Anesth Analg 2004;99:1283-1289
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000134685.75813.EB
CARDIOVASCULAR ANESTHESIA
The Effects of Argatroban on Thrombin Generation and Hemostatic Activation In Vitro
Kenichi A. Tanaka, MD,
Fania Szlam, MMSc,
Nobuyuki Katori, MD,
Nobukazu Sato, MD,
J. David Vega, MD, and
Jerrold H. Levy, MD
Department of Anesthesiology and Surgery (Cardiothoracic), Division of Cardiothoracic Anesthesia and Critical Care, Emory University School of Medicine, The Emory Healthcare, Atlanta, Georgia
Address correspondence and reprint requests to Kenichi A. Tanaka, MD, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd., N.E., Atlanta, GA 30322. Address e-mail to kenichi_tanaka{at}emoryhealthcare.org
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Abstract
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We evaluated argatroban, a direct thrombin inhibitor, as a heparin adjunct for anticoagulation. Platelet-poor plasma (PPP) was isolated from blood collected from 12 volunteers. Thrombin generation measurements were performed in donor PPP that was mixed with antithrombin (AT)-poor plasma to yield AT levels of 0%, 20%, 60%, and 100%. Effects of argatroban (0–1.0 µg/mL), heparin (0.25 U/mL), or the combination of argatroban (0.5 µg/mL) and heparin were also studied. The addition of increasing concentrations of argatroban, heparin, or both to donor PPP (AT level 
100%) caused progressive decreases in the lag time and peak formation of thrombin generation. Heparin (0.25 U/mL) at small AT concentrations had a minimal effect on lag time or peak thrombin formation; its effectiveness of inhibiting thrombin was directly correlated with the concentration of AT. Argatroban at 0.5 µg/mL was effective in decreasing thrombin formation at both low and normal AT levels, but it was most effective when combined with heparin. Additionally, blood samples were obtained from 47 cardiac surgical patients, and the interaction of heparin (>1.5 U/mL) and AT or argatroban on clot formation was evaluated with kaolin activated clotting times (ACTs). Significant increases of ACTs at all heparin levels were observed with the addition of argatroban (0.125 and 0.25 µg/mL). The addition of AT (0.2 U/mL) to heparinized blood samples further prolonged ACTs. In summary, we showed that argatroban, unlike heparin, could effectively reduce thrombin generation regardless of AT levels and could prolong ACTs in vitro at clinically used concentrations.
IMPLICATIONS: Argatroban can effectively reduce thrombin generation and prolong activated clotting in vitro. On the basis of its rapid binding to thrombin and its relatively short elimination half-life, argatroban may prove to be a useful adjunct for treating heparin resistance during cardiac surgery.
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Introduction
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Cardiopulmonary bypass (CPB) and extensive tissue injury during cardiac surgery require high levels of anticoagulation to inhibit activation of the hemostatic cascade. Currently, heparin is the drug of choice during CPB because of its reversibility, small cost, and relative safety. However, heparin anticoagulation is catalyzed by endogenous antithrombin (AT), and heparin resistance (insensitivity) is often encountered in cardiac patients with reduced AT levels secondary to prolonged IV heparin therapy (1). Also, clot-bound thrombin is not effectively inhibited by the heparin-AT complex, and platelet activation and fibrin formation may still occur (2,3). Inadequate thrombin suppression during CPB leads to excessive consumption of plasma coagulation factors and platelets (4–6), and microvascular bleeding follows after surgery. Argatroban has been approved for the treatment of heparin-induced thrombocytopenia (7). Argatroban is an arginine-derived synthetic low-molecular-weight direct thrombin inhibitor with a terminal elimination half-life of 39 to 51 min. Because argatroban does not depend on endogenous AT for its action, we postulated that it might be a useful adjunct for heparin anticoagulation in the setting of AT deficiency. In this in vitro study, by measuring thrombin generation and activated clotting times (ACT), we evaluated argatroban for its ability to supplement heparin anticoagulation.
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Methods
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Argatroban (Slonnon®) was a kind gift from Dai-ichi Pharmaceuticals (Tokyo, Japan). Tissue factor (TF) was from Dade-Behring (Innovin®; Malburg, Germany). AT-deficient plasma was purchased from American Diagnostica (Stamford, CT). Fluorogenic substrate (Z-Gly-Gly-Arg-AMC HCl; molecular weight, 616.07) for thrombin generation assay was obtained from Bachem (Switzerland). HEPES CaCl2, bovine serum albumin (BSA), and dimethyl sulfoxide were from Sigma (St. Louis, MO). TF was dissolved in 10 mL of sterile water and then further diluted with working HEPES buffer (20 mM HEPES, 140 mM NaCl, and BSA 5 mg/mL; 1:75). For the preparation of Fluca buffer, 1.750 mL of HEPES buffer (pH 7.35; 20 mM HEPES and 60 mg/mL BSA) was added to 0.2 mL of 1 M CaCl2 in a glass test tube, mixed, and warmed for a few minutes at 37°C. Just before use, 50 µL of 100 mM fluorogenic substrate made in dimethyl sulfoxide was added to the HEPES/CaCl2 solution and mixed to dissolve. This buffer contained 2.5 mM substrate and 100 mM CaCl2. For AT determinations, a commercially available Coatest AntithrombinTM kit was used (Diapharma Inc., Franklin, OH). The Coatest AT procedure is sensitive to 5% AT with a coefficient of variation <10%.
After institutional approval and informed written consent, blood was collected into Vacutainer tubes containing 3.2% sodium citrate from 12 volunteers, who had received no drugs in the preceding 2 wk and whose AT levels were measured. Platelet-poor plasma (PPP) was obtained by centrifugation (15 min at 2000g). In the initial experiments, a dose-response curve using donor PPP (AT level 100%) was generated for argatroban (0–1 µg/mL) and heparin (0.1–0.5 U/mL). On the basis of the initial results, the concentrations of drugs that caused 40% to 50% inhibition in thrombin generation were used in subsequent experiments: argatroban 0.5 µg/mL and heparin 0.25 U/mL. To obtain PPP with progressively depleted AT levels, an incremental portion of normal plasma was replaced with AT-deficient plasma to yield concentrations of AT of approximately 0, 20, 60, and 100 U/dL. Subsequently, plasma samples with different AT levels were tested for thrombin generation in the presence of heparin (0.25 U/mL final), argatroban (0.5 µg/mL final), or both. The method for the automated estimation of endogenous thrombin potential by using a commercially available fluorogenic substrate (Z-Gly-Gly-Arg-AMC) has been described by Hemker and Beguin (8). Briefly, for the thrombin generation experiments, 80 µL of PPP and 20 µL of the thrombin-generation trigger were added to wells of 96-well microtiter plate (Microfluor2; Labsystems, Finland), followed by 20 µL of substrate/calcium chloride buffer. The reaction was monitored with a microplate fluorometer (Fluoroskan Ascent; Labsystems, Finland) set at 390 nm (excitation wavelength) and 460 nm (emission wavelength). Fluorescence was recorded every 20 s for 90 min, and the acquired data were automatically processed by commercially available Thrombinoscope software (Synapse B.V), that displayed the reaction progress and calculated thrombin generation (peak thrombin level).
Residual blood samples from adult patients scheduled for elective cardiac surgery were evaluated after informed consent. The durations of IV heparin therapy and concomitant drug administration were recorded. Blood samples from patients with preexisting hemostatic disorders, renal disease, hepatic disease, warfarin, plasminogen activator, or glycoprotein IIb/IIIa receptor antagonists were not evaluated. Baseline platelet count, prothrombin time, and activated partial thromboplastin time (PTT) were recorded. ACTs were measured in duplicate (Hemotec; Medtronic, Englewood, CO). Baseline kaolin ACT was measured without the addition of heparin. Aliquots of blood (0.4 mL) were mixed with heparin (0.6–1.65 µL) to achieve a final concentration of bovine lung heparin 1.5, 2.5, and 4.1 U/mL (Upjohn, Kalamazoo, MI), and then ACTs were measured. Measurements of ACTs with heparin were also performed after the addition of one of the following agents: AT (Thrombate IIITM; Bayer, Inc., Elkhart, IN) at a final concentration of 0.2 U/mL (1.5 µL) or argatroban at a final concentration of 0.125 or 0.25 µg/mL. The sample for AT assay was collected into plastic tubes containing sodium citrate 3.2% (9:1 vol/vol), which was immediately centrifuged at 2000g for 15 min at 21°C to obtain plasma. The plasma was stored at –80°C for a batch AT assay.
Patients were divided into two groups after measurement of AT levels: those with AT 
80% (group L; n = 24) and those with AT >80% (group N; n = 23). All data were expressed as mean ± SD. Serial data for each group were evaluated by the repeated-measures analysis of variance, followed by the paired Student’s t-test with the Bonferroni correction. Differences among treatments were compared by using one-way analysis of variance. A P value 0.05 was considered significant. Regression analysis using the method of least squares was used to evaluate the relationship between AT levels and in vitro heparinized ACT in blood specimens.
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Results
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Our preliminary data show that heparin and argatroban cause dose-dependent inhibition of thrombin generation in PPP (Fig. 1). Effects of heparin and argatroban on thrombin generation in the presence of AT deficiency are summarized in Table 1. The thrombin generation was inversely correlated with AT levels (Fig. 2). The anticoagulant effect of heparin diminished as the AT level decreased, and the peak thrombin level was comparable between AT-deficient plasma with heparin and the control PPP without anticoagulant (Figs. 2 and 3). Argatroban exerted its anticoagulant effect even in the presence of severe AT deficiency (Fig. 4), and peak thrombin generation decreased even more as AT approached normal levels (100%) (Table 1). When heparin and argatroban were combined, a significant decrease in thrombin generation was noted in comparison to the nonanticoagulated control, especially when the AT level was more than 20% (Fig. 5).
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Figure 1. Effects of increasing concentrations of argatroban (0.1–1.0 µg/mL) on thrombin generation in control PPP triggered with tissue factor. PPP = platelet-poor plasma; ARG = argatroban.
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Figure 2. Effects of AT on thrombin generation in platelet-poor plasma (PPP) triggered with tissue factor. The peak thrombin generation was inversely correlated with AT level (0%, 20%, 60%, and 100%). AT = antithrombin.
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Figure 3. Heparin anticoagulation in the presence of AT deficiency. The heparin concentration was fixed at 0.25 U/mL. The anticoagulant effect of heparin diminished as the AT level decreased, and the peak thrombin level was comparable between AT-depleted plasma with heparin and the control platelet-poor plasma without anticoagulant (Fig. 2). AT = antithrombin; HEP = heparin.
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Figure 4. Argatroban anticoagulation in the presence of AT deficiency. The argatroban concentration was fixed at 0.50 µg/mL. Argatroban exerted its anticoagulant effect even in the presence of moderate to severe AT deficiency (0%, 20%, and 60%), and maximal anticoagulation was observed at a normal AT level (100%). AT = antithrombin; ARG = argatroban.
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Figure 5. Effect of combined heparin and argatroban in the presence of AT deficiency. Heparin 0.25 U/mL and argatroban 0.50 µg/mL were used. The peak thrombin generation was effectively decreased when the AT level was more than 20%. AT = antithrombin; ARG = argatroban; HEP = heparin.
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The demographic profiles for the subjects in groups L and N are presented in Table 2. There were more heparin-treated patients, PTT was significantly larger, and the AT level was lower in group L (P < 0.05). Baseline ACTs were 162 ± 30 s and 146 ± 22 s in groups L and N, respectively (P < 0.05). Adding heparin to these specimens to a final heparin level of 1.5, 2.5, and 4.1 U/mL resulted in an increase of ACT values (Fig. 6). The peak ACTs were 582 ± 125 s and 568 ± 131 s in groups N and L, respectively (P = 0.067). In both groups, the addition of AT to heparinized blood samples further prolonged ACTs, but the difference was significant only at the largest heparin concentration (4.1 U/mL) in group L (Fig. 1). When argatroban was added to each target concentration of heparin, the corresponding increases were significantly larger at all heparin levels when compared with heparin only (Fig. 6). ACT prolongations were generally larger with argatroban at 0.25 µg/mL than at 0.125 µg/mL, and AT-induced ACT prolongation was significantly less than both argatroban groups except at the largest heparin concentration (4.1 U/mL) in group L (Fig. 6A).
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Figure 6. A, Group L (AT 80%). B, Group N (AT >80%). In vitro activated clotting time (ACT) responses with heparin and heparin supplemented with antithrombin (0.2 U/mL) or argatroban at 0.125 or 0.25 µg/mL are shown. Data are mean ± SD. The addition of heparin produced prolongation of ACTs in both the L and N groups. Statistically significant ACT prolongations over nonsupplemented samples were found with argatroban (0.125 or 0.25 µg/mL) at all heparin levels. The addition of AT to heparinized (4.1 U/mL) samples significantly increased the ACT in group L. HEP = heparin; AT = antithrombin; ARG = argatroban (^ P < 0.05 versus AT; *P < 0.05 versus HEP; #P < 0.05 versus HEP plus ARG 0.125 µg/mL).
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Discussion
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We have shown that the combination of heparin and argatroban is effective in reducing thrombin generation in the presence of AT deficiency. Argatroban is a direct thrombin inhibitor which binds to thrombin in a rapid and reversible manner (9), although there is no antidote or reversal drug available to abolish its anticoagulant effects. It does not rely on endogenous AT for its action, and it competes with AT for thrombin (10). The first part of our study demonstrated that heparin anticoagulation was inversely correlated with AT levels (Fig. 3), whereas argatroban reduced thrombin generation regardless of AT levels (Fig. 4, Table 1). Further, because of its small molecular size (527 daltons), argatroban may be more effective in inhibiting clot-bound thrombin, which is resistant to neutralization by the heparin/AT complex (heparin, mean molecular weight 15,000). Thus, its direct, AT-independent anticoagulation effect theoretically supports its use as an AT alternative (11,12). The addition of argatroban to heparin may provide advantages by overcoming AT deficiency and inhibiting the catalytic activity of clot-bound thrombin. We expanded the experiments with ACT investigations to study the effects of AT or argatroban at varied heparin levels in blood samples from cardiac surgical patients preoperatively treated with heparin.
Although ACT systems do not directly measure thrombin formation, the changes in blood viscosity that are detected with those monitors reflect thrombin-induced fibrin formation and platelet activation (13). In clinical blood samples, statistically significant ACT prolongations over nonsupplemented samples were found with argatroban (0.125 or 0.25 µg/mL) at all heparin levels, suggesting that anticoagulation by argatroban is independent of AT levels or heparin concentration (Fig. 2). It should be noted, however, that we observed a trend of lower peak thrombin (Table 1) and higher ACTs (Fig. 6) in the N group (AT >80%). This would not be unexpected if the initial decrease in thrombin generation due to argatroban (rapid association-dissociation equilibrium) was further attenuated with irreversible inactivation with AT. Additional work is needed to help elucidate the interaction of AT and argatroban. Smaller increases in ACTs induced by the addition of AT 0.2 U/mL may be related to the heparin concentrations used in this study (1.5–4.1 U/mL). In the previous study from our group, AT supplementation caused statistically significant ACT prolongations over non-AT-supplemented samples only at larger heparin concentrations (5.4–6.8 U/mL) in heparin-treated patients (14).
The dosage that we used in this study was derived from clinical data. A single IV administration of 2.25 and 4.5 mg of argatroban (over 30 minutes) in healthy volunteers (mean weight, 70 kg) resulted in peak plasma concentrations of 0.125 and 0.25 µg/mL, respectively, and coagulation tests (thrombin time and activated PTT) returned to near baseline after 1.5 hours (15). Another study showed that the steady-state plasma argatroban concentration after a four-hour infusion at 2.5 µg · kg–1 · min–1 was approximately 0.5 µg/mL, with a half-life of 50 minutes (16). On the basis of the available pharmacokinetic data, it is possible to achieve an in vivo blood argatroban level that we used in the current study. Its relatively short half-life and hepatic clearance make argatroban a potential alternative to AT.
Currently, argatroban is indicated for the treatment of heparin-induced thrombocytopenia in the United States (7). Heparin-induced thrombocytopenia is associated with antibody formation against heparin/platelet factor-4 (PF4) complex. Heparin administration is associated with increased plasma PF4, which neutralizes heparin, but argatroban lacks these platelet-stimulating effects (17,18). Argatroban undergoes hepatic metabolism, and renal dysfunction does not affect its plasma half-life. For this reason, the drug has been used during hemodialysis in AT-deficient renal failure patients (11). This is in contrast to recombinant hirudin (Refludan®), which requires renal clearance and is associated with massive bleeding after hirudin-anticoagulated CPB in patients with renal insufficiency (19,20). Anticoagulation with argatroban in the presence of AT deficiency was also reported in patients with severe burn (12), postcardiovascular surgery, and disseminated intravascular coagulation (21). Persistent thrombin generation occurs during CPB (22), and uninhibited thrombin may induce inflammatory and procoagulant responses, leading to end-organ damage and consumptive coagulopathy (6). Furthermore, argatroban may circumvent other problems associated with heparin anticoagulation, such as inefficacy against clot bound thrombin and neutralization by PF4 (2,4,17). Dietrich et al. (23) and our group (24) have suggested a better-preserved hemostatic system in patients who underwent CPB with preoperative warfarin therapy; this is presumably attributed to a better preserved AT level. Bleeding complications from argatroban therapy are infrequent, provided that hepatic function is normal (16,25,26). Current strategies to supplement AT levels during cardiac surgery have several problems. Human plasma-derived AT concentrates are available, but its supply shortage can be a problem. Recombinant AT is still at the investigational stage (14). Further, fresh-frozen plasma can be administered in this setting, but transfusion is associated with anaphylaxis and other side effects. In summary, we showed that a clinical dose of argatroban can effectively reduce thrombin generation and prolong ACTs in vitro. On the basis of its rapid binding to thrombin and elimination half-life regardless of kidney function, argatroban may prove to be a useful adjunct to treat heparin resistance during CPB. Further studies are needed to elucidate the thrombin-argatroban interactions and determine the clinical usefulness of the drug for management of heparin resistance, prevention of excessive bleeding, and blood conservation, as well as prevention of thromboembolic sequelae.
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Footnotes
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Presented in part at the annual meeting of the American Society of Anesthesiologists, New Orleans, LA, October 14–17, 2001.
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Accepted for publication May 13, 2004.
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Abstract
Introduction
