Mechanisms of Improvement of Left Ventricular Function by Intracoronary Human Umbilical Cord-Derived Mesenchymal Stem Cell Infusion in Very Old Patients with Coronary Chronic Total Occlusion.

We have evaluated the safety and efficacy of intracoronary human umbilical cord-derived mesenchymal stem cell (hUCMSC) treatment for very old patients with coronary chronic total occlusion. hUCMSCs could improve in the degree of ischemic myocardium, decrease in the infarct size and rise in left ventricular ejection fraction, but the involved mechanisms remain to be fully identified. We analyzed levels of circulating leukocytes, highsensitivity C-reactive protein (hs-CRP), interleukins (ILs), tumor necrosis factor-a (TNF-a), soluble tumor necrosis factor receptor-1 (sTNFR-1), soluble tumor necrosis factor receptor-2 (sTNFR-2), NT-proBNP, BNP, angiotensin 1-7 (Ang1-7), angiotensin II (Ang II) and aldosterone (Ald) in patients with hUCMSC therapy at baseline, 12, and 24 months. Levels of Ang1-7, IL-10, IL-37 and IL-17 were increased at 12 months and 24 months; leukocytes, hs- CRP, IL-1.

Population pharmacokinetic analysis and dosing regimen optimization of aprotinin in neonates and young infants undergoing cardiopulmonary bypass.

The objective of this study was to determine an optimal dosing regimen for maintaining the therapeutic target range of aprotinin in neonates and young infants during cardiopulmonary bypass (CPB). A total of 27 patients scheduled for open heart surgery were enrolled. Aprotinin was administered a 25 000 KIU (kallikrein inhibition unit)/kg bolus before operation, a 35 000 KIU/kg for CPB circuit priming, and a 12 500 KIU/kg/hour continuous infusion intra- and immediate postoperative period. Blood samples were obtained at 12 time points per patient. Population pharmacokinetic modeling and Monte-Carlo simulations were used to optimize the aprotinin dosing regimen. No mortality or aprotinin-related complication was encountered. A CPB adjusted 2-compartment model best fit the data. Clearance was 687 mL/hour during CPB and 350 mL/hour pre- and post-CPB, and corresponding volumes of distribution were 1577 mL and 1352 mL, respectively. The simulations conducted showed that more than twice the dose administered in this study is required to maintain the target concentration of aprotinin. The pharmacokinetics of aprotinin appears to be affected more sensitively by CPB in neonates and young infants than in adults. Therefore, dosage adjustment considering these pharmacokinetic differences and the influence of CPB is needed in neonates and young infants.

Aprotinin modifies left ventricular contractility and cytokine release after ischemia-reperfusion in a dose-dependent manner in a murine model.

BACKGROUND: Periods of ischemia-reperfusion (I/R) during cardiac surgery are associated with transient left ventricular (LV) dysfunction and an inflammatory response. In this study, we examined the potential dose-dependent effects of aprotinin (APRO) on LV contractility and cytokine release in the setting of I/R. METHODS: An index of LV contractility, LV maximal elastance (E(max)), was measured at baseline, 30 min of ischemia, and 60 min of reperfusion by microtransducer volumetry. Mice were randomized as follows: (a) APRO 20,000 kallikrein-inhibiting units (KIU)/kg (n = 11); (b) APRO 4 x 10(4) KIU/kg (n = 10); (c) APRO 8 x 10(4) KIU/kg (n = 10); and (d) vehicle (saline; n = 10). APRO doses were calculated to reflect half, full, and twice the clinical Hammersmith dosing schedule. After I/R, plasma was collected for cytokine measurements. RESULTS: After I/R, E(max) decreased from the baseline value by more than 40% in the vehicle group as well as in the APRO 4 x 10(4) KIU/kg and APRO 8 x 10(4) KIU/kg groups (P < 0.05). However, E(max) returned to near baseline values in the APRO 2 x 10(4) KIU/kg group. Tumor necrosis factor (TNF) increased 10-fold after I/R, but it was reduced with higher APRO doses. CONCLUSIONS: This study demonstrated that a low dose of APRO provided protective effects on LV contractility, whereas higher doses suppressed TNF release. These unique findings suggest that there are distinct and independent mechanisms of action of APRO in the context of I/R.

Using activated clotting time to estimate intraoperative aprotinin concentration.

BACKGROUND: The use of aprotinin during cardiopulmonary bypass may be associated with renal dysfunction due to renal excretion of excess drug. We hypothesized that the difference between standard celite activated clotting time (ACT), which is prolonged by aprotinin, and kaolin ACT could provide an estimate of aprotinin blood level. METHODS: Fresh porcine blood was collected from six donor pigs and heparinized. Blood was stored at 4 degrees Celsius, rewarmed and aprotinin was added: 0, 100, 200, and 400 kallikrein inhibitor units/ml. Specimens were incubated at 37 degrees Celsius. Two pairs of ACT tubes (one celite and one kaolin) were measured at 37 degrees Celsius and 20 degrees Celsius using two Hemochron 401 machines. A generalized estimating equation (GEE) statistical approach was used to estimate actual aprotinin from differences in celite and kaolin ACT. RESULT: There was a significant relationship of the form y = exp(a+bx) between aprotinin concentration and the difference between celite and kaolin ACT at both 37 degrees Celsius (R(2) = 0.858) and 20 degrees Celsius (R(2) = 0.743). CONCLUSION: The time difference between celite and kaolin ACT may be a simple and inexpensive method for measuring the blood level of aprotinin during cardiopulmonary bypass. This technique may improve patient-specific dosing of aprotinin and reduce the risk of postoperative renal complications.

Is aprotinin safe to use in a cohort at increased risk for thrombotic events: results from a randomized, prospective trial in off-pump coronary artery bypass.

BACKGROUND: Multiple randomized trials have established a favorable safety profile for aprotinin use during cardiac surgery, but recent database analyses suggest an increased risk of adverse thrombotic events. Our group previously demonstrated that off-pump coronary artery bypass (OPCAB) is linked to a postoperative hypercoagulable state. In this study, we tested whether aprotinin influences thrombotic events after OPCAB. METHODS: Patients randomly received saline (n = 61) or aprotinin (2 x 10(6) kallikrein inhibiting units (KIU) loading dose, 0.5 x 10(6) KIU/hour [n = 59]) during OPCAB. Aprotinin levels (KIU/mL) were analyzed before, and 30 minutes (peak) and 4 hours after the loading dose. Estimated glomerular filtration rate (eGFR) was calculated daily based on Cockcroft equation with acute kidney injury (AKI) defined as eGFR less than 75% of baseline. Major adverse cardiac and cerebrovascular events (MACCE) were monitored during the first year, including acute graft failure by predischarge computed tomographic angiography. RESULTS: Compared with placebo, the aprotinin group developed a significantly lower eGFR on day 3 (p < 0.006), but this difference resolved by day 5. Peak aprotinin level correlated with the degree of eGFR decline noted on day 3 (r = 0.56, p < 0.03) and independently predicted postoperative AKI (odds ratio 8.8, p < 0.008). The receiver operating characteristic analysis demonstrated that peak aprotinin level strongly predicts AKI (area under the curve = 0.86, 95% confidence interval 0.69 to 1.00). The percentage of patients reaching the composite MACCE endpoint was significantly reduced in the aprotinin versus placebo group (12 vs 34%, p = 0.01). CONCLUSIONS: Compared with placebo, aprotinin use was associated with less MACCE but more AKI after OPCAB. The strong relationship between the peak aprotinin level and subsequent AKI suggests weight-based protocols for dosing aprotinin may reduce this risk.

Pharmacokinetics and normal scintigraphic appearance of 99mTc aprotinin.

OBJECTIVE: To confirm the pharmacokinetics and biodistribution of 99mTc aprotinin in normal volunteers and to determine the optimum time for scanning post-injection, prior to further investigations of 99mTc aprotinin as an imaging agent for amyloidosis. METHODS: Five patients (three men and two women, average age 49 years, age range 38-66 years) without a history of amyloidosis or any of the associated diseases, were included in this prospective study. Blood and urine were collected and images were performed of the whole body and wrists. CONCLUSIONS: Normal biodistribution of 99mTc aprotinin includes early cardiac and lung activity in the blood pool phase with subsequent hepatic activity and renal excretion with variable splenic activity. There is variable bowel uptake on later images. The best quality images were obtained 90 min post-intravenous administration, and this is likely to be the optimum time for clinical imaging.

The efficacy and safety of aprotinin for hemostasis during intracranial surgery.

OBJECT: The aim of this study was to determine the safety and efficacy of prophylactic high-dose intravenous aprotinin in reducing intraoperative blood loss in the neurosurgical population. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in parallel groups in two regional neurosurgical departments. One hundred patients with a preoperative diagnosis of intracranial meningioma or vestibular schwannoma subsequently confirmed on histological studies were included. All patients were older than 18 years of age, pregnancy had been excluded, there was no history of bleeding diathesis, no previous exposure to aprotinin, and no ingestion of antiplatelet or anticoagulant medications within the 2 weeks preceding surgery. Aprotinin was administered in doses of 30,000 kallikrein-inhibiting units (KIU)/kg body weight on induction of anesthesia and was continued as an infusion of 10,000 KIU/kg/hr until surgery was complete, or for a maximum of 8 hours. Intraoperative blood loss, blood transfusion, the Glasgow Outcome Scale score, and the Index of Independence were measured, and screening for deep vein thrombosis and the Mini-Mental State Examination were performed. CONCLUSIONS: Intraoperative blood loss was reduced from 1014 ml (geometric mean) to 508 ml (p = 0.028). Although this study was not designed to evaluate the need for blood transfusion, 37 U of blood was used in 11 patients in the aprotinin group and 58 U in 13 patients in the placebo group (not significant). There were no significant differences in postoperative thrombotic risk or other outcome measures between treatment groups. Aprotinin therefore can be safely used to reduce intraoperative blood loss in patients who are not receiving anticoagulation therapy.

High-dose aprotinin reduces activation of hemostasis, allogeneic blood requirement, and duration of postoperative ventilation in pediatric cardiac surgery.

BACKGROUND: Though multiple studies have affirmed the effectiveness of aprotinin in reducing blood loss in adult cardiac surgery, the possible benefit in pediatric cardiac surgery is controversial. METHODS: In a double-blind, randomized, and placebo-controlled study, the efficacy of aprotinin in attenuating the hemostatic and inflammatory activation during cardiopulmonary bypass in 60 patients weighing less than 10 kg was investigated. Secondary endpoints were the influence of aprotinin on the reduction of blood loss and allogeneic blood requirement, as well as postoperative oxygenation and length of mechanical ventilation. Aprotinin was administered in a high-dose of 3 x 10(4) KIU/kg plus a bolus of 5 x 10(5) KIU (not weight adjusted) added to the pump prime. RESULTS: Aprotinin plasma concentration at the end of cardiopulmonary bypass (CPB) was with 184 +/- 45 KIU/mL, within the targeted range of 200 KIU/mL. Coagulation and fibrinolysis were suppressed (F1.2 1 hour after CPB: 5.35 +/- 2.9 nmol/L vs 14.5 +/- 23.1 nmol/L; D-dimer 1 hour after CPB: 0.63 +/- 0.6 ng/mL vs 2.3 +/- 3.1 ng/mL; p < 0.05), inflammatory markers (interleukin [IL]-6, IL-8, IL-10) increased over time without significant differences between the groups, and only complement C3a activation was significantly attenuated at the end of CPB in the aprotinin group. Chest tube drainage was significantly reduced (24 hours: median 13.5 [IQR 12.2] mL/kg vs 19.4 [8.2] mL/kg; p < 0.05). All patients received one unit of packed cells to prime the heart lung machine. A second unit was needed significantly less often in the aprotinin group (13% vs 47%; p < 0.05). Postoperative oxygenation (pO2/FIO2 172 [IQR 128] mm Hg vs 127 [74]; p < 0.05) improved, and the time on ventilator was shorter in the aprotinin group (median 45 hours [IQR 94] vs 101 [IQR 74]; p < 0.05). No side effects were attributable to the use of aprotinin. CONCLUSIONS: High-dose aprotinin effectively attenuated hemostatic activation and reduced blood loss and transfusion requirement in pediatric cardiac surgery. Postoperative ventilation was also shortened in the aprotinin group.

Aprotinin reduces blood loss and the need for transfusion in orthognathic surgery.

A randomized, placebo-controlled, double-blind trial (n= 15 in each group) showed that patients given aprotinin intravenously (200 ml, [2000000 kallikrein inactivator units] before the operation and then 50 ml per h until the end of the operation) during simultaneous maxillary Le Fort 1 and mandibular sagittal split osteotomies, lost 52% less blood than controls (calculated by subtracting the volume of saline irrigant used from the volume of blood collected in the aspirator bottle and surgical drains). Patients given aprotinin lost a mean (SD) of 473 (190) ml compared with 986 (356) ml in controls. They also required significantly less transfused blood (1 was given 2 units in the aprotinin group compared with 9 given a mean of 1.5 units (range 1-4) in the control group). There were no complications attributable to this drug.

Is perioperative plasma aprotinin concentration more predictable and constant after a weight-related dose regimen?

UNLABELLED: To determine whether a weight-related dose had advantages over a fixed, large-dose regimen, we measured plasma concentrations of aprotinin by using an enzyme-linked immunosorbent assay method at set time points in 30 patients having heart surgery with cardiopulmonary bypass. A weight-related dose comprising a preincision bolus injection of 40,000 kallikrein-inhibiting units (KIU)/kg (5.6 mg/kg) with the same amount given in the oxygenator prime was compared with a large-dose regimen of 2 x 10(6) KIU (280 mg) preincision bolus and addition to prime, together with an infusion of 500,000 KIU/h (70 mg/h). Peak plasma concentration in the Weight-Related group was less variable than with the fixed-dose regimen. Forty percent of patients allocated to the fixed-dose regimen had an aprotinin concentration of more than 400 KIU/mL, compared with none in the Weight-Related group; this suggests a relative overdosing in the early surgical period in the Fixed-Dose group. There was great individual variability between patients in the time-concentration curves for aprotinin, with no difference between the two regimens. The weight-related dose regimen benefited by not requiring an intraoperative infusion while achieving the same plasma concentrations of aprotinin. IMPLICATIONS: Peak plasma concentrations of aprotinin were less variable with a weight-related dose schedule. This has implications for safety with regard to control of anticoagulation and cost in patients with small body mass. Plasma concentrations varied greatly with time between patients. This observation has implications for determining an optimal dose on the basis of aprotinin's currently known mechanisms of action.

Sustained elevated plasma aprotinin concentration in mice following intraperitoneal injections of w/o emulsions incorporating aprotinin.

This study was initiated to test the feasibility of w/o emulsions as a sustained release system for aprotinin following intraperitoneal injection in mice. The emulsion was well tolerated in mice and sustained release was observed over a period of 96 h. The time for maximum plasma concentration of aprotinin was 10 min and 12 h after injection of a control solution and the emulsion dosage form, respectively. Furthermore, the hemolytic activity of the emulsion constituents was low indicating a low acute toxicological potential of the emulsion. The present study also showed that the lipolytic activity in peritoneal exudate from mice is important for the clearance of oily vehicles from the peritoneal cavity with lipolytic rate constants ranging from 50 to 130 nmol free fatty acid released/min/mg exudate protein at 37 degrees C, pH 8.5. It was concluded that the w/o emulsion was well suited to provide sustained elevated plasma aprotinin concentrations in mice.

Determination of plasma aprotinin levels by functional and immunologic assays.

We compared a functional (amidolytic) and an enzyme-linked immunosorbent assay (ELISA) method for determining aprotinin concentration in 82 plasma samples obtained from patients undergoing cardiac surgery with aprotinin therapy. There was good correlation between methods (r = 0.87); however, aprotinin measurements by chromogenic assay were significantly higher than by ELISA [234 +/- 104 kallikrein inhibitory units (KIU)/ml versus 155 +/- 88 KIU/ml; P = 0.0001]. This appeared to be attributable to differences in the potency of the material used to standardize the assays. When results were corrected to allow for potency of the standard, there was no significant difference between chromogenic and ELISA methods (234 +/- 104 KIU/ml versus 240 +/- 137 KIU/ ml), although the ELISA results tended to be higher in some samples. These data suggest that aprotinin concentrations measured by these methods cannot be used interchangeably, and care must be taken when interpreting data from studies measuring aprotinin.

Plasma aprotinin concentrations during cardiac surgery: full- versus half-dose regimens.

UNLABELLED: Aprotinin is an effective but expensive drug used during cardiac surgery to reduce blood loss and transfusion requirements. Currently, aprotinin is administered to adults according to a fixed protocol regardless of the patient's weight. The purpose of this study was to determine aprotinin levels in patients receiving full- and half-dose aprotinin regimens by a simple functional aprotinin assay and to design a more individualized aprotinin dosage regimen for cardiac surgical patients. The mean plasma aprotinin concentration peaked 5 min after the initiation of cardiopulmonary bypass (full 401 +/- 92 KIU/mL, half 226 +/- 56 KIU/mL). The mean plasma aprotinin concentration after 60 min on cardiopulmonary bypass was less (full 236 +/- 81 KIU/mL, half 160 +/- 63 KIU/mL). There was large variation in the aprotinin concentration among patients. A statistically significant correlation was found between aprotinin concentration and patient weight (r(2) = 0.67, P < 0.05). IMPLICATIONS: The current dosing schedule for aprotinin results in a large variation in aprotinin plasma concentrations among patients and a large variation within each patient over time. We combined the information provided by our study with that of a previous pharmacokinetic study to develop a potentially improved, weight-based, dosing regime for aprotinin.

Effects of hemofiltration on serum aprotinin levels in patients undergoing cardiopulmonary bypass.

OBJECTIVE: To determine the effects of hemofiltration on serum aprotinin levels during cardiopulmonary bypass (CPB) surgery. DESIGN: Prospective, randomized study. SETTING: University of Washington Medical Center, single institution. PARTICIPANTS: Patients undergoing cardiac surgery without contraindications to aprotinin administration. INTERVENTIONS: Patients were randomized to full-Hammersmith and half-Hammersmith dosing regimens of aprotinin and were further randomized to hemofiltration or no hemofiltration. MEASUREMENTS AND MAIN RESULTS: Serum aprotinin levels were studied before CPB, 60 and 120 minutes into CPB, and at the end of CPB before protamine administration. Each group experienced a decrease in serum aprotinin levels with the institution of CPB, attributable to hemodilution and redistribution of aprotinin outside of the vascular compartment. During CPB, aprotinin levels declined further, but no significant difference was observed between patients who received hemofiltration and those who did not. Hematocrit values were significantly higher at the end of CPB in the hemofiltration groups. Patients receiving half-Hammersmith dosing regimens maintained aprotinin levels throughout CPB, which have been shown to inhibit plasmin but were lower than levels previously shown to inhibit kallikrein. CONCLUSIONS: Hemofiltration during CPB did not significantly alter serum aprotinin levels in patients receiving half-Hammersmith and full-Hammersmith dosing regimens of aprotinin.

Hemostasis management by use of Hepcon/HMS: increased bleeding without increased need for blood transfusion.

BACKGROUND: Extracorporeal circulation forces complete anticoagulation, most frequently achieved by complete heparinization. Activated clotting time (ACT) is the gold standard for monitoring, although there is a lack of correlation between heparin plasma level and ACT. Several systems for the estimation of free heparin have been developed: in this study we focused investigating on the influence of the Hepcon/HMS system on postoperative bleeding and transfusion requirements. METHODS: 114 patients were randomly assigned to one group monitored by use of Hepcon/HMS (group hepcon) and another group by use of ACT (ACT group); 7 patients were excluded due to re-exploration. 12 patients did not receive aprotinin; this part of the study was stopped early due to massive increased bleeding. 46 and 49 patients of groups hepcon and ACT, respectively, received aprotinin. RESULTS: Using aprotinin, in group hepcon total administered heparin was elevated by 13 % in contrast to group ACT while administered protamine was reduced by 20%. The ratio of antagonization was 82 +/- 17 % and 51 +/- 12 %, respectively. Coagulation parameters were not influenced except for increased postoperative ACT and PTT in the hepcon group. Bleeding of patients in that group was significantly increased during the first 6 hours, which led to an increased autologous retransfusion. Need for substitution of other blood components was not increased postoperatively. CONCLUSIONS: Use of the Hepcon/HMS-system for monitoring of heparinization during extracorporeal circulation is possible without increased risk of thromboembolism. Postoperative blood loss was slightly but significantly increased but there was no need for more heterogenous transfusion.

Aprotinin attenuates platelet accumulation in ischaemia-reperfusion-injured porcine skeletal muscle.

This purpose of this study was to evaluate the effect of aprotinin, a serine protease inhibitor, in ischaemia- and reperfusion-injured myocutaneous flaps and skin flaps. Flap survival, microcirculatory platelet accumulation, and regional blood flow were investigated in seventeen pigs which had been subjected to 8 h of ischaemia and 18 h of reperfusion. The pigs were randomly assigned to aprotinin treatment (n = 9) or saline (n = 8). In-vitro studies were performed to investigate the influence of aprotinin on the activated partial thromboplastin time. The survival of skeletal muscle correlated positively with the concentration of aprotinin (P = 0.02) and could not be explained by regional changes in blood flow. Platelet accumulation was decreased in aprotinin-treated muscle (P = 0.04). In-vitro (n = 10), 100 kallikrein inactivator units/ml aprotinin prolonged the activated partial thromboplastin time both in plasma (P = 0.001) and in blood (P = 0.002), suggesting an anticoagulant rather than a procoagulant effect. In conclusion, aprotinin at high concentrations may be beneficial for the survival of skeletal muscle and provides protection from platelet accumulation in the microcirculation of skeletal muscle exposed to ischaemia and reperfusion injury.

Maintenance of therapeutic plasma aprotinin levels during prolonged cardiopulmonary bypass using a large-dose regimen.

Aprotinin concentrations in the range of 127-191 kallikrein inactivator units (KIU)/mL at the end of cardiopulmonary bypass (CPB) (< 2 h duration) reduce transfusion requirements. It has been suggested that prolonged CPB may require higher infusion rates which significantly increase cost. We tested the hypothesis that large-dose aprotinin maintains therapeutic plasma levels during prolonged periods of CPB (< 2 h). Aprotinin was administered as follows: 2 x 10(6) KIU upon skin incision; 0.5 x 10(6) KIU/h x 4-h infusion on initiation of CPB; and 2 x 10(6) KIU added to the CPB prime solution. Aprotinin activity was measured 1) 30 min after initiation of drug administration (Pre-CPB); 2) 30 min after initiation of CPB (CPB + 30); 3) 90 min after initiation of CPB (CPB + 90); and 4) at CPB termination (End CPB). CPB duration (mean +/- SD) was 158 +/- 51 min. Plasma aprotinin concentrations (KIU/mL, mean +/- SD) were: 234 +/- 30 at Pre-CPB; 229 +/- 35 at CPB + 30; 184 +/- 27 at CPB + 90; and 179 +/- 22 at End CPB. In all patients, aprotinin levels at the completion of CPB were in the range previously reported to be effective. The authors conclude that large-dose regimen limited to 6 x 10(6) KIU maintained therapeutic plasma aprotinin concentrations during prolonged CPB.

Clotting and fibrinolytic disturbance during lung transplantation: effect of low-dose aprotinin. Groningen Lung Transplant Group.

UNLABELLED: Patients undergoing lung transplantation are often confronted with a bleeding problem that may be due in part to the use of cardiopulmonary bypass and its activation of blood clotting and fibrinolysis. OBJECTIVE: We performed a prospective study to determine whether and to what extent the clotting and fibrinolytic systems are being activated and whether low-dose aprotinin is effective in inhibiting blood activation during lung transplantation. METHODS: Thirty lung transplantations performed on 29 patients were divided into a group with cardiopulmonary bypass alone (n = 12), a group with cardiopulmonary bypass and 2 x 10(6) KIU aprotinin administered at the beginning of bypass in the pump prime (n = 12), and a group without cardiopulmonary bypass (n = 6). Serial blood samples were taken from the recipient before anesthesia, seven times during the operation, and 4 and 24 hours thereafter. RESULTS: Results show that in the group having cardiopulmonary bypass alone, the concentration of the clotting marker thrombin/antithrombin III complex increased significantly during the early phase of the operation (p < 0.01) and remained high until the end of the operation. Levels of tissue-type plasminogen activator, a trigger of fibrinolysis released by injured endothelium, also increased sharply in the early phase of the operation in the cardiopulmonary bypass group (p < 0.01), followed by a significant increase in fibrin degradation products (p < 0.01). In the aprotinin group, a significant reduction of thrombin/antithrombin III complex (p < 0.05), tissue-type plasminogen activator (p < 0.05), and fibrin degradation products (p < 0.05) was observed in the early phase of the operation compared with levels in the bypass group, but these markers increased late during bypass associated with a significant drop (p < 0.05) of plasma aprotinin level monitored by plasmin inhibiting capacity. In the nonbypass group, concentrations of thrombin/antithrombin III complex and tissue-type plasminogen activator also rose significantly (p < 0.05) in the early phase of the operation, but the levels were significantly lower than those of the bypass group (p < 0.05). Blood loss during the operation was 2521 +/- 550 ml in the bypass group, 1991 +/- 408 ml in the aprotinin/bypass group, and 875 +/- 248 ml in the nonbypass group. CONCLUSION: These results suggest that clotting and fibrinolysis are activated during lung transplantation, especially in patients undergoing cardiopulmonary bypass. Aprotinin in a low dose significantly reduced activation of clotting and fibrinolysis in the early phase of the operation but not during the late phase of lung transplantation.