Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Increased anticoagulation during cardiopulmonary bypass by aprotinin. 171 4

Activation of bovine plasma prekallikrein was investigated with several proteinases. Highly purified bovine plasma prekallikrein was rapidly activated to kallikrein [EC 3.4.21.8] by bovine activated Hageman factor, trypsin [EC 3.4.21.4] and Pronase P (proteinases from Streptomyces griseus) and more gradually by papain [EC 3.4.22.2] and ficin [EC 3.4.22.3]. Activation of prekallikrein was also observed with bovine plasmin [EC 3.4.21.7], but not with bovine clotting factors Xa (Stuart factor) [EC 3.4.21.6] and IXa (Christmas factor) or thrombin [EC 3.4.21.5]. Urokinase [EC 3.4.99.26], Reptilase, collagenase [EC 3.4.24.3], elastase [EC 3.4.21.11], alpha-chymotrypsin [EC 3.4.21.1], Nagarse [EC 3.4.21.14], and stem bromelain [EC 3.4.22 4] did not convert prekallikrein to kallikrein. Plasma kallikrein activated to Hageman factor released kinin rapidly from bovine high molecular weight (HMW) kininogen. However, from bovine low molecular weight (LMW) kininogen, liberation of kinin was extremely slow. The kallikrein activity was inhibited by soybean trypsin inhibitor (SBTI), Trasylol, diisopropylfluorophosphate (DFP), and N-alpha-tosyl-L-lysine chloromethylketone (TLCK), but not by egg-white trypsin inhibitor (EWTI), lima bean trypsin inhibitor (LBTI), heparin or hexadimethrine bromide (Polybrene). The kallikrein formed an enzyme-inhibitor complex with SBTI and Trasylol, but not with LBTI. Prekallikrein did not react with SBTI. Prekallikrein consists of a single polypeptide chain of molecular weight about 90,000, as estimated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Activation of prekallikrein by Hageman factor was found to involve cleavage of the single peptide bond on the disulfide-bridged polypeptide chain, and no change of molecular weight was observed during the activation. The peptide bond cleaved in prekallikrein by the activation was an Arg-X peptide bond on a disulfide-bridged polypeptide chain.
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PMID:Studies on prekallikrein of bovine plasma. II. Activation of prekallikrein with proteinases and properties of kallikrein activated by bovine Hageman factor. 676 24

A patient undergoing subtotal pancreatectomy and intraportal islet tissue autotransplantation for chronic pancreatitis developed severe portal hypertension (49 cm of H(2)O) and acute disseminated intravascular coagulation (DIC). In an attempt to identify the cause of these problems, portal pressure and the activities of the coagulation and fibrinolytic systems were studied in dogs undergoing intraportal autotransplantation of islet tissue. Following intraportal injection of the pancreatic tissue in five control dogs, the portal pressure rose to a maximum of 43.2 cm of H(2)O +/- 2.4 and major coagulation abnormalities occurred. The mean hematocrit value fell to 18% +/- 8.6, the mean platelet count to 218,000 +/- 31,000, the mean plasma fibrinogen to 40 mg/dl +/- 18, and the mean euglobulin clot lysis time (ECLT) to 25 min +/- 4. Partial thromboplastin time (PTT) became prolonged (233 secs +/- 30) and significant quantities of fibrinogen-fibrin degradation products (FDP-fdp) (1:128 +/- 32) appeared. These changes indicate the development of DIC probably secondary to significant amounts of tissue thromboplastin detected in the tissue homogenate infused at time of autotransplantation. In a group of seven dogs in whom heparin and Trasylol (aprotinin) were added to the pancreatic tissue at the time of transplantation, portal pressure rose only to a peak of 28.3 cm of H(2)O +/- 3.6 and no significant abnormalities occurred in mean hematocrit value, plasma fibrinogen, platelet count or ECLT. Minor prolongation of PTT occurred secondary to the activity of heparin. FDP-fdp (1:16) were present transiently during tissue injection. Four patients in whom heparin and Trasylol were added to the pancreatic tissue at the time of autotransplantation developed only minor elevations of portal pressure (mean 15.5 cm of H(2)O) without intravascular coagulopathy.
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PMID:Disseminated intravascular coagulation and portal hypertension following pancreatic islet autotransplantation. 676 51

Aprotinin is being used increasingly to limit cardiopulmonary bypass (CPB)-induced coagulation derangements. Since whole blood prothrombin time (PT) and activated partial thromboplastin time (APTT) assays are beneficial in the treatment of bleeding after CPB, we studied the potential effect of aprotinin on these whole blood assays. Blood specimens from 151 cardiac surgical patients were obtained in two phases: prior to heparin administration, before CPB, and subsequent to heparin neutralization after CPB. After collection, blood specimens were divided into two aliquots and mixed with either normal saline (NS) or aprotinin (A, 200 or 400 Kallikrein inhibiting units (KIU)/mL). Whole blood specimens were used to measure whole blood PT and APTT using CoaguChek Plus instruments. Whole blood PT results were similar between normal saline. (NS)- and aprotinin-spiked specimens before CPB (A, 12.9 +/- 1.5s; NS, 12.8 +/- 1.5s; P = 0.76) and after CPB (A, 17.5 +/- 2.4s; NS, 17.7 +/- 2.4s; P = 0.58). In contrast, whole blood APTT results were prolonged in aprotinin-spiked specimens prior to CPB (A, 63.3 +/- 32.2s; NS, 38.6 +/- 16.3s; P < 0.0001) and after CPB (A, 65.9 +/- 23.7s; NS, 45.7 +/- 14.4s; P < 0.0001). A dose-dependent prolongation of whole blood APTT by aprotinin was demonstrated by a greater mean difference in APTT (P = 0.0001) between specimens spiked with NS or 200 KIU (17.5 +/- 12.2s) vs 400 KIU (27.8 +/- 21.5s) of aprotinin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aprotinin prolongs whole blood activated partial thromboplastin time but not whole blood prothrombin time in patients undergoing cardiac surgery. 869 35

A variety of studies have been performed on the preservation of hemostasis by aprotinin during cardiopulmonary bypass (CPB). It appears that the mechanism of aprotinin to preserve hemostasis can be interpreted in different ways. Our previous studies suggested that preservation of platelet glycoprotein Ib (GpIb) antigen, and counteraction of heparin anticoagulation in the extrinsic clotting pathway might partly explain the preservative effect of aprotinin. A clinical study was therefore conducted to evaluate these effects during the use of low dose aprotinin. Improved agglutination by ristocetin (P < 0.05), and improved GpIb antigen expression (P < 0.05) during CPB showed better preserved platelet adhesive capacity in the aprotinin group than in the control group. Glycoprotein Ib antigen expression and the agglutination capacity with ristocetin during CPB were closely related (P < 0.05). Platelet GpIIb/IIIa antigen and adenosine diphosphate (ADP) aggregation were not significantly different between the aprotinin and control groups. Aprotinin had no effect on the extrinsic clotting pathway in the blood, since the thromboplastin clotting time was similar in both groups. These results indicate that the protection of platelet adhesive capacity during CPB is a main function of aprotinin, whereas no evidence was collected for enhanced extrinsic clotting by aprotinin during CPB.
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PMID:Aprotinin effect on platelet function and clotting during cardiopulmonary bypass. 751 34

Monitoring of coagulation is mandatory during liver transplantation (LT). Standard coagulation tests may be routinely used. However, they give static information and may be inadequate in case of severe coagulation defect. Interest has been recently focused on thromboelastography (TEG) which could give more suitable and rapid information in these cases. Few studies have evaluated the clinical interest of TEG compared to conventional tests. This comparison was the aim of the present study, performed in 89 patients scheduled for LT. The anaesthetic management as well as procedure of transfusion were similar in all patients. Before unclamping, 5000 KIU.kg-1 of aprotinin were injected. Routine tests and TEG were performed at the beginning and end of both pre-anhepatic and anhepatic phases, and 5, 30, 60, and 120 min after the revascularisation of the new liver. A phase of hypocoagulability was observed after unclamping. Biological signs included an increase in activated thromboplastin time, a reduction of alpha angle and maximum amplitude on TEG with a lengthening of its r + k component. A strong correlation existed between maximum amplitude and platelets, maximum amplitude and fibrinogen, alpha and fibrinogen at each time of the surgical procedure. Euglobulin lysis time decreased significantly after clamping, whereas fibrin degradation products increased at the same time. However, typical fibrinolysis with a clot lysis index (CLI) below 55% was only observed in 15 patients. Twelve of them had a CLI value reaching 0%, associated with severe generalized oozing. Aprotinin (200,000 to 600,000 KIU) corrected these abnormalities. These results show that TEG may not be very helpful to determine whether platelets or fibrinogen are involved in the phase of hypocoagulability detected after unclamping.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Monitoring of hemostasis during liver transplantation: contribution of thromboelastography]. 751 8

Since aprotinin has become extensively used during cardiopulmonary bypass the maintenance of safe anticoagulation is a concern. Aprotinin affects anticoagulation measurement by the activated clotting time. Therefore, a reliable new measurement is needed to monitor anticoagulation during cardiopulmonary bypass. In the present study, we tested the efficacy of two alternative measurements in which whole blood clotting was stimulated by high-dose thromboplastin or by high-dose thrombin. During cardiopulmonary bypass under standardized heparinization, the activated clotting time was twofold longer in the aprotinin group than in control group (p < 0.05), whereas high-dose thromboplastin and high-dose thrombin groups were not significantly affected by aprotinin. In laboratory tests using blood from healthy volunteers, all methods showed linear correlation with heparin concentration in the absence of aprotinin (p < 0.05). However, the activated clotting time measurement was prolonged more by heparin when aprotinin was present (p < 0.05), whereas high-dose thromboplastin and high-dose thrombin measurements were not. Moreover, these measurements were faster and more dependable than the activated clotting time. Therefore, high-dose thromboplastin time and high-dose thrombin time seem to be reliable for monitoring anticoagulation when aprotinin is used during cardiopulmonary bypass.
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PMID:Monitoring of anticoagulation in aprotinin-treated patients during heart operation. 752 56

Aprotinin has been reported to reduce bleeding in cardiac surgery patients. Its mechanisms of action on coagulation have not been fully elucidated. In a prospectively randomized study of 40 patients undergoing elective aortocoronary bypass grafting, the influence of high-dose aprotinin (2 million IU of aprotinin before CPB, 500,000 IU/h until the end of operation, 2 million IU added to the prime) (N = 20) on endothelial-related coagulation was compared to a nontreated control group (N = 20). Thrombomodulin (TM), protein C and (free) protein S as well as thrombin/antithrombin-III (TAT) plasma concentrations were measured by enzyme-linked immunosorbent assays (ELISA) before the aprotinin infusion, before cardiopulmonary bypass (CPB), during CPB and after CPB, at the end of surgery, 5 hours after CPB, and on the first postoperative day. All standard coagulation parameters (AT-III and fibrinogen plasma levels, platelet count, partial thromboplastin time) did not differ between the two groups. At baseline, TM plasma levels were within the normal range (< 40 ng/mL) and similar in both groups. During CPB, TM plasma concentrations decreased similarly in both groups (aprotinin: 18 +/- 6 ng/mL, control: 17 +/- 7 ng/mL) followed by a comparable increase in the postbypass period until the first postoperative day (aprotinin: 60 +/- 10 ng/mL, control: 53 +/- 11 ng/mL). Protein C and (free) protein S plasma levels also showed no differences between the two groups. On the first postoperative day, baseline values for protein C and protein S had not yet been reached.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does aprotinin influence endothelial-associated coagulation in cardiac surgery? 752 60

Aprotinin, a broad spectrum serine proteinase inhibitor, is becoming increasingly used to control bleeding during surgery. Heparinized patients treated with aprotinin for cardiac surgery have a much longer activated clotting time (ACT) than expected for the dose of heparin used and a similar effect has been observed with the activated partial thromboplastin time (APTT). Since APTT reagents vary in their sensitivity to heparin we compared the effect of aprotinin on 25 commercially available products with respect to the APTT response to heparin. Aprotinin (Bayer) was added to normal, pooled, citrated plasma at concentrations of 0, 100, 200, 300 and 400 kallikrein inhibition units (KIU)/ml and mucosal heparin was then added to give concentrations of 0, 0.25, 0.5, 0.75 and 1.0 IU/ml. Duplicate APTTs were performed on each of these 25 plasma samples according to the manufacturers' instructions. As expected, different commercial reagents exhibited different sensitivities to heparin. There was also variation in the sensitivity to aprotinin but this did not correlate with the heparin sensitivity. The prolongation of the APTT by heparin was markedly increased by aprotinin. For example, APTT ratios at 0.5 IU/ml heparin increased up to eight-fold in the presence of 'therapeutic' levels of aprotinin (200 KIU/ml) and this effect was even more pronounced at higher heparin levels. The activator used did not significantly influence the effect of aprotinin on the APTT although there was a trend for kaolin-activated reagents to be less affected by the addition of aprotinin to heparinised plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of aprotinin on the response of the activated partial thromboplastin time (APTT) to heparin. 768 30

Aprotinin is a nonspecific serine protease inhibitor extracted from bovine lung. It was first used during cardiopulmonary bypass to inhibit plasmin-induced complement activation. By chance significant reductions of blood loss and blood requirements were noted in treated patients. Subsequent investigation showed improved hemostasis to result from protection of platelet adhesive receptors (Gp Ib) at the onset of cardiopulmonary bypass. Without aprotinin the contact system of plasma is massively activated on first passage through the cardiopulmonary bypass circuit. Activation of the intrinsic coagulation pathway causes thrombin formation, which impairs platelet adhesive function. Aprotinin blocks contact activation of the kallikrein system during cardiopulmonary bypass and in synergy with heparin prevents thrombin formation through inhibition of the intrinsic clotting cascade. It is likely that neither thrombin nor platelets become involved in the blood-foreign surface contact activation process in aprotinin-treated patients. The fact that the hemostatic process is affected from the very beginning of cardiopulmonary bypass is substantiated by the fact that low-dose aprotinin therapy (2 x 10(6) KIU aprotinin added to the pump prime) leads to the same preservative effect on Gp Ib receptors and blood loss as continuous high-dose infusion (6 x 10(6) KIU) throughout the whole surgical procedure. In the presence of heparin aprotinin prolongs the activated clotting time and the in vitro activated partial thromboplastin time. This has important implications for heparin dosage. An inhibitory effect on the endothelial cell anticoagulant function may also have consequences during hypothermic low flow and circulatory arrest states.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aprotinin in perspective. 768 54


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