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PubMed1989

[Lactate dehydrogenase isoenzymes in radiation therapy of cancer patients].

Changes in the lactate dehydrogenase (LDH) isozymic spectrum have been examined in the patients with Stages I-III malignant tumors of the uterus before radiation therapy, during radiation reactions, and after these reactions have been remedied with polydesum and aminocaproic acid. A comparative analysis has shown that the blood serum LDH isozymic spectrum is changed in oncologic patients mainly at the expense of increased content of LDH4 and LDH5. Radiation reactions are associated with a considerable reduction of LDH1 activity and an essential rise of LDH3 and LDH4 activities, and an insignificant elevation of LDH2. The detected shifts in LDH isozymic spectrum during radiation reactions appear to be due to radiation toxemia. Detoxifying therapy with polydesum and epsilon-aminocaproic acid during 3-5 days helped normalize the LDH isozymic ratio.

Aged↗
PubMed1985

Quantitative characterization of the binding of plasminogen to intact fibrin clots, lysine-sepharose, and fibrin cleaved by plasmin.

The binding of human Glu- and Lys-plasminogens to intact fibrin clots, to lysine-Sepharose, and to fibrin cleaved by plasmin was quantitatively characterized. On intact fibrin clots, there was one strong binding site for Glu-plasminogen with a dissociation constant, Kd, of 25 microM and one strong binding site for Lys-plasminogen with a Kd of 7.9 microM. In both cases, the number of plasminogen binding sites per fibrin monomer was 1. Also, a much weaker binding site for Glu-plasminogen was observed with a Kd of about 350 microM. Limited digestion of fibrin by plasmin created additional binding sites for plasminogen with Kd values similar to the binding of plasminogen to lysine-Sepharose. This was predictable given the observations that plasminogen binds to lysine-Sepharose and can be eluted with epsilon-aminocaproic acid [Deutsch, D.G., & Mertz, E.T. (1970) Science (Washington, D.C.) 170, 1095-1096] and that plasmin preferentially cleaves fibrin at the carboxy side of lysyl residues [Weinstein, M.J., & Doolittle, R.F. (1972) Biochim. Biophys. Acta 258, 577-590], because the structures of the lysyl moiety in lysine-Sepharose and of epsilon-aminocaproic acid are identical with the structure of a COOH-terminal lysyl residue created by plasmin cleavage of fibrin. The Kd for the binding of Glu-plasminogen to lysine-Sepharose was 43 microM and for fibrin partially cleaved by plasmin 48 microM. The Kd for the binding of Lys-plasminogen to lysine-Sepharose was 30 microM. With fibrin partially cleaved by plasmin, there were two types of binding sites for Lys-plasminogen, one with a Kd of 7.6 microM and the other with a Kd of 44 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1985

Assay of human fibrinopeptides by high-performance liquid chromatography.

Fibrinopeptides A, AP, and B, desarginine fibrinopeptide B, and a previously unknown peptide corresponding to B beta 3-14 were resolved within 10 min by an HPLC technique using an isocratic solvent system (22% acetonitrile in 0.1% trifluoroacetic acid) and a 0.46 X 10-cm Spherisorb ODS-2 (3-micron) octadecylsilane column. Fibrinopeptides A and AY eluted in the same peptide peak. The method was used to evaluate a carboxypeptidase which converts fibrinopeptide B into its desarginine form. Fifty percent inhibition of this activity occurred at 1.7 mM epsilon-aminocaproic acid (EACA). At saturating substrate concentrations the rates of total fibrinopeptides A and B release were unaffected by 125 mM EACA, a concentration at which the carboxypeptidase activity is completely inhibited.

Amino Acid Sequence↗
PubMed2005

Heparin-bonded cardiopulmonary bypass circuits reduce the rate of red blood cell transfusion during elective coronary artery bypass surgery.

OBJECTIVE: This study compared the transfusion rates of patients treated with heparin-bonded circuits with the transfusion rates of patients treated with standard bypass circuits with and without -aminocaproic acid (EACA). DESIGN: Prospective double-blind (drugs), open trial (cardiopulmonary bypass circuits). SETTING: University medical center. PARTICIPANTS: Seventy-one patients undergoing elective am admission coronary artery bypass graft surgery. MEASUREMENTS AND MAIN RESULTS: Patients were randomized to receive either heparin-coated cardiopulmonary bypass circuits (HBCPB), nonheparin-coated cardiopulmonary bypass circuits and EACA (EACPB), or nonheparin-coated bypass circuits and placebo (control). Patients were transfused if their hematocrit was <18% while on cardiopulmonary bypass or <25% at any time after the cardiopulmonary bypass period. The rate and number of transfused packed red blood cells (pRBCs), platelets, fresh frozen plasma, and cryoprecipitate were measured. A Fisher exact test showed that the transfusion rate was as follows: the HBCPB group (5.0%), the EACPB group (18.2%), and the control group (36%), (p = 0.034). CONCLUSIONS: The heparin-bonded cardiopulmonary bypass-treated patients in this study received fewer pRBCs than did the control group. A nonsignificant reduction in the pRBC transfusion rate was found between those with heparin-bonded bypass circuits and those with standard circuits who received epsilon-aminocaproic acid.

Aged↗
PubMed1977

Purification and some properties of the Glu- and Lys-human plasmin heavy chains.

The heavy polypeptide chains of human Glu-plasmin and human Lys-plasmin have been isolated in native solvents, after partial reduction and carboxymethylation of the corresponding plasmins. Two major forms of each heavy chain can be eluted, after adsorption to Sepharose/lysine, utilizing a gradient of epsilon-aminocaproic acid as the eluant. The elution profile of these heavy chains is practically identical to the elution behavior previously observed for human Glu- and Lys-plasminogen, and human Glu- and Lys-plasmin adsorbed to these columns. Sedimentation velocity analysis of the heavy chain of human Glu-plasmin, in the presence of epsilon-aminocaproic acid, demonstrated that a gross conformational alteration occurs in this peptide accompanying binding of this amino acid. A much smaller conformational alteration occurs under similar circumstances with the human Lys-plasmin heavy chain. We find that the NH2-terminal peptide released in the Glu-plasminogen to Lys-plasminogen and Glu-plasmin to Lys-plasmin conversions is also released in the Glu-plasmin heavy chain to Lys-plasmin heavy chain conversion. This reaction is catalyzed at a significant rate only by plasmin and not by urokinase. Finally, no strong interaction between streptokinase and the isolated plasmin heavy chains is observed.

Fibrinolysin↗
PubMedDate not supplied

Comparative studies on the amino acid derivatives of indometacin.

A series of amino acid derivatives of indometacin (IND) was investigated in regard to their protein binding and prostaglandin synthetase inhibition in vitro, and to acute toxicity, anti-inflammatory, antiedemic, analgesic actions, and the influence on the central nervous system in vivo. In biochemical tests the compounds were several times less potent than IND. They differed among themselves in the respect of toxicity, which was always much lower than that of IND. Out of eight compounds investigated N-IND-glycine (K1) and N-IND-epsilon-aminocaproic acid (K5) exerted more favorable antiedemic and analgesic action than IND did. Both the derivatives only weakly inhibited the cotton-pellet granuloma formation. K1 acted similarly to IND in the arthritis test. K1, K5 and IND similarly irritated the gastric mucosa. A modification of IND structure by introduction of glycine or epsilon-aminocaproic acid resulted in two new anti-inflammatory agents of more favorable therapeutic index in the antiedemic and analgesic action and of much lower toxicity than the reference compound.

Amino Acids↗
PubMed2003

Electrochemiluminescence assay for basic carboxypeptidases: inhibition of basic carboxypeptidases and activation of thrombin-activatable fibrinolysis inhibitor.

Carboxypeptidases catalyze the removal of the C-terminal amino acid residues in peptides and proteins and exert important biological functions. Assays for carboxypeptidase activity that rely on change of absorbance generally suffer from low sensitivity and are difficult to adapt to high-throughput screening. We have developed a sensitive, robust assay for basic carboxypeptidase activity that makes use of electrochemiluminescent (ECL) detection of reaction product. In this assay, a peptide substrate contains the epitope for antibody (G2-10) binding which is masked by a C-terminal arginine. Carboxypeptidase activity exposes the epitope, allowing the binding of ruthenylated G2-10 which is then detected using ECL. High sensitivity allowed detection limits of 1-2 pM enzyme for carboxypeptidase B and activated thrombin-activatable fibrinolysis inhibitor (TAFIa). The inhibition of several basic carboxypeptidases by commercially available inhibitors was studied. This antibody-based method can be extended to other sensitive detection techniques such as amplified luminescent proximity homogeneous assay. The high sensitivity of the assay allowed the determination of the activatable levels of TAFI in human and other animal plasma in the presence of epsilon -aminocaproic acid, an active-site inhibitor that stabilizes TAFIa. A method to isolate in situ activated TAFIa from human serum in the presence of epsilon -aminocaproic acid was also developed.

Animals↗
PubMed1973

Plasmin-induced platelet aggregation and platelet release reaction. Effects on hemostasis.

Trypsin-activated pig plasmin and human plasmin activated by streptokinase (SK) caused aggregation of a suspension of washed platelets from human, rabbit, or pig blood. The platelet aggregation was reversible, but it was accompanied by a significant release of adenine nucleotides, serotonin, and platelet fibrinogen. Platelet fibrinogen was eventually digested. The effect of plasmin on platelets was inhibited by soybean trypsin inhibitor, epsilon aminocaproic acid, Persantin, prostaglandin E(1), and phenylbutazone. Short treatment of platelets with plasmin enhanced their sensitivity to ADP; however, this sensitivity was lost during longer incubation with plasmin. This enzyme also made platelets less sensitive to collagen and thrombin. Injecting SK into rabbits (10,000 U/kg body weight) caused a transitory drop of platelet count. These platelets lost part of their serotonin and fibrinogen. The administration of Persantin or of epsilon aminocaproic acid to rabbits before the injection of SK protected platelets from the loss of serotonin. Pretreatment with Persantin also resulted in partial protection of platelet fibrinogen in rabbits injected with SK. Platelets obtained from rabbits that had received both Persantin and SK were much more reactive with collagen than platelets obtained from rabbits injected with SK alone. Rabbits pretreated with Persantin did not show prolongation of the primary bleeding time that occurred after SK injection to control rabbits. It is suggested that plasmin generated after SK injection causes platelet release reaction in vivo. This may contribute to the hemostatic defect occurring during thrombolytic therapy or during systemic activation of fibrinolysis due to the other factors.

Adenine Nucleotides↗
PubMed1979

Cyclized dipeptide model for a beta-bend.

A cyclic dipeptide in which L-Ala-Gly was cyclized with epsilon-aminocaproic acid has been synthesized as a model for a beta-bend. Its conformational properties have been examined by means of conformational energy calculations and nuclear magnetic resonance, infrared, Raman, and circular dichroism spectroscopy in various solvents. These calculations and experiments suggest that a type II beta-bend exists in the Ala-Glymoiety, with an NH...O = C hydrogen bond in the epsilon-aminocaproic acid portion of the molecule, and that the molecule adopts a unique conformation in solution. In contrast, an open-chain analog of this compound exists in solution as an ensemble of conformations but with a significant amount of a type II beta-bend structure in the ensemble.

Circular Dichroism↗
PubMed2004

Identification of sequences in apolipoprotein(a) that maintain its closed conformation: a novel role for apo(a) isoform size in determining the efficiency of covalent Lp(a) formation.

We have previously demonstrated that, in the presence of the lysine analogue epsilon-aminocaproic acid, apolipoprotein(a) [apo(a)] undergoes a conformational change from a closed to an open structure that is characterized by a change in tryptophan fluorescence, an increase in the radius of gyration, an alteration of domain stability, and an enhancement in the efficiency of covalent lipoprotein(a) [Lp(a)] formation. In the present study, to identify sequences within apo(a) that maintain its closed conformation, we used epsilon-aminocaproic acid to probe the conformational status of a variety of recombinant apo(a) isoforms using analytical ultracentrifugation, differential scanning calorimetry, intrinsic fluorescence, and in vitro covalent Lp(a) formation assays. We observed that the closed conformation of apo(a) is maintained by intramolecular interaction(s) between sequences within the amino- and carboxyl-terminal halves of the molecule. Using site-directed mutagenesis, we have identified the strong lysine-binding site present within apo(a) kringle IV type 10 as an important site within the C-terminal half of the molecule, which is involved in maintaining the closed conformation of apo(a). Apo(a) exhibits marked isoform size heterogeneity because of the presence of varying numbers of copies of the kringle IV type-2 domain located within the amino-terminal half of the molecule. Using recombinant apo(a) species containing either 1, 3, or 8 copies of kringle IV type 2, we observed that, while apo(a) isoform size does not alter the affinity of apo(a) for low-density lipoprotein, it affects the conformational status of the protein and therefore influences the efficiency of covalent Lp(a) assembly. The inverse relationship between apo(a) isoform size and the efficiency of covalent Lp(a) formation that we report in vitro may contribute to the inverse relationship between apo(a) isoform size and plasma Lp(a) concentrations that has been observed in vivo.

Amino Acid Sequence↗
PubMedDate not supplied

Systemic hemostatic medications for reducing surgical blood loss.

OBJECTIVE: To review randomized trials involving the use of systemic hemostatic medications for reducing surgical blood loss. DATA SOURCES: Articles were obtained through searches of MEDLINE (1966-September 2000). The bibliographies of retrieved publications were reviewed for additional references. STUDY SELECTION: All randomized studies and pharmacoeconomic evaluations that involved medications used for systemic hemostasis in the perioperative period were included. DATA EXTRACTION: Randomized studies involving conjugated estrogens, aminocaproic acid, tranexamic acid, desmopressin, and aprotinin for systemic hemostasis were extracted. Studies of proton-pump inhibitors for upper gastrointestinal bleeding and octreotide for variceal bleeding were excluded, as were trials involving the use of any hemostatic agent for cardiovascular surgery. The primary outcome under review was a reduction in bleeding as defined by reduced transfusion requirements. DATA SYNTHESIS: There is limited efficacy and toxicity information concerning the use of conjugated estrogens for reducing surgery-related bleeding. Similarly, there are a limited number of randomized studies involving aminocaproic acid and tranexamic acid, and with the exception of tranexamic acid for reducing transfusion requirements with knee surgery, the study results are either conflicting or negative. For desmopressin, evidence from a substantial number of randomized trials documents its lack of efficacy. Aprotinin has reduced bleeding and transfusion requirements in a number of randomized studies involving patients undergoing orthopedic surgery, but cost-effectiveness studies are needed to better define its therapeutic role. Trials of aprotinin during hepatic surgery have yielded conflicting results. CONCLUSIONS: Most hemostatic medications used for reducing surgery-related bleeding have limited or contradictory evidence of efficacy.

Adult↗
PubMed1979

Evidence that protease inhibitors reduce the degradation of parathyroid hormone and calcitonin injected subcutaneously.

1 Agents known to delay absorption from a subcutaneous site were tested in chicks for their ability to prolong the hypercalcaemic response to parathyroid hormone (PTH). 2 Polyvinylpyrrolidone was found to enhance the response but gelatine greatly reduced the 2 h hypercalcaemia. 3 The reduction by gelatine was reversed when the protease inhibitor aprotinin was added to the injection vehicle, and hypercalcaemia then persisted for more than 8 h. 4 Of other protease inhibitors studied, epsilon-aminocaproic acid was also found to enhance the hypercalcaemic response to subcutaneous PTH and its fragments but, unlike aprotinin, it was ineffective in the presence of gelatine. 5 By radioimmunoassay and bioassay respectively, it was confirmed that aprotinin raised circulating levels of PTH and also of another peptide hormone, calcitonin, injected subcutaneously. 6 Addition of calcium to the solutions injected subcutaneously abolished the hypercalcaemic response to PTH while injection of calcium and PTH simultaneously but at separate sites left the response unaltered. 7 The two protease inhibitors, epsilon-aminocaproic acid and aprotinin, each restored the response to subcutaneous PTH despite the presence of calcium at the injection site. 8 It was concluded that protease inhibitors injected subcutaneously with PTH and calcitonin in the chick reduced the rate of degradation of these hormones and that the proteases responsible for hormone degradation at the subcutaneous injection site may be released or activated by calcium ions.

Animals↗
PubMed1995

Tissue-type plasminogen activator (tPA) interacts with urokinase-type plasminogen activator (uPA) via tPA's lysine binding site. An explanation of the poor fibrin affinity of recombinant tPA/uPA chimeric molecules.

Differential scanning calorimetry was used to study the domain structure and intramolecular interactions of tPA/uPA chimeras. A high temperature transition centered near 90 degrees C was observed upon melting of the tPA/uPA chimera (amino acids 1-274 of tPA and 138-411 of uPA) and its variant lacking the finger and epidermal growth factor-like modules (residues 1-3 and 87-274 of tPA and 138-411 of uPA). Since neither of the two parent plasminogen activators display such a stable structure, one may suggest that a new stabilizing intramolecular interaction occurs in the chimeras. We found that occupation of the lysine binding site of tPA by a lysine or arginine side chain from the urokinase moiety is responsible for the high temperature transition as well as for the failure of the chimeras to exhibit the expected fibrin binding properties. All uPA species, single- and two-chain high molecular weight uPA (Pro-Uk and HMW-Uk) and two-chain low molecular weight uPA (LMW-Uk), interact intermolecularly with tPA and its kringle-containing derivatives. This intermolecular interaction was strongly inhibited by epsilon-aminocaproic acid indicating that the lysine binding site of tPA is involved. The binding of uPA with the fluorescein-labeled A-chain of tPA, registered by changes in fluorescence anisotropy, was estimated to have a Kd range of 1-7 microM. The interaction of tPA with uPA determined by solid-phase assays appeared to be tighter, with a Kd range of 50-300 nM. Two synthetic peptides, with and without carboxyl-terminal lysine, corresponding to urokinase residues 144-158 and 144-157, were approximately 100-fold more potent than epsilon-aminocaproic acid with respect to inhibition of the tPA-uPA interaction, indicating that the tPA binding site on urokinase is located within this sequence, close to the activation site Lys158-Ile159. The discovered intermolecular interaction may be related to the reported synergistic effect of simultaneous administration of these two plasminogen activators.

Amino Acid Sequence↗
PubMed2004

Photo-induced processes in vitamin B6 compounds.

In this work, we applied multi-wavelength stopped-flow spectroscopy (MSFS) to study the chemical equilibria between tautomeric or hydrated forms of various vitamin B6 compounds and the Schiff base formed by epsilon-aminocaproic acid (= 6-aminohexanoic acid) with pyridoxal 5'-phosphate at 25 degrees and variable pH. Since some of these compounds are photosensitive, we analyzed the possible occurrence of any secondary photo-induced processes under the conditions of irradiation in the MSFS equipment (continuous irradiation with light from a 75-W Xe lamp spanning the wavelength range of 200-700 nm). To determine the tautomeric composition of these compounds, the electronic absorption spectra were analyzed by means of log-normal curves. Continuous irradiation of pyridoxamine and pyridoxal 5'-phosphate over the wavelength range of 200-700 nm displaces the chemical equilibrium between the tautomeric or hydrated forms of these compounds. However, the Schiff base of epsilon-aminocaproic acid with pyridoxal 5'-phosphate is insensitive to the radiation used. The photo-induced processes detected in pyridoxamine and pyridoxal 5'-phosphate should be taken into account in examining vitamers by MSFS. In fact, these additional processes should be considered in studying the mechanism of action of vitamin B6-dependent enzymes by the MSFS technique, whenever some free vitamer may be present in solution.

Light↗
PubMed1987

Analysis of ligand-binding to the kringle 4 fragment from human plasminogen.

The interaction of the isolated human plasminogen kringle 4 with the four omega-amino acid ligands epsilon-aminocaproic acid (epsilon ACA), N alpha-acetyl-L-lysine (AcLys), trans-aminomethyl(cyclohexane)carboxylic acid (AMCHA) and p-benzylaminesulfonic acid (BASA) has been further characterized by 1H-NMR spectroscopy at 300 and 600 MHz. Pronounced high-field shifts, reaching approximately 3 ppm, are observed for AMCHA resonances upon binding to kringle 4, which underscores the relevance of ligand lipophilic interactions with aromatic side chains at the binding site. Ligand titration curves for the nine His and Trp singlets found in the kringle 4 aromatic spectrum reveal a striking uniformity in the kringle response to the various ligands. The average binding curves exhibit a clear Langmuir absorption isotherm saturation profile and the data were analyzed under the assumption of one (high affinity) binding site per kringle. Equilibrium association constants (Ka) and first order dissociation rate constants (k off) were derived from linearized expressions of the Langmuir isotherm and of the spectral line-shapes, respectively. The results for the four ligands, at approximately 295 K, pH 7.2, indicate that: AMCHA exhibits the strongest binding (Ka = 159 mM-1) and epsilon ACA the weakest (Ka = 21 mM-1) with AcLys and BASA falling in between; epsilon ACA dissociates readily (k off = 5.3 X 10(3) s-1) and AMCHA associates the fastest (k on = 2.0 X 10(8) M-1 s-1) while the kinetics for BASA exchange is relatively slow (k off = 0.8 X 10(3) s-1, k on = 0.6 X 10(8) M-1 s-1); the ligand-binding kinetics is close to diffusion-controlled.

Aminocaproates↗
PubMed1996

[Reduction of blood loss in orthotopic liver transplantation with the use of aprotinin].

UNLABELLED: The impact of aprotinin on blood losses during orthotopic liver transplantation (OLT) has been studied retrospectively. PATIENTS AND METHODS: From September 1984 to July 1995, 152 patients underwent 168 OLT in our center. Seventy three patients (group I) received epsilon-aminocaproic acid as an antifibrinolytic agent and 95 patients (group II) received aprotinin. RESULTS: There was a significant reduction in the mean duration of the surgery (I = 743 +/- 25 min; II = 302 +/- 10 min; p < 0.001) and in the post reperfusion time (I = 282 +/- 13 min; II = 126 +/- 6 min; p < 0.001) in the group II. The need for blood products during the operation was also reduced (blood units; I = 21.7 +/- 2.3 units; II = 4.6 +/- 0.4 units; p < 0.001). There was less infectious and hemorrhagic complications requiring reoperation in group II. We have not seen an increased incidence of thrombotic complications in the patients receiving aprotinin. Other variables such as the use of hemoclips, veno-venous bypass and the type of preservation solution were also considered. CONCLUSION: Aprotinin use during OLT is efficient and superior to epsilon-aminocaproic acid in reducing blood losses. Combined with the non-utilisation of a veno-venous by-pass and the use of hemoclips, it helps reduce the operating time and the postoperative complications.

Adult↗
PubMed2001

A cohort study of coagulation parameters and the use of blood products in surgery of the thoracic and thoracoabdominal aorta.

OBJECTIVES: We sought to study the hemostatic profile and the use of blood products in patients undergoing thoracic and thoracoabdominal aortic aneurysm repair. METHODS: This is a cohort study comparing three groups of patients: 7 undergoing elective acute normovolemic hemodilution (ANH); 15 undergoing elective procedures without ANH (non-ANH); and 8 undergoing repair of ruptured thoracoabdominal aneurysms. A control group of 10 patients was used for comparison of preoperative hemostasis. The parameters studied were platelet concentration, partial thromboplastin time (PTT), and international normalized ratio (before and after surgery), packed red blood cells, fresh frozen plasma, platelets, cryoprecipitates, donor exposure, and use of desmopressin and epsilon-aminocaproic acid. Analysis of variance and multiple stepwise regression analysis were used. RESULTS: Before operation the patients with aneurysms had PTTs prolonged compared with control subjects (P <.05). After operation the ANH group had higher platelet counts than the ruptured group (P =.001) and higher platelet counts (P =.05) and lower PTTs (P =.001) than the non-ANH group. The ANH group was transfused fewer platelets than the non-ANH group (P =.001) and less of every blood product than the ruptured group (P =.05); statistically significant differences were not observed for packed red blood cells, fresh frozen plasma, or platelets. The ANH group was exposed to an average of 65 donors fewer than the ruptured group (P <.001) and 34 fewer than the non-ANH group (P <.05). These differences could not be explained by baseline coagulation status or by the intraoperative use of desmopressin or epsilon-aminocaproic acid. CONCLUSIONS: The coagulation abnormality identified before surgery is that of higher PTT values, suggesting a disturbance of the extrinsic coagulation pathway. Blood losses, donor exposure, and platelet use were highest in the ruptured group and lowest in the ANH group. After surgery the ruptured group exhibited the worst coagulation parameters, and the ANH group exhibited the best with higher platelet count and lower PTT values than the other groups. The ANH technique appears to be an useful adjunct in the anesthetic management of these patients.

Acute Disease↗
PubMed2005

Review and application of serine protease inhibition in coronary artery bypass graft surgery.

PURPOSE: Current pharmacologic agents, aprotinin, epsilon aminocaproic acid, and tranexamic acid, used to decrease blood loss and transfusion requirements during coronary artery bypass graft (CABG) surgery are discussed. Aprotinin is the only agent that also modulates the systemic inflammatory responses that are generated by contact activation during CABG surgery. These responses are largely mediated by serine proteases such as kallikrein, thrombin, and plasmin. SUMMARY: Aprotinin is a naturally occurring polypeptide that has a concentration-dependent effect to inhibit serine proteases. Two aprotinin dosing regimens are indicated in the United States (U.S.) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) during the course of CABG surgery. Serum concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin activity resulting in attenuation of the systemic inflammatory response to bypass, whereas serum concentrations achieved with the half-dose regimen only inhibit plasmin activity. The efficacy and safety of aprotinin have been studied in randomized controlled trials in over 5,000 patients. Aprotinin is well tolerated compared to placebo. Treatment-emergent adverse events are similar to those associated with CPB surgery. However, because aprotinin is a bovine protein, there is a small, but manageable risk of hypersensitivity reactions. Epsilon aminocaproic acid and tranexamic acid are lysine analogs that reduce bleeding by inhibiting the conversion of plasminogen to plasmin, a serine protease responsible for breaking down fibrinogen to fibrin. Although they are commonly used to decrease bleeding associated with CABG surgery with CPB, they are not currently approved by the U.S. Food and Drug Administration (FDA) for CABG surgery. CONCLUSION: Aprotinin is the only agent that has an FDA indication to prevent blood loss and transfusion during CABG surgery, and the additional benefit of attenuating the systemic inflammatory response associated with CABG with CPB.

Aprotinin↗