Ulm, Univ., Diss., 2007.

Graduation date: 1997

Η πλειοτροπίνη (pleiotrophin, PTN), είναι ένας αυξητικός παράγοντας 18 kDa με υψηλή συγγένεια για την ηπαρίνη. Το μόριο της PTN είναι πολύ συντηρημένο μεταξύ των ειδών και έχει 50% ομολογία με τη midkine, με την οποία συγκροτεί μια νέα οικογένεια αυξητικών παραγόντων. Υψηλά επίπεδα της πρωτεΐνης έχουν ανιχνευθεί σε πολλούς καρκινικούς όγκους, αλλά και κυτταρικές σειρές που προέρχονται από διάφορους τύπους καρκίνου σε ανθρώπους. Αρκετές είναι οι αναφορές που υποδεικνύουν την PTN ως μόριο που ρυθμίζει τον πολλαπλασιασμό, τη μετανάστευση και τη διαφοροποίηση κυττάρων. Επίσης, έχει προταθεί θετική συσχέτιση της PTN με την αγγειογένεση in vivo, αλλά και με κυτταρικές λειτουργίες που σχετίζονται με την αγγειογένεση in vitro. Ασκεί τη βιολογική της δράση μετά από αλληλεπίδραση με πρωτεογλυκάνες της επιφάνειας του κυττάρου ή μετά από δέσμευση σε ειδικούς υποδοχείς, όπως o υποδοχέας με δράση φωσφατάσης τυροσίνης β/ζ (RPTPβ/ζ) και ο υποδοχέας του αναπλαστικού λεμφώματος με δράση κινάσης τυροσίνης (ALK). Στην παρούσα εργασία διαπιστώθηκε η έκφραση του υποδοχέα RPTPβ/ζ στα κύτταρα HUVEC, T98G, MO59K, U87MG, LN18, C6 και LNCaP, ενώ ο υποδοχέας ALK ανιχνεύεται σε μικρότερα επίπεδα στα κύτταρα T98G, MO59K, LN18, C6 και LNCaP. Η PTN αλληλεπιδρά με τη διαμεμβρανική μεγάλη ισομορφή του υποδοχέα RPTPβ/ζ με υψηλό βαθμό γλυκοζυλίωσης σε όλα τα υπό μελέτη κύτταρα, ενώ φαίνεται πως η διμερισμένη μορφή της, μοριακού μεγέθους 36 kDa, είναι αυτή που δεσμεύεται στους υποδοχείς της. Καθώς η PTN έχει πρόσφατα ταυτοποιηθεί ως σημαντικός αυτοκρινής παράγοντας για την καρκινική σειρά LNCaP και με βάση αποτελέσματα που δείχνουν ότι τα δύο άκρα του μορίου ίσως να παίζουν σημαντικό ρόλο στις βιολογικές δράσεις του αυξητικού παράγοντα, δημιουργήθηκαν σταθερά διαμολυσμένα καρκινικά κύτταρα προστάτη LNCaP που υπερεκφράζουν την αλληλουχία HΔ111-136 της PTN, από την οποία λείπουν τα 26 αμινοξέα του καρβόξυτελικού άκρου (HΔ111-136) και σταθερά διαμολυσμένα κύτταρα LNCaP που υπερεκφράζουν την αλληλουχία 9-110 που κωδικοποιεί τα αμινοξέα (Η9-110). Τα κύτταρα αυτά θα χρησιμοποιηθούν προκειμένου να βρεθεί αν τα άκρα του μορίου που εκφράζεται ενδογενώς εμπλέκονται με κάποιο τρόπο στις παρατηρούμενες βιολογικές δράσεις του μορίου. Στο πλαίσιο της προσπάθειας διαλεύκανσης της σχέσης δομής-δράσης της PTN, προηγούμενα αποτελέσματα της ερευνητικής μας ομάδας έχουν δείξει ότι η πλασμίνη πρωτεολύει την ΡΤΝ, οδηγώντας στο σχηματισμό πέντε πεπτιδίων με διαφορετικές δράσεις σε αγγειογενετικές διαδικασίες in vitro και in vivo. Επιπλέον, o αναστολέας της πλασμίνης απροτινίνη αναστέλλει την πρωτεόλυση της ΡΤΝ από πλασμίνη, ενώ είναι γνωστό ότι επάγει την αγγειογένεση in vivo στο μοντέλο της χοριοαλλαντοϊκής μεμβράνης εμβρύου όρνιθας, τη μετανάστευση ενδοθηλιακών κυττάρων καθώς και τη μετανάστευση και τον πολλαπλασιασμό λείων μυϊκών κυττάρων Με βάση τα παραπάνω δεδομένα, μελετήθηκε η πιθανή εμπλοκή της ΡΤΝ στις διεγερτικές δράσεις της απροτινίνης σε ανθρώπινα ενδοθηλιακά HUVEC και καρκινικά κύτταρα προστάτη LNCaP. Διαπιστώθηκε πως η απροτινίνη επάγει τη μετανάστευση ανθρώπινων ενδοθηλιακών και καρκινικών κυττάρων προστάτη. Επίσης, εκτός από αναστολή της πρωτεόλυσης της ΡΤΝ, η απροτινίνη επάγει και την έκκριση της ΡΤΝ στο θρεπτικό μέσο των κυττάρων HUVEC και LNCaP, μέσω ενεργοποίησης του μεταγραφικού παράγοντα AP-1 και μεταγραφής του γονιδίου της ΡΤΝ. Η ΡΤΝ φαίνεται να εμπλέκεται στην επαγόμενη από απροτινίνη κυτταρική μετανάστευση μέσω του υποδοχέα της RΡΤΡβ/ζ και στους δύο τύπους των υπό μελέτη κυττάρων, ενισχύοντας την υπόθεση ότι η ΡΤΝ μέσω του υποδοχέα της RΡΤΡβ/ζ παίζει σημαντικό ρόλο στη μετανάστευση των κυττάρων που επάγεται από διάφορους παράγοντες. / Pleiotrophin (PTN) is an 18-kDa growth factor that has a high affinity for heparin. It is highly conserved between species and shares a 55% amino acid sequence homology with midkine. The two proteins form a new family of structurally related heparin binding growth factors. A potential role of PTN in human cancers has been suggested after the detection of PTN mRNA and/or protein in various human cancer cell lines and tumour specimens of diverse origin. Many data have shown that PTN mediates proliferation, migration and cell differentiation. Moreover, it has been suggested that PTN acts as an angiogenic molecule in vivo and in vitro. It exerts its biological activity through interaction with cell surface proteoglycans and more specific receptors like receptor protein tyrosine phosphatase β/ζ (RPTPβ/ζ) and anaplastic lymphoma kinase (ALK). In the present study, RPTPβ/ζ protein expression has been detected in HUVEC, T98G, MO59K, U87MG, LN18, C6 and LNCaP cells, while ALK receptor is expressed as a protein at lower levels in T98G, MO59K, LN18, C6 and LNCaP cells. Interestingly, dimmers of PTN with a molecular mass of 36 kDa seem to interact with the transmebrane long isoform of RPTPβ/ζ, in all cells under study. It was also observed that dimerized PTN, is capable of co-immunoprecipitating with ALK in LNCaP cells, although this interaction could not be verified in all assays. As PTN has been recently identified as an important autocrine growth factor for the LNCaP prostate cancer cell line and based on data showing the important role of the terminal domains of PTN on its biological activities, we have developed stably transfected LNCaP cell lines overexpressing PTN lacking 25 aminoacids from its C-terminal region or the sequence that corresponds to aminoacids 9-110 of the growth factor. These cell lines are going to be used in order to investigate the implication of the terminal domains of the endogenously expressed molecule in the observed biological activities. In the frame of structure - function analysis of PTN, previous results of our group have shown that through proteolytic activity, plasmin can generate five peptides that correspond to distinct domains of the molecule, which can either activate or inhibit angiogenesis. Aprotinin, a serine protease inhibitor, enhances angiogenesis in the in vivo model of the chick embryo chorioallantoic membrane. Furthermore, aprotinin induces HUVEC migration, smooth muscle cell migration and proliferation, as well as LNCaP cell proliferation. The goal of this study was to evaluate the possible implication of PTN in aprotinin-induced stimulatory activities in human endothelial and prostate cancer cells. Our data demonstrate that aprotinin induces LNCaP and HUVEC cell migration. In line with its inhibitory effect on plasmin, aprotinin increased the amounts of the full length PTN detected in the culture medium of LNCaP and HUVEC cells. This increase seems to be due partly to inhibition of PTN proteolysis and partly to transcriptional activation of the PTN gene, as evidenced by the increased luciferase activity of a reporter gene vector carrying the full length promoter of the ptn gene. The latter seems to be dependent on the activation of the transcription factor AP-1. Finally, PTN seems to mediate the stimulatory effects of aprotinin in cell migration through its receptor RΡΤΡβ/ζ in LNCaP and HUVEC cells, strengthening the hypothesis that PTN plays an important role in cell migration induced by many factors.

Die orthotope Lebertransplantation (OLT) ist in den letzten Jahren zu einer etablierten Methode in der Behandlung von infausten Lebererkrankungen geworden und hat deren Prognose wesentlich verbessern können. Während der Lebertransplantation kommt es immer wieder zu bedrohlichem intraoperativem Blutverlust, der sowohl die Kurz- als auch die Langzeitprognose der Lebertransplantierten entscheidend beeinflussen kann. Ziel war es, die pathophysiologischen Hämostasevorgänge bei OLT weitergehend zu untersuchen und Möglichkeiten der therapeutischen Beeinflussung zu erarbeiten. Es konnte gezeigt werden, daß sich der erhöhte Blutverlust während der anhepatischen Phase durch eine gesteigerte fibrinolytische Aktivität erklärt und daß dabei sowohl das extrinsische Fibrinolysesystem mit dem Gewebeplasminogenaktivator t-PA als auch das intrinsische Fibrinolysesystem mit urokinase-type PA (u-PA) und dem FXII-abhängigen PA beteiligt sind. Zur Bestimmung des letzteren wurde eine chromogene Substratmethode entwickelt. Venöse Stauung, Kontaktaktivierung beim Passieren des Blutes durch den veno-venösen Bypass, fehlende hepatische Clearance sind dabei die wichtigsten Auslösefaktoren. In der Reperfusionsphase konnten Zeichen einer gesteigerten Prothrombinaktivierung gemessen werden, so daß DIC-artige Hämostaseveränderungen für die postreperfusionellen Blutverluste verantwortlich gemacht werden. Eine Korrelation zur anhepatischen Fibrinolyse besteht nicht. Die Spenderleber spielt eine entscheidene Rolle bei den postreperfusionellen Hämostaseveränderungen. Leukozytäre Aktivierungsprodukte wie extrazelluläre Proteinasen und Zytokine werden aus der Spenderleber freigesetzt und stören systemisch das hämostatische Gleichgewicht. Parallel kommt es nach Reperfusion zu einer Verminderung der Thrombozytenzahl und ihrer Aggregabilität. Diese scheint partiell durch die aggregationshemmende Wirkung der University of Wisconsin Konservierungslösung bedingt zu sein, in der die Spenderleber bis zur Transplantation aufbewahrt wird. Die Gabe des Proteaseninhibitors Aprotinin scheint Hyperfibrinolysezeichen, maximalen Anstieg der t-PA Aktivität, Transfusionsbedarf und endotheliale Schäden in der Spenderleber zu reduzieren, wobei in einer offenen und randomisierten Studie der Vorteil einer kontinuierlichen Infusionsgabe gegenüber einer dreimaligen Bolusgabe deutlich wurde. In einer weiteren offenen und randomisierten Therapiestudie wurde versucht durch intraoperative Prostaglandin E1(PG E1)- Gabe endotheliale Aktivierungsprozesse in der Spenderleber zu beeinflussen. Tatsächlich führte eine PGE1-Infusion zu einem signifikant schwächeren postreperfusionellen Abfall sowohl der Thrombozytenzahl als auch der thrombozytären Aggregationsfähigkeit. / The orthotopic liver transplantation (OLT) has become an established method in the treatment of end stage liver disease and has ameliorated its prognosis substantially. During liver transplantation severe haemorrhage intraoperatively clearly influences the patient´s short and long-term outcome. The pathophysiology of hemostasis during OLT was studied and new strategies of therapy developed. It could be demonstrated that the high blood loss during the anhepatic phase is caused by increased fibrinolytic activity involving the extrinsic fibrinolytic system with tissue-type plasminogen activator (t-PA) as well as the intrinsic fibrinolytic system with urokinase-type PA (u-PA) and the FXII-dependent PA. For the easier determination of the later a chromogenic substrate method was developed. High venous pressure, contact activation initiated by the contact of the patient's blood with the veno-venous bypass and the lack of hepatic clearance are the main initiating factors of fibrinolysis during the anhepatic phase. In the reperfusion phase signs of increased prothrombin activation could be measured so that a DIC-like constellation could be made responsible for the blood loss after reperfusion of the graft liver. There was no correlation to the preceding anhepatic fibrinolysis. The graft liver plays an important role in inducing hemostatic disturbances during reperfusion. Activation products of leukocytes like extracellular proteinases and cytokines are released out of the graft liver and seem to induce hemostatic imbalances systemically. In parallel there is a decrease of platelet count and platelet aggregability. This seems to be induced in part by the University of Wisconsin solution in which the graft liver is kept until transplantation. Aprotinin, a protease inhibitor, given during OLT seems to reduce signs of hyperfibrinolysis, maximal t-PA values, transfusion requirements and endothelial damage of the graft´s liver vascular bed. In an open and randomised clinical trial the advantage of a continuous aprotinin infusion in comparison to a three times bolus application was demonstrated. In another open and randomised study prostaglandin (PG)E1 was given in order to influence endothelial activation processes in the graft liver. The administration of PGE1 was leading to a significant lower decrease of platelet count and platelet aggregability.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Kalp ve Damar Cerrahisi Anabilim Dalı, 2006. / Bibliyografya var.

The overall objective of this study was to investigate how NS0 cell proliferation is regulated in protein-free media. The hypothesis was that during the adaptation to growth factor-free media, animal cell lines start to produce their own autocrine growth factors to support proliferation, and after some time in a culture the effects of these factors are lost which results in cessation of proliferation. A chemically defined, protein-free and animal component-free medium was developed for the NS0 cells. This medium was comprised of a basal hybridoma medium to which phosphatidyl¬choline, cholesterol, β-cyclodextrin, ferric citrate and amino acids were added. A fed-batch process was then developed in this medium. The feed profile was optimised in a step-wise manner with a final feed solution containing glucose, glutamine, lipids, amino acids, vitamins, sodium selenite and ethanolamine. Specifically, supplementation with lipids (cholesterol) had a drastic effect on cell growth. Calcium, magnesium and potassium were not depleted during culture and a feed containing also iron, lithium, manganese, phosphorous and zinc did not significantly enhance the cell yield further. More than 8 x 106 viable cells mL-1 and 600 mg antibody L-1 was obtained in the final fed-batch. This corresponded to a 4.3-fold increase in viable cell yield and an 11.4-fold increase in product yield compared to bioreactor batch culture when the dilution of the fed-batch culture was also accounted for. The presence of autocrine growth factors in NS0 cell cultures was initially investigated by studying the effects of conditioned medium (CM). Concentrated CM had a significant positive effect on cell growth and part of this effect could be attributed to factor(s) eluting from a gel-filtration column at 20-25 kDa. In the search for cell-derived factors affecting cell growth the following proteins were identified as released/secreted by the NS0 cells; cyclophilin A, cyclophilin B, cystatin C, D-dopachrome tautomerase, IL-25, isopentenyl-diphosphate delta-isomerise, macrophage migration inhibitory factor (MIF), β2-microglobulin, niemann pick type C2, secretory leukocyte protease inhibitor (SLPI), thioredoxin-1, TNF-α, tumour protein translationally controlled-1 and ubiquitin. Zymogram electrophoresis further identified aspartic acid, papain-like cysteine (including cathepsin L) and serine protease activity in the CM. Pro/cathepsin L, CypB, EGF, IFN-α/β/γ, IGF-I/II, leukaemia inhibitory factor, IL-6, IL-11, IL-25, MIF, oncostatin M, TGF-β and TNF-α were excluded as involved in autocrine regulation of NS0 cell proliferation. The serine protease activity was suggested to affect the cells negatively and since the serine protease inhibitor SLPI is also present in NS0 CM, a balance in serine protease activity may be crucial for optimal cell growth. Further, the receptor gp130, known to be associated with myeloma cell growth, was shown to be essential for NS0 cell proliferation as demonstrated by siRNA gene silencing. The results suggested that autocrine regulation of proliferation in NS0 cell cultures involves the receptor subunit gp130. / QC 20100920

Introdução. A Aprotinina parece reduzir o uso de transfusões, o processo inflamatório e o dano miocárdico, pós-CEC. Material e Métodos. Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada imediatamente antes da CEC. A resposta inflamatória sistêmica e disfunções hemostáticas e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com p<0,05. Resultados. Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no CTIP e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24 h PO, no Grupo Controle. Ocorreu preservação da concentração plaquetária com a Aprotinina enquanto no grupo Controle houve plaquetopenia desde o início da CEC. As perdas sangüíneas foram semelhantes nos dois grupos. No grupo Aprotinina surgiu leucopenia significativa, em CEC, seguida de leucocitose. Fator de necrose tumoral alfa (TNF-) , Interleucinas (IL)-6, IL-8, IL-10, proporção IL-6/IL-10, troponina I cardíaca (cTnI), fração MB da creatinofosfoquinase (CKMB), transaminase glutâmico-oxalacética (TGO) e fração amino-terminal do peptídio natriurético tipo B (NT-proBNP) não apresentaram diferenças marcantes intergrupos. A proporção IL-6/IL-10 PO aumentou no grupo Controle. A lactatemia e acidose metabólica pós-CEC foi mais intensa no grupo Aprotinina. Não houve complicações com o uso da Aprotinina. Conclusão. A Aprotinina não minimizou as manifestações clínicas e os marcadores séricos de resposta inflamatória sistêmica e miocárdicos, mas preservou quantitativamente as plaquetas. / Introduction. Aprotinin seems to reduce the need for transfusion, the inflammatory process and myocardial damage after extracorporeal circulation (ECC). Material and Methods. A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered immediately before ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. Results. The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of hospitalization, or regarding the use of inotropic drugs and renal function. The partial arterial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) was significantly reduced 24 h after surgery in the Control Group. Platelet concentration was preserved with the use of Aprotinin, whereas thrombocytopenia occurred in the Control Group since the beginning of ECC. Blood loss was similar for both groups. Significant leukopenia was observed in the Aprotinin Group during ECC, followed by leukocytosis. Tumor necrosis factor alpha (TNF-), interleukins (IL)-6, IL-8, IL-10, IL-6/IL-10 ratio, cardiac troponin I (cTnI), creatine kinase MB fraction (CKMB), glutamic-oxaloacetic transaminase (GOT) and the aminoterminal fraction of natriuretic peptide type B (NT-proBNP) ndid not differ significantly between groups.The postoperative IL-6/IL-10 fraction increased significantly in the Control Group. Post-ECC blood lactate concentration and metabolic acidosis was more intense in the Aprotinin Group. There were no complications with the use of Aprotinin. Conclusion. Aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory, systemic and myocardial response, but quantitatively preserved the platelets.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(論文) 学位授与年月日:平成3年2月1日 服部寿門氏の博士論文として提出された

Introdução. A Aprotinina parece reduzir o uso de transfusões, o processo inflamatório e o dano miocárdico, pós-CEC. Material e Métodos. Estudo prospectivo randomizado em crianças de 30 dias a 4 anos de idade, submetidas à correção de cardiopatia congênita acianogênica, com CEC e divididas em dois grupos, um denominado Controle (n=9) e o outro, Aprotinina (n=10). Neste, a droga foi administrada imediatamente antes da CEC. A resposta inflamatória sistêmica e disfunções hemostáticas e multiorgânicas foram analisadas por marcadores clínicos e bioquímicos. Foram consideradas significantes as diferenças com p<0,05. Resultados. Os grupos foram semelhantes quanto às variáveis demográficas e intra-operatórias, exceto por maior hemodiluição no Grupo Aprotinina. Não houve benefício quanto aos tempos de ventilação pulmonar mecânica, permanência no CTIP e hospitalar, nem quanto ao uso de inotrópicos e função renal. A relação PaO2/FiO2 (pressão parcial de oxigênio arterial/fração inspirada de oxigênio) apresentou queda significativa com 24 h PO, no Grupo Controle. Ocorreu preservação da concentração plaquetária com a Aprotinina enquanto no grupo Controle houve plaquetopenia desde o início da CEC. As perdas sangüíneas foram semelhantes nos dois grupos. No grupo Aprotinina surgiu leucopenia significativa, em CEC, seguida de leucocitose. Fator de necrose tumoral alfa (TNF-) , Interleucinas (IL)-6, IL-8, IL-10, proporção IL-6/IL-10, troponina I cardíaca (cTnI), fração MB da creatinofosfoquinase (CKMB), transaminase glutâmico-oxalacética (TGO) e fração amino-terminal do peptídio natriurético tipo B (NT-proBNP) não apresentaram diferenças marcantes intergrupos. A proporção IL-6/IL-10 PO aumentou no grupo Controle. A lactatemia e acidose metabólica pós-CEC foi mais intensa no grupo Aprotinina. Não houve complicações com o uso da Aprotinina. Conclusão. A Aprotinina não minimizou as manifestações clínicas e os marcadores séricos de resposta inflamatória sistêmica e miocárdicos, mas preservou quantitativamente as plaquetas. / Introduction. Aprotinin seems to reduce the need for transfusion, the inflammatory process and myocardial damage after extracorporeal circulation (ECC). Material and Methods. A prospective randomized study was conducted on children aged 30 days to 4 years submitted to correction of acyanogenic congenital heart disease with ECC and divided into two groups: Control (n=9) and Aprotinin (n=10). In the Aprotinin Group the drug was administered immediately before ECC and the systemic inflammatory response and hemostatic and multiorgan dysfunctions were analyzed on the basis of clinical and biochemical markers. Differences were considered to be significant when P<0.05. Results. The groups were similar regarding demographic and intraoperative variables, except for a greater hemodilution in the Aprotinin Group. The drug had no benefit regarding time of mechanical pulmonary ventilation, permanence in the postoperative ICU and length of hospitalization, or regarding the use of inotropic drugs and renal function. The partial arterial oxygen pressure/inspired oxygen fraction ratio (PaO2/FiO2) was significantly reduced 24 h after surgery in the Control Group. Platelet concentration was preserved with the use of Aprotinin, whereas thrombocytopenia occurred in the Control Group since the beginning of ECC. Blood loss was similar for both groups. Significant leukopenia was observed in the Aprotinin Group during ECC, followed by leukocytosis. Tumor necrosis factor alpha (TNF-), interleukins (IL)-6, IL-8, IL-10, IL-6/IL-10 ratio, cardiac troponin I (cTnI), creatine kinase MB fraction (CKMB), glutamic-oxaloacetic transaminase (GOT) and the aminoterminal fraction of natriuretic peptide type B (NT-proBNP) ndid not differ significantly between groups.The postoperative IL-6/IL-10 fraction increased significantly in the Control Group. Post-ECC blood lactate concentration and metabolic acidosis was more intense in the Aprotinin Group. There were no complications with the use of Aprotinin. Conclusion. Aprotinin did not minimize the clinical manifestations or serum markers of the inflammatory, systemic and myocardial response, but quantitatively preserved the platelets.