Effects of aprotinin on plasma coagulation kinetics determined by thrombelastography: role of Factor XI

BACKGROUND: Aprotinin is commonly administered in settings involving cardiopulmonary bypass and liver transplantation to decrease peri-operative bleeding. Thrombelastography has been utilized to monitor coagulation in these settings, and aprotinin delays clot initiation, presumably by inhibiting kallikrein; however, aprotinin also inhibits Factor XI (FXI), a contact system protein. Thus, it was hypothesized that celite-activated thrombelastography coagulation kin-etics would be decreased via aprotinin-mediated FXI inhibition. METHODS: Citrated normal plasma and prekallikrein-deficient (<1% normal activity) plasma were exposed to 0, 200, 400 or 800 kallikrein inhibitory units (KIU)/ml (n = 6 per condition). Samples were recalcified and celite-activated in a thrombelastograph, with clot initiation (R, s) determined. To confirm contact system specificity, additional prekallikrein-deficient samples with 0 or 800 KIU/ml aprotinin were activated with tissue factor (n = 4 per condition). RESULTS: Exposure of celite-activated, normal plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 167 +/- 14, 253 +/- 10, 293 +/- 22 and 349 +/- 21 s, respectively, which were significantly different from one another (P < 0.05). Exposure of celite-activated, prekallikrein-deficient plasma to aprotinin 0, 200, 400 or 800 KIU/ml resulted in R values of 366 +/- 15, 630 +/- 64, 698 +/- 46 and 850 +/- 47 s, respectively, which were significantly different from one another (P < 0.05). There were no significant differences in R values between tissue factor-activated, prekallikrein-deficient plasma samples with 0 or 800 KIU/ml aprotinin. CONCLUSIONS: These data support a role for the inhibition of FXI as the mechanism for aprotinin-mediated delayed contact system clot initiation determined by thrombelastography.     

Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass.

To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator, we tested this drug in a prospective, randomized, double-blind, placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion, starting before operation and continuing until after cardiopulmonary bypass; additionally, 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding, respectively two thirds and one third of the total perioperative blood loss, were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss, corrected to a hemoglobin concentration of 7 mmol/L, was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss, furthermore, significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass, which led to a reduction in heparin usage. The improved hemostasis during operation, despite the prolonged activated clotting time, might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass, thus allowing retransfusion through cardiotomy suction to be continued, which saves the blood that is currently lost with vacuum suction.     

Increased anticoagulation during cardiopulmonary bypass by aprotinin.

In this prospective study, the effect of the antiproteinase aprotinin on anticoagulation during cardiopulmonary bypass was compared with placebo treatment in a randomized double-blind fashion. The kallikrein-inhibiting capacity was significantly increased in aprotinin-treated patients and decreased in the control patients. The intrinsic clotting system was also inhibited by aprotinin. We demonstrated during cardiopulmonary bypass and in vitro a significantly prolonged activated clotting time and a remarkable prolongation of the activated partial thromboplastin time by aprotinin at low heparin concentrations, whereas the antithrombin III consumption was significantly reduced. Aprotinin synergistically enhanced the anticoagulation by heparin, which allowed reduced heparinization. This is of clinical importance for use in both heparin-resistant and heparin-sensitive patients undergoing cardiopulmonary bypass and may also have advantages for routine use during bypass to reduce the adverse effects of heparin-protamine complexes.     

Reliability of the Heparin Management Test for Monitoring High Levels of Unfractionated Heparin: In Vitro Findings in Volunteers versus In Vivo Findings during Cardiopulmonary Bypass

Background: The authors assessed the heparin management test in vitro in volunteers and in vivo during cardiopulmonary bypass.

Methods: In vitro, the heparin management test was analyzed for heparin levels between 0 and 6 IU/ml using variations in hematocrit, platelets, procoagulants, and storage time. The in vivo studies consisted of two groups: In group I (cardiopulmonary bypass <= 90 min, n = 40), anticoagulation was performed according to the activated clotting time (with or without aprotinin); in group II (cardiopulmonary bypass >= 180 min, with aprotinin) included use (n = 10) and nonuse of coumadin (n = 10) and anticoagulation according to the automated heparin dose-response assay. Tests were performed in duplicate (whole blood, two heparin management test analyzers) and compared with anti-Xa activity (plasma).

Results: In vitro, the results of the heparin management test (n = 1,070) correlated well with heparin concentration (r2 = 0.98). Dilution and storage time did not affect the heparin management test; a hematocrit of 60% and reduced procoagulants (10%) prolonged clotting time. In vivo, the correlation (heparin management test vs. anti-Xa) was strong in group I (r2 = 0.97 [with aprotinin] and 0.96 [without aprotinin]; n = 960) and group II without coumadin (r2 = 0.89, n = 516). In group II with coumadin, the overall correlation was r2 = 0.87 and 0.79 (n = 484), although the range varied widely (0.57-0.94, between-analyzer differences 0-47%).     

Is the kaolin or celite activated clotting time affected by tranexamic acid?

BACKGROUND: During cardiopulmonary bypass, the activated clotting time is frequently used for determination of anticoagulation, and either Celite or kaolin are used as activators. If aprotinin is administered concomitantly, the Celite activated clotting time (C-ACT) becomes significantly higher than the kaolin activated clotting time (K-ACT). Therefore, insufficient anticoagulation using C-ACT in the presence of aprotinin is a major concern. Whether the application of tranexamic acid (TA), a pharmacologic alternative to aprotinin, has similar effects has not been studied before. METHODS: An in vitro study using the blood of healthy volunteers was performed. Both C-ACT and K-ACT were measured at baseline, after adding TA, and after adding TA and heparin. In addition, 30 patients undergoing primary cardiac operations had simultaneous measurements of C-ACT and K-ACT after skin-incision, 5 minutes after the application of heparin and TA, every 30 minutes during cardiopulmonary bypass, and 10 minutes after the application of protamine. RESULTS: In vitro, C-ACT and K-ACT correlated significantly at each measurement. Tranexamic acid had no influence on the activated clotting time. In vivo, C-ACT and K-ACT did not differ significantly, but at each time C-ACT tended to be greater than K-ACT (p = 0.086). The average difference between K-ACT and C-ACT was stable before and after the application of TA (p = 0.85) but the variability of the differences significantly increased during cardiopulmonary bypass (p < 0.001). CONCLUSIONS: Application of TA does not seem to differentially affect the mean C-ACT and K-ACT. No recommendation seems warranted to prefer one activator over the other in patients receiving TA.     

Reliability of the heparin management test for monitoring high levels of unfractionated heparin: in vitro findings in volunteers versus in vivo findings during cardiopulmonary bypass

BACKGROUND: The authors assessed the heparin management test in vitro in volunteers and in vivo during cardiopulmonary bypass. METHODS: In vitro, the heparin management test was analyzed for heparin levels between 0 and 6 IU/ml using variations in hematocrit, platelets, procoagulants, and storage time. The in vivostudies consisted of two groups: In group I (cardiopulmonary bypass /= 180 min, with aprotinin) included use (n = 10) and nonuse of coumadin (n = 10) and anticoagulation according to the automated heparin dose-response assay. Tests were performed in duplicate (whole blood, two heparin management test analyzers) and compared with anti-Xa activity (plasma). RESULTS: In vitro, the results of the heparin management test (n = 1,070) correlated well with heparin concentration (r2 = 0.98). Dilution and storage time did not affect the heparin management test; a hematocrit of 60% and reduced procoagulants (10%) prolonged clotting time. In vivo, the correlation (heparin management test vs. anti-Xa) was strong in group I (r2 = 0.97 [with aprotinin] and 0.96 [without aprotinin]; n = 960) and group II without coumadin (r2 = 0.89, n = 516). In group II with coumadin, the overall correlation was r2 = 0.87 and 0.79 (n = 484), although the range varied widely (0.57-0.94, between-analyzer differences 0-47%). CONCLUSIONS: The results of the heparin management test were influenced by hematocrit, plasma coagulation factors, and the heparin level, but not by use of aprotinin. The heparin management test provided reliable values in vitro in group I, and in group II without coumadin but was less reliable in group II with coumadin.     

Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization.

Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action, 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally, 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1,431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group, 2.3 +/- 2.2 U of homologous blood or blood products were given, and in the aprotinin group, 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).(ABSTRACT TRUNCATED AT 250 WORDS)     

在体外及体外循环中抑肽酶对ACT的影响

选择健康献血员及心内直视手术病，观察抑肽酶对全血活化凝血时间的影响。结果：在体外肝素剂量与ＡＣＴ有显著线性相关。抑肽酶单狡应用并不使ＡＣＴ延，但与肝素合用可协同性延长ＡＣＴ值；在体外循环中抑肽酶延长ＡＣＴ的值更为显著，一般超过８００ｓ。结论：抑肽酶可与肝素协同性延长ＡＣＴ，体外循环中应用抑肽酶时应以ＡＣＴ大于８００ｓ作为肝素抗凝标准。     

Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation

Subclinical plasma coagulation during cardiopulmonary bypass has been associated with marked platelet and clotting factor consumption in monkeys. To better define subclinical coagulation in man, we measured plasma fibrinopeptide A concentrations before, during, and after cardiopulmonary bypass. Patients were assigned to one of three groups of heparin management: group 1 (n = 10)--initial heparin dose 300 IU/kg, with supplemental heparin if the activated coagulation time fell below 400 seconds; group 2 (n = 6)--initial heparin dose 250 IU/kg, with supplemental heparin if activated coagulation time was less than 400 seconds; and group 3 (n = 5)--initial heparin dose 350 to 400 IU/kg, with supplemental heparin if whole blood heparin concentration was less than or equal to 4.1 IU/ml. Activated coagulation time and heparin concentration were measured every 30 minutes during cardiopulmonary bypass, and fibrinopeptide A was measured at hypothermia, normothermia, and whenever activated coagulation time was less than 400 seconds. Quantitative and qualitative blood clotting competence was assessed after cardiopulmonary bypass, including mediastinal drainage for the first 24 hours. Fibrinopeptide A values were markedly elevated during cardiopulmonary bypass but were well below the levels present before and after cardiopulmonary bypass. Fibrinopeptide A correlated inversely with heparin concentration during cardiopulmonary bypass (r = -0.46, p = 0.03), but higher fibrinopeptide A levels during cardiopulmonary bypass did not correlate with post-cardiopulmonary bypass coagulopathy. Group 3 patients received the highest heparin doses (p less than 0.05) and had the greatest postoperative blood loss (p less than 0.05). Protamine dose and heparin concentration during cardiopulmonary bypass correlated best with postoperative mediastinal drainage. Our findings support the following conclusions: (1) compensated subclinical plasma coagulation activity occurs during cardiopulmonary bypass despite activated coagulation time greater than 400 seconds or heparin concentration greater than or equal to 4.1 IU/ml; (2) post-cardiopulmonary bypass mediastinal drainage correlates strongly with increased heparin concentration during cardiopulmonary bypass (p less than 0.05) and protamine dose (p less than 0.05); and (3) during cardiopulmonary bypass at both normothermia and hypothermia, activated coagulation times greater than 350 seconds result in acceptable fibrinopeptide A levels and post-cardiopulmonary bypass blood clotting.     

Clinical measures of heparin's effect and thrombin inhibitor levels in pediatric patients with congenital heart disease

In this investigation, we examined the relationship among three thrombin inhibitors, antithrombin III (ATIII), heparin cofactor II (HCII), and alpha-2-macroglobulin (alpha2M), and several clinical tests of heparin's effect in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass. One hundred eighteen children were stratified into six age groups: <1 mo, 1-3 mo, 3-6 mo, 6-12 mo, 12-24 mo, and >10 yr. Baseline ATIII, HCII, and alpha2M values were measured. Baseline celite- and kaolin-activated clotting times (ACT) were also measured and repeated 3 min after a standard heparin dose of 400 U/kg. Differences in ACT values before and after heparin administration and a heparin dose-response relationship were calculated for each patient. Kaolin-activated ACT tests showed less variation after heparin administration than celite-activated tests. In contrast to what has been demonstrated in adults, ATIII showed no positive correlation with the clinical tests of heparin's effect nor did the other thrombin inhibitors. Additionally, patients <1 mo old had unexpectedly low levels of alpha2M accompanying their expected low levels of ATIII and HCII. Our findings raise concerns about the ability of heparin to adequately anticoagulate these neonates during cardiopulmonary bypass and, consequently, challenge the accuracy of ACT prolongation to truly reflect the extent of their anticoagulation.     

Diminished anticoagulant response to heparin in patients undergoing coronary artery bypass grafting

Patients are at risk for a diminished anticoagulant response to heparin during coronary artery bypass graft operations. To answer the question of whether preoperative heparin therapy and intra-aortic balloon counterpulsation are associated with a diminished response in the period before cardiopulmonary bypass, we observed prospectively the baseline and postheparinization activated clotting times in 76 patients undergoing elective coronary artery bypass graft procedures. They included 42 patients who had received preoperative heparin therapy (26 had intra-aortic balloon pumps and 16 did not). Thirty-four comparison patients (controls) were matched for age, sex, race, and heparin lot. Patients receiving preoperative heparin therapy, either with or without intra-aortic balloon pumps, had significantly lower activated clotting times than patients in the control group after a 300 IU/kg dose of porcine intestinal heparin. Total preoperative heparin dose, days of preoperative heparin therapy, and baseline activated clotting times were not predictive of heparin resistance. In conclusion, patients receiving preoperative heparin therapy (with or without intra-aortic balloon pumps) are at increased risk for inadequate heparinization before cardiopulmonary bypass.     

Monitoring of heparin-induced anticoagulation with kaolin-activated clotting time in cardiac surgical patients treated with aprotinin.

High-dose aprotinin appears to enhance the anticoagulant effects of heparin, as documented by increases in the activated clotting times (ACTs) during cardiopulmonary bypass; hence, some authorities have advocated reducing the dose of heparin in patients treated with aprotinin. An in vitro study by our group suggested that the increase of the ACT in the presence of aprotinin and heparin may be due to the use of celite as surface activator. We compared celite and kaolin as surface activators for the measurement of the ACT in cardiac surgical patients treated with aprotinin and in patients given no aprotinin. This double-blind, randomized, placebo-controlled study included 30 patients, of whom 14 received aprotinin and 16 received a placebo. Before, during, and after cardiopulmonary bypass, the ACT was measured with two Hemochron 400 systems with 12 mg of either celite (C-ACT) or kaolin (K-ACT) used as surface activator and with one Hepcon HMS system (HR-ACT), which uses kaolin as activator. The latter also was used for measurement of the blood heparin concentration. The ACTs of blood without heparin did not differ between aprotinin and control patients. During anticoagulation with heparin and cardiopulmonary bypass, the average C-ACTs were 784 +/- 301 s (aprotinin) and 496 +/- 120 s (control) (P < .001); the K-ACTs were 502 +/- 131 s (aprotinin) and 458 +/- 101 s (control) (P > .05); the HR-ACTs were 406 +/- 87 s (aprotinin) and 423 +/- 82 s (control) (P > .05), which was consistently less than C-ACT and K-ACT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monitoring activated clotting time for combined heparin and aprotinin application: in vivo evaluation of a new aprotinin-insensitive test using Sonoclot.

OBJECTIVE: Kaolin-based activated clotting time assessed by HEMOCHRON (HkACT) is a clinical standard for heparin monitoring alone and combined with aprotinin during cardiopulmonary bypass (CPB). However, aprotinin is known to prolong not only celite-based but also kaolin-based activated clotting time. Overestimation of activated clotting times implies a potential hazardous risk of subtherapeutic heparin anticoagulation. Recently, a novel 'aprotinin-insensitive' activated clotting time test has been developed for the SONOCLOT analyzer (SaiACT). The aim of our study was to evaluate SaiACT in patients undergoing CPB in presence of heparin and aprotinin. METHODS: Blood samples were taken from 44 elective cardiac surgery patients at the following measurement time points: baseline (T0); before CPB after heparinization (T1 and T2); on CPB, before administration of aprotinin (T3); 15, 30, and 60 min on CPB after administration of aprotinin (T4, T5, and T6); after protamine infusion (T7). On each measurement time point, activated clotting time was assessed with HkACT and SaiACT, both in duplicate. Furthermore, the rate of factor Xa inhibition and antithrombin concentration were measured. Statistical analysis was done using Bland and Altman analysis, Pearson's correlation, and ANOVA with post hoc Bonferroni-Dunn correction. RESULTS: Monitoring anticoagulation with SaiACT showed reliable readings. Compared to the established HkACT, SaiACT values were lower at all measurement time points. On CPB but before administration of aprotinin (T3), SaiACT values (mean+/-SD) were 44+/-118 s lower compared to HkACT. However, the difference between the two measurement techniques increased significantly on CPB after aprotinin administration (T4-T6; 89+/-152 s, P=0.032). Correlation of ACT measurements with anti-Xa activity was unchanged for SaiACT before and after aprotinin administration (r2=0.473 and 0.487, respectively; P=0.794), but was lower for HkACT after aprotinin administration (r2=0.481 and 0.361, respectively; P=0.041). On CPB after administration of aprotinin, 96% of all ACT values were classified as therapeutic by HkACT, but only 86% of all values were classified therapeutic if ACT was determined by SaiACT. Test variability was comparable for SaiACT and HkACT. CONCLUSIONS: The use of SaiACT may result in more consistent heparin management that is less affected by aprotinin and a corresponding increase in heparin administration for patients receiving aprotinin.     

Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery

OBJECTIVE: The purpose of this report is to describe the clinical use of antithrombin III concentrate in 53 patients who were found, in the operating room before cardiopulmonary bypass, to be heparin resistant. METHOD: Resistance to heparin was determined to be present when greater than 600 U/kg body weight of heparin failed to prolong the kaolin-activated clotting time to more than 600 seconds in 53 aprotinin-treated patients. Blood samples were obtained for subsequent antithrombin III activity determination. Patients were then administered 500 U of antithrombin III concentrate, and the activated clotting time was remeasured. If the activated clotting time remained less than 600 seconds, a second 500-U dose was given. RESULTS: Of the 53 patients, 45 (85%) had subnormal measured antithrombin III activity, and the mean plasma antithrombin III activity level for the entire group was 67% (normal 80%-120%). Administration of antithrombin III concentrate (500 U in 45 patients and 1000 U in 8 patients) resulted in prolongation of the mean activated clotting time from 492 to 789 seconds without additional heparin. The mean heparin dose response increased from 36.5 to 69.3 s x U(-1) x mL(-1) with antithrombin III treatment. Only one patient did not achieve the target activated clotting time, despite administration of greater than 600 U/kg heparin and 1000 U of antithrombin III concentrate, and was treated with fresh-frozen plasma. CONCLUSIONS: On the basis of the criterion used in this report, most of the patients defined as being heparin resistant had subnormal plasma antithrombin III activity. Treatment with antithrombin III concentrate resulted in potentiation of the heparin effect to meet predetermined activated clotting time thresholds and allow for cardiopulmonary bypass.     

Effects of heparin, haemodilution and aprotinin on kaolin-based activated clotting time: in vitro comparison of two different point of care devices

BACKGROUND: During cardiopulmonary bypass (CPB), measurement of kaolin-based activated clotting time (kACT) is a standard practice in monitoring heparin-induced anticoagulation. Despite the fact that the kACT test from the Sonoclot Analyzer (SkACT) has been commercially available for several years, no published data on the performance of SkACT are available. Thus, the aim of this in vitro study was to compare SkACT with an established kACT from Hemochron (HkACT). METHODS: Blood was withdrawn from 25 patients before elective cardiac surgery. SkACT and HkACT were measured in duplicate after in vitro administration of heparin (0, 1, 2 and 3 U/ml), calcium-free lactated Ringer's solution (25% and 50% haemodilution) and aprotinin (200 kIU/ml). RESULTS: A total of 600 duplicate kACT measurements were obtained from 25 cardiac surgery patients. Overall, mean bias +/- SD between SkACT and HkACT was 7 +/- 70 s (1.3% +/- 14.1%). Administration of heparin, haemodilution and aprotinin induced a comparable effect on both activated clotting time (ACT) tests. Mean bias ranged from -4 +/- 39 s (-1.7% +/- 12.9%) to 4 +/- 78 s (3.2% +/- 15.6%) for heparinzed blood samples after haemodilution or aprotinin application and increased after combined aprotinin administration and haemodilution. After haemodilution and administration of aprotinin, both ACT tests were less reliable for values >480 s in heparinized blood samples. CONCLUSION: Accuracy and performance of SkACT and HkACT were comparable after in vitro administration of heparin, aprotinin and haemodilution. Both ACT tests were considerably affected by aprotinin and haemodilution.     

Monitoring activated clotting time for combined heparin and aprotinin application: an in vitro evaluation of a new aprotinin-insensitive test using SONOCLOT

The kaolin-based activated clotting time (ACT) is commonly used for monitoring heparin-induced anticoagulation alone and combined with aprotinin during cardiopulmonary bypass. However, aprotinin prolongs ACT measurements. Recently, a new so-called 'aprotinin-insensitive' ACT test (SaiACT) has been developed for the SONOCLOT analyzer. In this study we evaluated and compared this new test for the SONOCLOT analyzer in vitro with an established kaolin-based ACT from HEMOCHRON (HkACT). Twenty-five patients undergoing elective valve surgery donated 80 mL of blood after induction of anesthesia. The blood was withdrawn in citrated tubes and processed to analyze effects of heparin (0, 1, 2, and 3 U x mL(-1)), aprotinin (0, 200 kIU x mL(-1)), and 25% hemodilution with calcium-free lactated Ringer's solution on ACT measurements. A total of 400 blood samples were analyzed and ACT was measured in a wide, clinically relevant range in duplicate with SaiACT and HkACT. Addition of aprotinin to heparinized blood samples induced no significant changes of SaiACT measurements. By contrast, HkACT readings increased significantly: aprotinin prolonged HkACT in heparinized blood samples by 20% +/- 37% (2 U x mL(-1)) and 24% +/- 18% (3 U x mL(-1)), respectively, and in vitro hemodilution increased this effect. IMPLICATIONS: Current standard techniques to measure heparin-induced anticoagulation during cardiopulmonary bypass are affected by aprotinin, a drug widely used in this setting. The aim of this study was to investigate in vitro a new, so-called 'aprotinin-insensitive' test from SONOCLOT to measure heparin-induced anticoagulation more reliably in combination with aprotinin.     

Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass

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 10(4) KIU/kg; n = 6). Platelet count, platelet aggregation, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, alpha2-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, beta-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 alpha2-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.     

Does aprotinin influence the inflammatory response to cardiopulmonary bypass in patients?

OBJECTIVES: Aprotinin has been shown to have anti-inflammatory properties, but its effects on the inflammatory reaction to cardiopulmonary bypass remain controversial. This prospective, randomized, double-blind study evaluated the influence of aprotinin on various blood markers of inflammation during and after cardiopulmonary bypass. METHODS: Sixty male patients underwent coronary artery bypass grafting. The patients were randomized into 3 groups: a placebo group, a second group receiving 2,000,000 KIU of aprotinin followed by an infusion of 500,000 KIU/h and 2,000,000 KIU in the pump prime, and a third group receiving half this dosage. Measurements of tumor necrosis factor, interleukin 6, interleukin 8, interleukin 10, endotoxin, histamine, complement factors, prekallikrein, and prostaglandin D(2) were obtained at baseline, 30 minutes after study drug loading, 10 minutes after the beginning of cardiopulmonary bypass, before the end of bypass, 4 hours after bypass, and on the first and second postoperative days. RESULTS: Aprotinin had no significant effect on any of these parameters. As expected, aprotinin reduced early blood loss in both treated groups. CONCLUSIONS: These results indicate that aprotinin at doses currently used to reduce blood loss has no significant influence on the systemic inflammatory response during moderate hypothermic cardiopulmonary bypass in human subjects, as assessed by the mediators measured in this study.     

Reduction of postoperative blood loss and donor blood use in heart surgery with aprotinin: experience with various dosages]

The effect of high dose aprotinin was evaluated in a prospective study on 100 patients undergoing cardiopulmonary bypass. Special attention was made on postoperative blood loss and transfusions of bank blood postoperatively. In the first part of the study, after induction of anesthesia, a loading dose of 2,000,000 kallikrein-inhibiting-unit (KIU) = 280 mg aprotinin was given intravenously over a 30-min period. Immediately afterward, a continuous infusion of 500,000 KIU/h was started and maintained until skin closure. Another 2,000,000 KIU was added to the priming volume of the heart-lung machine. A control group of 50 patients was randomized with similar indication for surgery and past cardiac history. The total loss from the thoracic drains was significantly reduced in the aprotinin group as compared with the loss in the control group (490 +/- 265 ml versus 1045 +/- 380 ml). In a separate group of risk patients (redo-operations, infective endocarditis) the total blood loss was even more significant reduced in the aprotinin group (690 +/- 195 ml versus 1585 +/- 290 ml). Patients of the aprotinin group received markedly less bank blood postoperatively (350 +/- 100 ml versus 900 +/- 240 ml without aprotinin). Part II of the study (36 patients) consisted of lower dosage (2,000,000 KIU intravenously during induction of anesthesia only or 2,000,000 KIU in the priming volume of the heart-lung machine only). Patients who received aprotinin in the heart-lung machine only showed no significant difference regarding blood loss and blood requirement to patients with high dose aprotinin. It appears possible that aprotinin reduces the activation of the coagulation during cardiopulmonary bypass and preserves platelet function without affecting platelet consumption during the extracorporeal circulation. The results of our study demonstrate that high dose aprotinin markedly reduces blood loss as well as homologous blood requirement in the early postoperative course of cardiosurgical patients. Similar effects due to reduced aprotinin dose have been observed in patients receiving aprotinin in the extracorporeal circulation only.     

Aprotinin and hemostasis monitoring concerns during cardiac surgery

Aprotinin (Trasylol) is a serine protease inhibitor, isolated from bovine lung that initially was marketed for the treatment of pancreatitis. In the mid 1980s, reports of its ability to decrease hemorrhaging after cardiopulmonary bypass surgery introduced the drug to the realm of cardiac surgery. Unfortunately, its introduction into this arena was followed by the publication of multiple studies and case reports that blamed aprotinin for poor outcomes in the form of early graft closure. More than 17 years have passed since the initial article describing the use of aprotinin during cardiopulmonary bypass, and with time there has been a significant increase in scientific knowledge and clinical experience. Interestingly, modern literature does not support the dogma that aprotinin is a procoagulant. Aprotinin increases the activated partial thromboplastin time (aPTT), as well as the kaolin- and celite-activated clotting time (ACT), regardless of heparin. Aprotinin, because of its ability to inhibit kallikrein, has been found to decrease thrombin antithrombin III complexes, fibrin-split products, fibrinopeptide 1+2, prothrombin fragments, and all markers of thrombin formation. Some authors have suggested that it may have a synergistic effect with heparin to ensure graft patency. Anticoagulation monitoring during the use of aprotinin also has been developed based on early studies. Aprotinin administration does influence the results of various ACT tests, and consequently different methods of testing anticoagulation have been developed. Researchers have demonstrated that the celite ACT is not "artificially" prolonged in the presence of heparin and aprotinin, rather the kaolin ACT is "artificially" shortened. This article will review the scientific literature with regard to aprotinin's anticoagulatory effects and review the current recommendations for hemostasis monitoring during the use of aprotinin.