Aprotinin Therapy Research Articles

Fatal pulmonary hypertension after heart transplantation: Sequelae of postactinic pulmonary vascular changes

Fatal pulmonary hypertension after heart transplantation: Sequelae of postactinic pulmonary vascular changes

Aprotinin. A review of its pharmacology and therapeutic efficacy in reducing blood loss associated with cardiac surgery.

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) experience transient haemostatic defects as a result of adverse changes to their blood components, blood cells and specific coagulation proteins. Aprotinin is a naturally occurring serine protease inhibitor isolated from bovine lung tissue which inhibits kallikrein and plasmin. A high dose aprotinin regimen (aprotinin 280mg loading dose over 20 to 30 minutes after anaesthesia induction followed by 70 mg/h for the duration of the operation and 280mg added to the priming fluid of the CPB circuit) has been used during CPB in order to reduce perioperative bleeding. Recent clinical trials confirm the efficacy of high dose aprotinin in reducing blood loss and transfusion requirements associated with primary cardiac procedures such as coronary artery bypass graft (CABG) or heart valve replacement surgery. High dose aprotinin is also effective in procedures known to possess a high risk for excessive blood loss, such as repeat CABG or heart valve replacement surgery, cardiac surgery in patients with infective endocarditis, or in patients receiving aspirin (acetylsalicylic acid) before surgery. Studies indicate that low dose aprotinin (280mg added to CPB pump prime fluid) is effective in reducing blood loss and transfusion requirements in patients undergoing primary CABG surgery. Additionally, low dose aprotinin regimens (both 280mg added to CPB pump prime fluid and 50% of the high dose regimen) have shown some benefit in repeat CABG surgery; however, more studies are needed to confirm these results. Data from clinical trials indicate that aprotinin is well tolerated. The types and incidences of adverse events reported with aprotinin therapy are generally consistent with those associated with major cardiac surgery, and are not significantly different from those observed in control groups. A trend towards lower graft patency rates, detected by ultrafast computerised tomography (CT), has been observed in aprotinin recipients in 2 US trials. These differences did not reach statistical significance and should be interpreted with caution since the ability of ultrafast CT to determine graft patency has not been validated. Mildly elevated plasma creatinine levels are more commonly observed in aprotinin-treated patients; these changes are transient in the majority of patients. Both high dose and low dose aprotinin regimens (280mg added to CPB pump prime fluid or 50% of the high dose regimen) have reduced blood loss and transfusion requirements in patients undergoing primary and repeat cardiac surgery. The role of aprotinin in paediatric cardiac surgery needs further clarification, while well-designed studies comparing aprotinin with other agents which inhibit fibrinolysis are also awaited with interest.(ABSTRACT TRUNCATED AT 400 WORDS)

Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage

Nowadays in many European heart centers the activation of the fibrinolytic system, always occurring during cardiopulmonary bypass, is routinely reduced by high-dose application of the proteinase inhibitor aprotinin (total of >4 million KIU). In this study parameters of myocardial ischemic injury were investigated with the aim of identifying further benefits of aprotinin, particularly the protection of the myocardium during the ischemic period of aortic crossclamping. Forty patients with coronary artery disease who underwent aorta-coronary bypass grafting were randomly and in a double-blind fashion divided into two groups, one that received high-dose aprotinin therapy and one that received only saline solution. Markers such as troponin T, with high specificity for detection of myocardial ischemia and infarction, and markers with more general specificity such as creatine kinase, its isoenzyme, and lactate dehydrogenase showed significantly increased values after ischemia in both groups. In patients who received high-dose aprotinin therapy 3 days after cardiopulmonary bypass all parameters measured showed significantly lower levels compared with those in the control group. Therefore we can presume that the application of high-dose aprotinin provides myocardial protection from perioperative ischemic injury. (J T HORAC C ARDIOVASC S URG 1995;109:1164-72)

The effects of aprotinin on chromogenic peptide substrate and other assays for components of the coagulation, fibrinolysis and plasma kallikrein systems

Plasma samples containing a range of aprotinin levels (0–400 KIU/ml) were tested in chromogenic peptide substrate assays for antithrombin III, protein C, plasma kallikrein inhibition, plasminogen, antiplasmin, tissue plasminogen activator and plasminogen activator inhibitor. No effect on the antithrombin III assay was seen. Aprotinin produced significantly reduced values in the assays for protein C, plasminogen and tissue plasminogen activator, and significantly increased values for kallikrein inhibition, antiplasmin and plasminogen activator inhibitor. Immunochemical assays for plasminogen activator including a new assay (BIA-t-PA) and plasminogen activator inhibitor were not affected by aprotinin. When plasma samples from patients undergoing cardiopulmonary bypass, with and without high dose aprotinin therapy, were tested in the chromogenic substrate assay for plasminogen activator inhibitor, markedly elevated apparent inhibitor levels were found in the aprotinin group.

Celite and kaolin produce differing activated clotting times during cardiopulmonary bypass under aprotinin therapy.

Since the introduction of the proteinase inhibitor aprotinin in cardiac surgery, a strong increase of the activated clotting time (ACT) during the extracorporeal circulation phase (ECC) was reported in many clinical studies, but with a lack of correlation between ACT and heparin concentration. In searching for a cause of this inconsistency we investigated different surface activators of the ACT in a clinical study. During ECC ACT was measured in parallel, using a Hemochron device and corresponding tubes (nominally 12 mg celite activator) for celite ACT, and a HemoTec device with corresponding double tubes (nominally 0.1 ml kaolin activator) for kaolin ACT. Under the conditions of ECC, the kaolin ACT values (482 +/- 145 sec) were significantly lower than the celite ACT values (985 +/- 267 sec). These results were confirmed in ex-vivo experiments using an activated partial thromboplastin time (aPTT) model. With heparin alone, aPTT activated with celite and kaolin were similar. Including aprotinin in this model, the celite aPTT showed no correlation to the heparin concentration, whereas the kaolin aPTT remained well correlated to the heparin concentration and similar to the values without aprotinin. With aprotinin alone there were no changes of the aPTT times, whereas the celite ACT times were without any correlation. Our results indicate that using kaolin instead of celite the ACT measurements under aprotinin therapy stay in the same ranges as without application of aprotinin: aprotinin has no detectable influence on kaolin-activated ACT. In our opinion, kaolin should be used as the surface activator for ACT measurements under the conditions of ECC, heparinization, and aprotinin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemorrhage, coagulation, and transfusion: a risk-benefit analysis

Transfusion risks include the possibility of ABO/ Rh incompatibility, sepsis, febrile reactions, immunosuppression, and viral transmission; incidences and consequences of these complications are reviewed. Predonation of autologous blood generally reduces the need for homologous blood by about 30% to 40%, but relatively few coronary artery bypass surgery (CABG) patients predonate blood. Drug products to decrease blood use include 1-deamino-8- d-arginine vasopressin (DDAVP), tranexamic acid, epsilon-aminocaproic acid, and aprotinin. A recent study suggests that a subgroup of patients with abnormal platelet function may benefit from a platelet therapy such as DDAVP. The prophylactic use of tranexamic acid reduces cardiac surgery postoperative blood loss, as measured by chest-tube output, by about 30%; unfortunately, data demonstrating a reduction in transfusion requirements are not available. Aprotinin use is associated with major reductions in blood transfusion requirements. Aprotinin provides platelet protection during cardiopulmonary bypass. Duration of stay in the intensive care unit was not increased by use of aprotinin, thus alleviating some concerns that aprotinin might promote coronary thrombosis. A recent report cites early graft closure as a major concern with aprotinin therapy, but data from other studies show no significant differences in rates of graft closure between patients receiving and those not receiving aprotinin. Routine use of a thromboelastogram with all cardiopulmonary bypass surgery at the University of Washington Hospital has reduced use of blood products by 30%.

Postoperative Hemostasis and Fibrinolysis in Patients Undergoing Cardiopulmonary Bypass with or without Aprotinin Therapy

Intra- and postoperative blood loss during open heart surgery is reduced by approximately 50% when aprotinin, a potent inhibitor for plasmin and kallikrein, is administered during surgery. But whether aprotinin increases the risk of thrombotic complications remains controversial. The aim of this study was to evaluate the effects of aprotinin administration on coagulation and fibrinolysis during and after cardiopulmonary bypass (CPB). Thirty patients undergoing CPB were randomly assigned to two comparable groups for a double-blind study (16 patients receiving high-dose aprotinin, 14 patients receiving placebo). Patients' plasma levels of ATM (thrombin-induced modified antithrombin III), FbDP (fibrin degradation products, D-Dimers), t-PA (tissue-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor type 1) were measured at regular intervals. In both groups, ATM level increased during surgery (from less than 30 to 90-110 ng/ml) and returned to normal 24 h after surgery and remained unchanged thereafter. Aprotinin reduced this increase in ATM levels (p = 0.02 at 30 min after the start of CPB). The FbDP generated during surgery was greatly reduced in the aprotinin group (945 ng/ml) in comparison with the placebo group (1889 ng/ml, p = 0.004). After surgery, FbDP levels decreased in both groups with nadirs at 2nd day (placebo group: 940 ng/ml and aprotinin group: 865 ng/ml) indicating a hypofibrinolytic period. Then, the FbDP level in both groups started to increase up to the 9th day, in an identical manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Perioperative approaches to coagulation defects

Cardiac surgical procedures are known to be associated with coagulation defects and disordered hemostasis. Excessive perioperative and postoperative bleeding and the need for considerable volumes of blood and blood product transfusions are well recognized. The risks of blood transfusion with high donor-exposure levels have focused attention on blood conservation as a priority in reducing the complications of cardiac operations. Hemostatic defects may be related to patient-inherent coagulopathies, preexisting associated pathology, and preoperative drug therapy. In addition, hemostatic defects are induced during the operation itself. Two principal therapeutic approaches to this complex problem have evolved. Although different, these approaches are not mutually exclusive and may be used complementarily. The first is autotransfusion and the second is hemostatic drug therapy. Although many drugs have been tried, including antifibrinolytic agents (e-aminocaproic acid, tranexamic acid), platelet-preserving agents (prostacyclin, dipyridamole), and desmopressin, the only drug that has shown significant and consistent efficacy in reducing bleeding in cardiac surgery patients is the serine protease inhibitor aprotinin. Aprotinin has been shown to be highly effective in reducing blood loss and blood and blood product transfusion requirements in high-risk patients. Clinical experience with aprotinin therapy in cardiac patients and specific issues such as dosage regimens and the target automated clotting time levels in patients on high-dose aprotinin therapy are outlined. Indications for the use of aprotinin and the balance between risk and benefit are discussed.

Blood conservation techniques for cardiac surgery: a survey of French centres.

A survey resulting from a partnership between CECEC (Centre d'Etudes en Circulation Extra-Corporelle) and Laboratoires Hoechst, France was carried out amongst all French adult cardiac surgery centres. The aim of this study was to investigate the various strategies used to decrease blood loss during open-heart surgery. Due to an exceptionally high response rate, we are able to report the current practice of French cardiac centres which account for 75% of open-heart adult surgery. The three most interesting strategies for blood conservation appear to be haemodilution, blood salvage from the extracorporeal circuit and previously deposited autologous blood transfusion, yet the three methods which are predominantly used are haemodilution (92.7%), aprotinin therapy (87.8%) and blood salvage from the extracorporeal circuit (82.9%).

Aprotinin therapy in cardiac operations: A report on use in 41 cardiac centers in the United Kingdom

Aprotinin, a serine protease inhibitor, has recently been shown to reduce blood loss in cardiac surgical patients. Data on the safety and efficacy of aprotinin therapy administered to 671 cardiac surgical patients in 41 United Kingdom cardiac surgical units have been submitted to interim analysis. The patients studied were in high-risk categories for excessive bleeding, including 457 redo operations and 79 patients with active infective endocarditis. Overall mortality was 12% in redo cases and 5.1% in first-time operations. Adverse events were reported in only 20 patients (3%). Median blood loss at 24 hours after operation was 400 mL, and median transfusion volume throughout the operative and postoperative period was 2 units. These data confirm that the use of aprotinin therapy in high-risk cardiac surgical patients is associated with a low incidence of adverse events.

Topical use of aprotinin in open heart operations

Among various pharmacological agents used to reduce bleeding after open-heart operations, high-dose aprotinin therapy seems most promising. However, its longterm effects are still obscure; there is almost always possibility of bypass graft occlusions produced by the hypercoagulable state induced by aprotinin in coronary bypass operations. Topical application of aprotinin into the pericardial cavity could prevent the adverse effects. Fifty patients were prospectively studied to evaluate the effects of topical aprotinin. One million KIU of aprotinin was poured into the pericardial cavity before closure of the sternotomy in group 1 (n = 25). Patients in group 2 (n = 25) served as controls. Total postoperative bleeding was significantly reduced in group 1 when compared with that of group 2 (722.7 ± 230.8 versus 1,282.6 ±225.7 mL; p < 0.01). The use of banked donor blood products was significantly less in group 1 than in group 2 (0.33 ± 0.67 versus 1.36 ± 0.86 units; p < 0.01). These results show that topical use of aprotinin reduces postoperative blood loss and need for transfusion. It seems promising and warrants further studies to be done.

Activated Clotting Time, Anticoagulation, Use of Heparin, and Thrombin Activation during Extra-corporeal Circulation: Changes under Aprotinin Therapy

In a prospective randomized double-blind study, the activated clotting time (ACT), heparin use, parameters of anticoagulation, and thrombin activation during extracorporeal circulation were studied in 20 patients who underwent aortocoronary bypass operations. The patients were divided into two groups: Group A was given a placebo, while Group B was given aprotinin according to the high-dosage Trasylol scheme. During ACT-controlled heparinization (ACT > 460 s) there was a significant heparin reduction in Group B (22,100 USP-E) in comparison to Group A (35,200 USP-E). Despite this lower quantity of total heparin, the ACT in Group B was significantly extended (Group B = 837 s, Group A = 492 s). The ACT did not correlate thereby with the heparin concentration or the total quantity of heparin in either group. In contrast to the control group, there was no increased thrombin generation in the aprotinin group. The thrombin-antithrombin III complexes (Group A = 143 micrograms/L, Group B = 102 micrograms/L) as well as the specific dimers (Group A = 2755 ng/ml, Group B = 448 ng/ml) were significantly lower under the use of aprotinin. The connection between the ACT, the heparin concentration, and the aprotinin concentration was further investigated in an ex-vivo model. The ACT samples were diluted with the aim of eliminating the influence of aprotinin. Under these conditions it was shown that for heparin concentrations between 2-4 U/ml there was a parallel shift of the ACT/heparinconcentration curve with the addition of aprotinin in a defined concentration range of 200-300 KIU.(ABSTRACT TRUNCATED AT 250 WORDS)

The prolonged activated clotting time (ACT) with aprotinin depends on the type of activator used for measurement

In cardiopulmonary bypass (CPB) surgery high dose heparin is necessary to inhibit the clotting cascade which is activated through damage to the vessels (extrinsic pathway) as well as contact activation of the blood with the various artificial surfaces of the CPB machine (intrinsic pathway). In most European heart surgery centres, the fibrinolytic activation that always occurs in CPB due to contact activation is reduced by the proteinase inhibitor aprotinin. Monitoring of anticoagulation during CPB is performed with the activated whole blood clotting time (ACT). The two machines commonly used for this purpose, Hemotec and Hemochron, use different contact system activators, kaolin and celite. These activators displayed highly significant differences, in both in vitro tests (modified APTT with whole blood in a neutral coagulometer), and ACT in both machines where aprotinin and heparin were used, as well as with parallel measurements with the two machines with blood from patients undergoing CPB with high dose aprotinin therapy (P < 0.001). The Hemotec machine with kaolin as activator was not affected by aprotinin throughout surgery, while the Hemochron clotting times almost doubled as soon as aprotinin and heparin were combined. Our studies show that for the determination of ACT in CPB were high dose aprotinin therapy is used only ACT determinations with machines using kaolin as activator yield accurate results.

The prolonged activated clotting time (ACT) with aprotinin depends on the type of activator used for measurement

In cardiopulmonary bypass (CPB) surgery high dose heparin is necessary to inhibit the clotting cascade which is activated through damage to the vessels (extrinsic pathway) as well as contact activation of the blood with the various artificial surfaces of the CPB machine (intrinsic pathway). In most European heart surgery centres, the fibrinolytic activation that always occurs in CPB due to contact activation is reduced by the proteinase inhibitor aprotinin. Monitoring of anticoagulation during CPB is performed with the activated whole blood clotting time (ACT). The two machines commonly used for this purpose, Hemotec® and Hemochron®, use different contact system activators, kaolin and celite. These activators displayed highly significant differences, in both in vitro tests (modified APTT with whole blood in a neutral coagulometer), and ACT in both machines where aprotinin and heparin were used, as well as with parallel measurements with the two machines with blood from patients undergoing CPB with high dose aprotinin therapy (P < 0.001). The Hemotec machine with kaolin as activator was not affected by aprotinin throughout surgery, while the Hemochron clotting times almost doubled as soon as aprotinin and heparin were combined. Our studies show that for the determination of ACT in CPB where high dose aprotinin therapy is used only ACT determinations with machines using kaolin as activator yield accurate results.

Choc anaphylactique lors de l'utilisation de l'aprotinine à fortes doses en chirurgie cardiaque

A 77-year-old man was admitted for mitral valve replacement, 46 days after a failed conservative mitral surgery where he received high-dose aprotinin. Twenty minutes after induction of anaesthesia, 250 UPh E of aprotinin were infused intravenously ; before the end of this infusion, bronchospasm, systemic hypotension and generalized rash were noted. Immediate treatment included intravenous adrenaline and methylprednisolone ; cardiovascular stability was restored after 10 minutes. Immediate histamine liberation was confirmed by the analysis of the time course of the clinical events, a previous contact and positive skin tests. Aprotinin has the antigenic molecular structure of natural proteins. Since 1987, it is used in cardiac surgery to reduce postoperative blood loss : to prevent serious allergic reactions to aprothinin, it is necessary, in patients known to have had previous aprotinin therapy, to perform skin testing with diluted aprotinin before infusion.

Aprotinin therapy for reoperative myocardial revascularization: A placebo-controlled study

We tested the efficacy and safety of aprotinin in 169 patients undergoing isolated reoperative myocardial revascularization. Patients were randomly assigned to high-dose aprotinin, low-dose aprotinin, or placebo treatment groups in a double-blind, placebo-controlled study. Treatment groups did not differ significantly with respect to age, sex, red cell mass, number of grafts, use of internal thoracic artery, or incidence of preoperative aspirin therapy. Patients treated with aprotinin had a significant reduction in postoperative chest tube drainage (720 ± 753, 866 ± 1,636, and 1,121 ± 683 mL, respectively, for high-dose aprotinin, low-dose aprotinin, and placebo; p < 0.001). Transfusion requirements were reduced in aprotinin-treated patients (2.1 ± 4.2,4.8 ± 11.8, and 4.1 ± 6.2 units for high-dose, low-dose, and placebo, respectively; p < 0.001). A similar reduction in chest tube drainage and transfusion requirements was seen in patients using aspirin preoperatively. Q-wave myocardial infarctions were increased in the aprotinin subgroups (17.5%, 14.3%, and 8.9% for high-dose, lowdose, and placebo groups; not significant). Acute vein graft thrombosis was found in six of 12 vein grafts studied at postmortem examination in patients receiving aprotinin but not in any of five grafts in patients receiving placebo. We conclude that aprotinin is extremely effective in reducing bleeding and transfusion requirements and may increase the risk of graft thrombosis.

In vitro effects of aprotinin on activated clotting time measured with different activators

The effects in vitro of aprotinin on the activated clotting time measured with both celite- and kaolin-activated tubes were investigated in 21 consecutive patients requiring cardiopulmonary bypass. Four whole-blood samples (2 ml per sample) from each patient were tested simultaneously with Hemochron automated timing systems (International Technidyne Corp., Edison, N.J.) before, during, and after cardiopulmonary bypass. One tenth milliliter of either aprotinin (at a final concentration of 80, 120, or 180 KIU/ml) or saline solution was mixed in vitro with blood samples before determination of the activated clotting time. Aprotinin had no inhibitory effect on the activated clotting times of unheparinized blood. After heparin administration, aprotinin in the above concentrations prolonged the activated clotting times measured with celite-activated tubes by 47% to 71%, as compared with the measurements of the activated clotting time without the addition of aprotinin. The activated clotting times in kaolin-activated tubes were not increased, however, by the in vitro addition of aprotinin. Our in vitro results indicate that aprotinin in concentrations from 80 to 180 KIU/ml does not significantly enhance the inhibitory effects of heparin on the intrinsic coagulation system as evaluated by measurement of the activated clotting times in kaolin-activated tubes. The anticoagulation effect of heparin in patients receiving aprotinin infusion should be monitored with kaolin-activated instead of celite-activated tubes because the celite makes the measured activated clotting time unreliable in patients receiving aprotinin therapy. These in vitro results require confirmation in vivo in patients receiving aprotinin therapy.

High-dose aprotinin in cardiac surgery: Three years' experience in 1,784 patients

The effect of the proteinase-inhibitor aprotinin on blood loss and homologous blood requirement in cardiac surgery was investigated. In a prospective study, 902 adult patients were treated with high-dose aprotinin (total > 5 × 10 6 kallikrein inactivator units [KIU]; group A), while 882 patients without aprotinin administration served as the controls (group C). Both groups were operated on between January 1987 and October 1989, and included patients with primary coronary artery bypass grafting (n = 525 group C, n = 560 group A), valve replacement (n = 292 group C, n = 264 group A), or combined procedures (n = 65 group C, n = 78 group A), as well as cardiac reoperations (n = 91 group C, n = 110 group A). The average blood loss 36 hours postoperatively in the aprotinin group was 679 ± 419 mL, compared with 1,038 ± 671 mL in the control group ( P < 0.05). Total homologous blood requirement was also significantly less in group A (942 ± 1,630 mL) compared with group C (1,999 ± 2,283 mL) ( P < 0.05), a reduction of 53%. Serum creatinine concentrations did not show intergroup differences on the first postoperative day (group A, 1.2 ± 0.7; group C, 1.3 ± 0.5 mg /dL) or on discharge from the intensive care unit (ICU). Thus, impairment of renal function as a consequence of aprotinin treatment was not observed. Three patients developed signs of mild circulatory depression after injection of aprotinin, which responded promptly to vasopressor therapy. This study confirmed the efficacy of high-dose aprotinin therapy to reduce postoperative blood loss and the safety of this treatment. Therefore, the routine use of aprotinin can be recommended for patients undergoing cardiac surgery.

Aprotinin Does Not Inhibit the Release of PGI2 or vWF from Cultured Human Endothelial Cells

The release of prostacyclin (PGI2) and von Willebrand factor (vWF) from human umbilical vein endothelial cells (HUVEC) was examined to determine if aprotinin had any effects on these endothelial cell reactions. These end-points were chosen to indicate if this serine protease inhibitor caused alterations in the control of haemostatic function by endothelium, in the light of the improvement in haemostasis seen in patients given aprotinin therapy at the time of open heart surgery. Stimuli used to promote secretion of prostacyclin and vWF were human alpha-thrombin, histamine, protamine sulphate, poly-L-lysine and phorbol myristate acetate. Aprotinin (30 microMs) had no significant effect on the basal or stimulated release of PGI2 or vWF from HUVEC.

The effects of aprotinin on hemostatic function during cardiac surgery

The mechanism of action by which large doses of aprotinin decrease blood loss during cardiac surgery is not completely understood. In a prospective, controlled study, 30 patients undergoing cardiac surgery were given high-dose aprotinin in accordance with a commonly used regimen. Twenty untreated but otherwise comparable patients served as the control group. The effects of aprotinin therapy during cardiopulmonary bypass on coagulation parameters, the kallikreinkinin system, fibrinolysis, platelet stimulation, and the release of elastase from neutrophils were studied. The fibrinolysis parameters were the only measurements that showed clear and significant differences between the two groups. Aprotinin almost completely inhibited the formation of fibrin and fibrinogen degradation products. It is assumed that inhibition of systemic fibrinolysis and suppression of local fibrinolysis contribute to the hemostatic action of aprotinin. The study did not demonstrate a significant protective effect of aprotinin on platelets. In addition, the dose of aprotinin administered did not affect the kallikrein-kinin system or elastase. Therefore, these data suggest that the previously demonstrated hemostatic effects of aprotinin derive primarily from its antifibrinolytic action.