, or 6.7 U/mL, respectively. These specimens were further subdivided and placed either into vials containing aprotinin (400 KIU/mL) or not containing aprotinin (control). Whole blood and plasma heparin concentration were then measured using both specimens. Blood specimens obtained after heparin administration were subdivided into aprotinin (400 KIU/mL) and control specimens and used to measure celite ACT in duplicate.

Phase II Study
In phase II, the effect of aprotinin on ACT, whole blood heparin, and plasma heparin measurements was evaluated ex vivo. This phase involved 10 patients who were treated with aprotinin to minimize perioperative blood loss before and during extracorporeal circulation. In these 10 patients, blood specimens (n = 5 to 8) were obtained before aprotinin and heparin administration and 10 minutes after each of the following: aprotinin administration, heparin administration, initiation of CPB, achievement of hypothermia, initiation of rewarming, and immediately before discontinuation of CPB. Celite ACT, kaolin ACT, whole blood, and plasma heparin measurements were then obtained using these specimens.

Coagulation Assays
Single blood specimens obtained from either radial or femoral intraarterial catheters after removal of six dead space volumes or from the CPB arterial cannula were used for coagulation analysis by both routine laboratory and on-site, whole blood assays. During phase I, celite ACT was measured using the Hemochron 801 instrument (International Technidyne, Edison, NJ), whereas during phase II, both celite (Hemochron 801) and kaolin ACT using the automated clot timer instrument (ACT; Medtronic Hemotec) were measured. ACT assays were performed in duplicate and values were expressed as the mean of duplicate measurements. For heparin concentration measurements, blood specimens were divided into two aliquots. One aliquot was injected into a blue-top vacutainer tube (1/10 vol, 0.129 mol/L sodium citrate; Becton Dickinson, Rutherford, NJ), refrigerated and transported to the laboratory for stat processing. After processing, an aliquot of plasma from each blood specimen was labeled, frozen, and stored for later measurement of heparin concentration. Plasma heparin concentration was determined with an anti-Factor Xa (Xa) chromogenic substrate assay as previously described [13]. A second aliquot was used intraoperatively to measure whole blood (WB) heparin concentration in duplicate with an on-site protamine titration assay (Hepcon; Medtronic Hemotec). These replicate measurements of whole blood heparin concentration were then used to determine mean whole blood heparin concentration values. In addition, both hematocrit and core temperature values were quantified with each specimen collection. Hematocrit (Hct) values were used to convert whole blood (WB) heparin concentration into plasma equivalent (PE) values with the following formula: .

Statistical Analysis
Student's paired t test was used to compare mean ACT values, whole blood, and plasma heparin measurements in aprotinin-treated and control specimens. Ordinary (nonweighted) least squares linear regression was used to estimate a linear relationship and generate correlation coefficients between plasma anti-Xa heparin concentration measurements and on-site, whole blood assays with p values less than 0.05 considered statistically significant. The impact of aprotinin on the relationship between whole blood and plasma anti-Xa heparin measurements was assessed by comparing the response of these assays between aprotinin-treated and control specimens before and during CPB using bootstrap analysis.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Effect of Aprotinin Added to Blood In Vitro on Celite Activated Clotting Time, Whole Blood, and Anti-Xa Heparin Measurements
In phase I, mean whole blood heparin concentration measurements were similar (p = 0.97) in aprotinin-treated (1.9 ± 1.7 U/mL) and control (1.9 ± 1.8 U/mL) specimens. Mean plasma equivalent whole blood heparin concentration values were also similar (p = 0.99) in aprotinin-treated (3.2 ± 2.8 U/mL) and control (3.2 ± 3.0 U/mL) specimens. Whole blood heparin measurements were also similar between specimens with and without aprotinin at each respective heparin concentration (0 U/mL, p = 1.0; 0.7 U/mL, p = 0.96; 1.4 U/mL, p = 0.97; 2.7 U/mL, p = 0.28; 4.9 or 6.7 U/mL, p = 0.59). Plasma heparin measurements were similar (p = 0.95) in aprotinin-spiked (2.7 ± 2.5 U/mL) and control (2.8 ± 2.5 U/mL) specimens. Plasma heparin measurements were also similar between specimens with and without aprotinin at each respective heparin concentration (0 U/mL, p = 0.89; 0.7 U/mL, p = 0.74; 1.4 U/mL, p = 0.21; 2.7 U/mL, p = 0.92; 4.9 or 6.7 U/mL, p = 0.86). After systemic heparin administration (3.26 ± 0.62 U/mL), mean (1,260 ± 387 s) and median (1,194: 991 to 1499 s) celite ACT values were markedly longer (p < 0.0001) in aprotinin-treated (400 KIU) specimens when compared with mean (536 ± 88 s) and median (521: 504 to 601 s) celite ACT values in control specimens.

Effect of Systemic Administration of Aprotinin on Celite Activated Clotting Time, Kaolin Activated Clotting Time, Whole Blood, and Anti-Xa Heparin Measurements
After systemic administration of heparin and aprotinin, weak correlations were obtained between celite (r = 0.50) and kaolin (r = 0.53) ACT values and plasma anti-Xa heparin measurements during the CPB interval (phase II). In contrast, an excellent correlation (r = 0.93) was obtained between whole blood (PE) and plasma anti-Xa heparin measurements after heparin and aprotinin administration during CPB.

Effect of Aprotinin on Correlations Between Whole Blood and Anti-Xa Heparin Concentration
Figure 1 illustrates the linear relationships between whole blood (PE) and plasma heparin concentration in both aprotinin and control specimens generated from in vitro datafig 1. Linear regression revealed a good relationship between whole blood (PE) and anti-Xa heparin measurements (WB = 1.11Xa + 0.08; r² = 0.89) in control specimens without aprotinin. Linear regression also revealed a good relationship between whole blood (PE) and anti-Xa heparin measurements (WB = 1.04Xa + 0.31; r² = 0.89) in specimens with aprotinin added in vitro. The relationship and linear fit between whole blood (PE) and plasma heparin measurements were similar in the presence or absence of aprotinin as demonstrated by statistically similar slopes (p = 0.1) and percent variance-explained values (p = 0.73). Figure 2 illustrates the linear relationship between whole blood (PE) and anti-Xa heparin measurements from the ex vivo phasefig 2. Linear regression also revealed a good relationship between whole blood (PE) and anti-Xa heparin measurements (WB = 0.91Xa + 0.40; r² = 0.87) in specimens with aprotinin (ex vitro).

View larger version (24K): [in this window] [in a new window]   Fig 1. . Relationship of plasma equivalent (PE) whole blood heparin concentration (WB Heparin Conc) and plasma anti-Xa heparin concentration (Plasma anti-Xa Heparin Conc) in specimens spiked in vitro with heparin (Control) or heparin and aprotinin (Aprotinin). Whole blood heparin concentration (U/mL) was determined with an automated protamine titration method (Hepcon). Hematocrit values were used to convert whole blood heparin concentration into PE whole blood values with the following formula: . Plasma heparin concentration (U/mL) was measured with a laboratory-based anti-Xa chromogenic assay. See text for linear regression equations and statistical analysis.

View larger version (21K): [in this window] [in a new window]   Fig 2. . Relationship of plasma equivalent (PE) whole blood heparin concentration (WB Heparin Conc) and plasma anti-Xa heparin concentration (Plasma anti-Xa Heparin Conc) in specimens obtained from patients receiving aprotinin. Blood specimens (n = 5 to 8) were obtained before aprotinin and heparin administration and 10 minutes after each of the following: aprotinin administration, heparin administration, initiation of CPB, achievement of hypothermia, initiation of rewarming, and immediately before discontinuation of CPB. Whole blood heparin concentration (U/mL) was determined with an automated protamine titration method (Hepcon). Hematocrit values were used to convert whole blood heparin concentration into PE whole blood values with the following formula: . Plasma heparin concentration (U/mL) was measured with a laboratory-based anti-Xa chromogenic assay. See text for linear regression equations and statistical analysis.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Transfusion of blood and blood products currently is being reviewed with intense scrutiny as a consequence of increased awareness of the hazards and costs of transfusion. Consequently, innovative strategies, such as the use of aprotinin [1] to reduce bleeding and transfusion requirements, have been investigated. Although aprotinin has some anticoagulant properties [3], potentially it can increase circulating procoagulants [14], decrease heparin anticoagulant effect because of heparin-aprotinin binding [15], and potentially enhance hemostasis by plasmin inhibition [16] and protein C inhibition [17]. These effects may alter hemostasis toward increased fibrin formation and deposition and its use may be associated with an increased incidence of thromboembolic complications. This concern has been substantiated with demonstration of clot formation on pulmonary artery catheters [18] and increased thromboembolic complications in certain cardiac patient subsets [7, 8]. Accordingly, recommendations have been made to use aprotinin with caution along with careful maintenance of adequate anticoagulation [9].

Heparin administration for CPB can be based on either a fixed dosage schedule or on results of monitoring assays. A limitation of the fixed dosage schedule is the lack of confirmation that adequate anticoagulation has been maintained. There is considerable variability in heparin anticoagulant response related to the source of heparin (bovine lung versus porcine mucosal), the method of preparation, and the molecular weight distribution of various preparations [19]. However, the clinical significance of this variability is not well established. In addition, cardiac surgical patients may be predisposed to a higher incidence of heparin resistance attributable to preoperative heparin therapy, preoperative nitroglycerin infusion, perioperatively acquired ATIII deficiency, or a combination of these factors [20, 21]. Potential variables that have been shown to alter the anticoagulant response to heparin have been summarized previously [22]. Monitoring the heparin anticoagulant effect enables physicians to direct heparin administration and determine when additional anticoagulation or alternative interventions such as clotting factor repletion are indicated [23]. A second limitation of fixed dosage regimens involves the heparin pharmacokinetic profile during CPB. Substantial variability in heparin concentration can occur during the peri-CPB interval [11]. Previous studies have demonstrated a fourfold variation in heparin half-life [20]. Neither total heparin dose nor total time on CPB can predict adequately heparin concentrations at the end of CPB [11]. This may be related to the variable degree of hemodilution demonstrated by the significant correlation between hematocrit values and heparin concentration during CPB [11].

The ACT is used routinely to assess adequacy of anticoagulation before and during extracorporeal circulation. Although the optimal ACT value for CPB has not been established, values between 400 and 480 seconds are commonly maintained. Our in vitro data confirm previous in vitro [5] and ex vivo [6] data that demonstrate prolongation of celite ACT by aprotinin. Initial suggestions to maintain celite ACT more than 750 seconds [24] have been supported by corresponding studies showing that patients receive lower heparin doses and have lower heparin levels when their heparin dosing schedule is guided by celite ACT protocols in the setting of concurrent aprotinin administration [25]. These initial suggestions have been supplemented by current recommendations that advise use of clotting assays that are unaffected by aprotinin [9]. Kaolin ACT is less affected by aprotinin administration as compared with celite ACT [5, 6]. However, monitoring coagulation in the perioperative period exclusively with the ACT may be misleading as previous studies have illustrated that ACT values do not correlate well with plasma heparin measurements during extracorporeal circulation [11, 26]. This may be attributable, at least in part, to the intrinsic imprecision of ACT measurements during anticoagulation, the effects of CPB-related hypothermia and hemodilution on the ACT [11, 26], and possibly, activation or depression of platelet function [22]. Our data confirm the poor correlation of celite and kaolin ACT values with plasma heparin concentration during the CPB interval in patients that receive aprotinin. Because kaolin or celite ACT may not reflect accurately heparin concentration in patients on CPB when aprotinin is used, a particular heparin concentration, as defined by the target ACT before CPB, cannot be maintained adequately during CPB using ACT measurements. In addition, our ex vivo data demonstrate when pre-CPB heparin levels are maintained, mean kaolin and celite ACT values are prolonged significantly beyond clotting times previously recommended for the CPB interval. Another assay to monitor heparin anticoagulant effect during CPB is the high-dose thrombin time (HiTT; International Technidyne, Edison, NJ). Although this assay may have clinical utility to monitor anticoagulation during CPB as it is unaffected by aprotinin [27], preliminary evidence indicates that a major limitation may include its inability to reflect heparin levels accurately [28]. More extensive validation in controlled clinical studies is needed to compare the HiTT to the ACT, heparin concentration and to sensitive markers of coagulation activation during the CPB period.

Whole blood heparin measurements using an automated protamine titration assay have been shown to correlate extremely well with plasma anti-Xa heparin measurements before and during extracorporeal circulation [11]. Our data illustrate that this whole blood heparin assay using a thromboplastin reagent for activation is not affected by in vitro concentrations of aprotinin exceeding those observed with full therapeutic doses [29] despite previous data indicating that aprotinin may affect extrinsic coagulation pathway reactions [12]. Our data also demonstrate that the excellent correlation between whole blood and anti-Xa heparin measurements is preserved in patients receiving aprotinin. Furthermore, stable heparin levels were maintained during the CPB interval when this method was used to direct heparin administration as evidenced by similar plasma heparin concentrations in the pre-CPB and terminal CPB periods. A major limitation of whole blood heparin monitoring entails the lack of confirmation of adequacy of heparin anticoagulant effect. This instrument provides rapid and accurate determination of heparin concentration as well as an assessment of heparin anticoagulant effect (ACT). It is of interest to note that in a recent multicenter evaluation the incidence of thrombotic complications was not increased in aprotinin-treated patients in whom heparin administration was based on either whole blood heparin measurements or on a fixed dose regimen [30].

In conclusion, our data confirm that although celite-activated ACT measurements are substantially prolonged by aprotinin, whole blood and plasma heparin measurements are unaffected by aprotinin. Our data also demonstrate that kaolin- and celite-activated ACT correlate weakly with plasma anti-Xa heparin levels during CPB in the presence of aprotinin. Furthermore, whole blood measurements correlate well with plasma anti-Xa heparin measurements before and during CPB in the presence of aprotinin. Therefore, the on-site automated protamine titration assay can be used to monitor accurately whole blood heparin concentration in patients receiving aprotinin. Use of this system to maintain stable heparin concentrations and assess heparin anticoagulant effect may reduce potential thrombotic complications associated with administration of aprotinin.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study was supported in part by a research grant from Medtronic Hemotec.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Despotis, Department of Anesthesiology, Washington University School of Medicine, Box 8054, 660 S Euclid Ave, St. Louis, MO 63110.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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