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At least 1,243 records · Page 69Linked to original sources
PubMed2005

Antifibrinolytic use and bleeding during surgery on the descending thoracic aorta: a multivariate analysis.

OBJECTIVES: The purpose of this study was to determine the potential benefit of antifibrinolytic (AF) therapy in improving hemostasis in descending aortic surgery in which extracorporeal distal perfusion is used. DESIGN: Retrospective database study. SETTING: University hospital. PARTICIPANTS: Seventy-two patients who underwent descending thoracic or thoracoabdominal aortic replacement during the period from January 1993 through December 1996 when the use of AF therapy was emerging. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Seventy-two records met criteria for inclusion. The use of AF therapy had no significant effect on any bleeding or transfusion outcome in any model. Excessive chest tube drainage postoperatively was independently associated with repeat surgery and intraoperative hypothermia. The risk of receiving a red blood cell (RBC) transfusion was independently predicted by low preoperative hemoglobin and age > or =65 years. Cross-clamp was an independent predictor of receiving a transfusion of non-RBC products (p = 0.03). CONCLUSIONS: The authors could not show a beneficial effect of AF therapy on bleeding and transfusion, although current practice shows that this therapy continues to be used. Because heterogeneity of patient population exists and bias cannot be completely excluded, a prospective investigation evaluating efficacy and safety in this population is warranted.

Aged↗
PubMed1985

Dental extractions in hemophilia: reflections on 10 years' experience.

During the past ten years we have witnessed a remarkable reduction in complications following dental extractions in patients with hemophilia. Thirty-six of 100 patients experienced delayed bleeding during the first half of this period; fourteen of 112 patients had a hemorrhagic problem after extraction during the second half. From a major undertaking involving hospitalization and general anesthesia, it has become a simple procedure in the outpatient office. During the entire period, no changes were made in the transfusion policy or in the oral administration of antifibrinolytic agents. Factors contributing to the favorable evolution have been the increasing experience of the oral surgeon, the improving dental status of our hemophilia patients, prophylactic measures to reduce gingival inflammation, and changes in the composition and amount of material used to pack the dental sockets.

Aminocaproic Acid↗
PubMed1996

Crystal structures of the recombinant kringle 1 domain of human plasminogen in complexes with the ligands epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic Acid.

The X-ray crystal structures of the complexes of the recombinant kringle 1 domain of human plasminogen (Klpg) with the ligands epsilon-aminocaproic acid (EACA) and trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (AMCHA), which are representative of a class of in vivo antifibrinolytic agents, have been determined at 2.1 angstroms resolution. Each Klpg/ligand unit cell contained a dimer of the complexes, and some small differences were noted in the kringle/ligand interatomic distances within the monomeric components of the dimers. The structures obtained allowed predictions to be made of the amino acid residues of Klpg that are likely important to ligand binding. In the crystal structure, the anionic center of Klpg responsible for coordinating the amino group of the ligands is composed of both Asp54 and Asp56, and the cationic center that stabilizes binding of the carboxylate moiety of the ligands is Arg70, with a possible contribution from Arg34. A hydrogen bond between the carboxylate of the ligand to the hydroxyl group of Tyr63 also appears to contribute to the kringle/ligand binding energies. The methylene groups of the ligand are stablized in the binding pocket by van der Waals contacts with side-chain atoms of Trp61 and Tyr71. These conclusions are in general agreement with site-directed mutagenesis results that implicate many of the same amino acid residues in the binding process, thus showing that the crystal and solution structures are in basic accord with each other. Further comparisons of the X-ray crystal structures of the Klpg/ligand complexes with each other and with apo-Klpg show that while small differences in Klpg side-chain geometries may exist in the three structures, the binding pocket can be considered to be preformed in the apokringle and not substantially altered by the nature of the omega-amino acid ligand that is inserted into the site. From the similar geometries of the binding of EACA and AMCHA, it appears that the kon is an important component to the tighter binding of AMCHA to Klpg, as compared to EACA. Ordered solvation effects of the bound AMCHA may contribute to its longer lifetime on Klpg, thereby retarding koff, both effects thus accounting for the higher binding energy of AMCHA as compared to EACA.

Aminocaproic Acid↗
PubMed1993

Amino acids of the recombinant kringle 1 domain of human plasminogen that stabilize its interaction with omega-amino acids.

A series of strategically designed recombinant (r) mutants of the kringle 1 region of human plasminogen ([K1HPg]) have been constructed and the resulting gene products employed to reveal the identities of the residues that contribute to stabilization of the binding of omega-amino acid ligands to this domain. On the basis of determinations of the binding constants of the ligands, 6-aminohexanoic acid and trans-4-(aminomethyl)cyclohexane-1-carboxylic acid, to a variety of these mutants, we find that the anionic site of the polypeptide responsible for stabilization of the amino group of the ligands consists of both D54 and D56 and the cationic site of the polypeptide that interacts with the carboxylate group of the ligand is composed solely of R70. The main hydrophobic interactions that stabilize binding of these ligands, likely by interactions with the ligand hydrophobic regions, are principally due to W61, Y63, and Y71. The results obtained are consistent with conclusions that could be made from analysis of the X-ray crystal structure of r-[K1HPg] and from previous studies from this laboratory regarding the binding of ligands of this type to the kringle 2 region of tissue-type plasminogen activator ([K2tPA]). It thus appears as though a common ligand binding site has evolved in different kringles with ligand specificity differences between r-[K2tPA] and r-[K1HPg] perhaps explainable by the different nature of the cationic sites on these polypeptides that are involved in coordination to the ligand carboxylate groups.

Amino Acid Sequence↗
PubMed1993

Specific anionic residues of the recombinant kringle 2 domain of tissue-type plasminogen activator that are responsible for stabilization of its interaction with omega-amino acid ligands.

The involvement of specific aspartic acid (D) and glutamic acid (E) residues of the recombinant (r) kringle 2 (K2) domain of tissue-type plasminogen activator (tPA) in stabilizing its interaction with omega-amino acid ligands has been assessed by examination of these binding events subsequent to site-directed mutagenesis of the relevant amino acid residues. We have expressed and purified nonconservative alanine (A) replacement mutants at the following amino acid sequence locations in r-K2tPA:E17 (r-[K2tPA/E17A]), E75 (r-[K2tPA/E75A]), and D78 (r-[K2tPA/D78A]). More conservative E for D replacements were generated at the only other anionic (at neutral pH) amino acids of r-[K2tPA], viz., D57 (r-[K2tPA/D57E]) and D59 (r-[K2tPA/D59E]). Each of these variant polypeptides was then utilized for binding investigations with a series of omega-amino acids. No substantial differences were found in the binding constants (pH 8.0, 25 degrees C) for the ligands, 6-aminohexanoic acid (6-AHxA), 7-aminoheptanoic acid (7-AHpA), L-lysine, and trans-(aminomethyl)cyclohexane-1-carboxylic acid (AMCHA), among wild-type (wt) r-K2tPA, r-[K2tPA/E17A], r-[K2tPA/E75A], and r-[K2tPA/D78A]. On the other hand, dramatic effects on this same binding were observed in recombinant mutants with alterations at D57 and D59. In these cases, even with the most conservative replacements, i.e., r-[K2tPA/D57E] and r-[K2tPA/D59E], the Kd values for these ligands were increased approximately 3-6-fold and 18-85-fold, respectively. NMR analysis of these variants suggested that no substantial gross conformational changes occurred as a result of the mutations made, but some localized alterations in amino acid microenvironments did take place.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Plasmin is a specific stimulus of the 5-lipoxygenase pathway of human peripheral monocytes.

The objective of this study was to characterize the plasmin-induced stimulation of leukotriene (LT) B4 biosynthesis in human peripheral monocytes (PM). Plasmin up to 175 x 10(-3) CTA U/ml triggers a concentration-dependent release of 5-lipoxygenase-derived LTB4 while release of the cyclooxygenase products thromboxane (TX) B2 and prostaglandin (PG) E2 remained unaffected. The stimulatory effect appeared to be specific in as much as 1) it was found in PM, but not in polymorphonuclear neutrophils (PMN), 2) it requires the lysine binding sites of plasmin molecule since it was inhibited by the lysine analogues 6-aminohexanoic acid (6-AHA) and trans-4(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), 3) the intact catalytic center of plasmin is required since neither plasminogen nor catalytic center-blocked plasmin share the stimulatory effect of active plasmin, 4) other serine proteases such as alpha-chymotrypsin, human neutrophil elastase and cathepsin G did not stimulate release of detectable amounts of LTB4 from PM. In addition, catalytic center-blocked plasmin antagonized the stimulatory effect of active plasmin. Plasmin-mediated monocyte activation apparently proceeds via a pertussis toxin-sensitive G protein. Plasmin did not increase inositol (1,4,5) trisphosphate levels, but a time- and concentration-dependent stimulation of cyclic GMP formation was observed. The data show that plasmin is a specific stimulus for human peripheral monocytes. Plasmin may be an important link between the coagulation cascade and inflammatory reactions.

Adult↗
PubMed1991

Studies on the mechanism for the gastric mucosal protection by famotidine in rats.

The effect of famotidine on gastric lesions induced by the decrease in mucosal defensive resistance was investigated in rats and compared with those of cimetidine, pirenzepine and cetraxate. Famotidine (0.03, 0.1 and 0.3 mg/kg, p.o.) inhibited dose-dependently the development of gastric lesions produced by taurocholate-histamine in doses that suppressed histamine-induced acid secretion in pylorus-ligated rats. The H2-antagonist also prevented gastric mucosal lesions induced by taurocholate-serotonin, iodoacetamide, acidified aspirin and acidified ethanol. Cimetidine, pirenzepine and cetraxate showed the inhibitory effects on almost all types of the gastric lesions, but their inhibitory effects were much less potent than those of famotidine. On the other hand, famotidine inhibited the decreases of gastric mucosal blood flow induced by acidified ethanol and the mucosal contents of glycoprotein induced by water immersion restraint stress. In addition, famotidine increased the transgastric potential difference (PD) and promoted the recovery of decreased transgastric PD induced by acidified ethanol in rats. These results suggest that the preventive effect of famotidine on gastric lesions is attributable not only to suppression of acid secretion but to activation of the gastric mucosal defensive mechanisms.

Animals↗
PubMedDate not supplied

Preoperative test of bleeding time in ear surgery.

In 300 patients subjected to ear surgery the bleeding time according to Ivy was determined preoperatively. In 25 cases prolonged bleeding time was found. Further investigations revealed mild thromboasthenia in 4 cases and enhanced fibrinolytic activity in one instance. In 10 patients the cause was intake of drugs containing acetylsalicylic acid. During operation the patients were treated with AMCA and in two cases fresh blood also was given. Even slightly enhanced bleeding can affect the results in microsurgery of the ear. We therefore suggest that bleeding time should be determined as a preoperative routine in order to detect the patients in need of specific treatment. Patients also should be recommended to avoid drugs containing acetylsalicylic acid for a fortnight before surgery.

Adolescent↗
PubMed1998

Loss of cell viability dramatically elevates cell surface plasminogen binding and activation.

The plasminogen activation cascade is focused at the cell surface by virtue of the presence of plasminogen and plasminogen activator receptors. We have utilized flow cytometric plasminogen (plg) binding and activation assays to examine both plasminogen binding and activation on the surface of specific subpopulations of U937 cells (viable, apoptotic, and dead cells). A direct relationship was found to exist between cell viability (propidium iodide uptake) and the magnitude of lysine-dependent plasminogen binding, with apoptotic and dead subpopulations of cells binding up to 100-fold more plasminogen than viable cells. Despite the high level of lysine-dependent plasminogen binding on dead cells, plasminogen activation was minimal due to low levels of cell-surface urokinase plasminogen activator. Plasminogen activation readily occurred on the surface of apoptotic cells because of a dramatic increase in both lysine-dependent plasminogen binding and endogenous urokinase plasminogen activator. These results indicate that colocalization of plasminogen and urokinase plasminogen activator are paramount for plasminogen activation to proceed on the cell surface. Our data also strongly implicate the involvement of the plasminogen activation cascade in apoptosis, especially on urokinase plasminogen activator-expressing cell types. The current study clearly supports the important role of flow cytometry in cellular plasminogen binding and activation studies.

Amino Acid Chloromethyl Ketones↗
PubMed1985

Clinical and laboratory investigation of the effects of epsilon-aminocaproic acid on hemostasis.

We previously reported that epsilon-aminocaproic acid (EACA) prolonged the bleeding time in patients with intracranial aneurysms when given in doses of 36 to 48 gm/day. We now show that doses of 24 gm/day also prolong the bleeding time, but only after 72 hours of continuous infusion. The effect on the bleeding time correlates with the duration of EACA therapy but not with the plasma level of the drug. Bleeding times return toward normal within 72 hours of discontinuing EACA infusions. The factors responsible for the bleeding time prolongation were investigated. In vitro, EACA inhibited adenosine diphosphate- and collagen-induced platelet aggregation and the release of platelet adenosine triphosphate and serotonin. It also prevented the adenosine diphosphate-stimulated binding of fibrinogen to intact as well as to chymotrypsin-treated platelets. However, platelets obtained from patients who had received EACA showed little functional impairment. This observation indicates that the focus of EACA activity in vivo is probably not the platelet per se, but the platelet-vessel wall interaction or a vascular component alone. EACA did not enhance prostacyclin production or release from cultured bovine endothelial cells. The fact that the effects of the drug on the bleeding time were related to the duration of EACA therapy suggests that an accumulation of the drug on the vessel wall may be required before alterations in hemostasis are observed. EACA in a daily dose of 24 gm significantly impaired fibrinolysis, but supranormal levels of fibrinolytic activity were observed within 72 hours of stopping the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminocaproates↗
PubMed1992

The cationic locus on the recombinant kringle 2 domain of tissue-type plasminogen activator that stabilizes its interaction with omega-amino acids.

The properties of the cationic locus within the recombinant (r) kringle 2 domain (residues 180-261) of tissue-type plasminogen activator ([K2tPA]) that are responsible for stabilization of its interaction with the carboxylate moiety of omega-amino acid ligands have been assessed by determination of the binding constants of several such ligands to a variety of r-[K2tPA] mutants obtained by oligonucleotide-directed mutagenesis. We have generated, expressed in Escherichia coli, and purified alanyl mutants of individual histidyl,lysyl, and arginyl residues of r-[K2tPA] and determined the dissociation constants of several omega-amino acids, viz., 6-aminohexanoic acid (6-AHxA), 7-aminoheptanoic acid (7-AHpA), L-lysine (L-Lys), and trans-(aminomethyl)cyclohexane-1-carboxylic acid (AMCHA), to each of the r-[K2tPA] variants. We find that K33 plays the most significant role as a cationic partner of the complementary carboxylate group of these ligands. When K33 is altered to a variety of other amino acids, the K33R mutant best stabilizes binding of all of these ligands. However, the r-K33L and r-K33F variants selectively interact with 7-AHpA almost as strongly (ca. 2-fold reduction in binding strength) as wild-type r-[K2tPA]. Increased polarity (K33Q) or a negative charge (K33E) at this sequence position significantly destabilizes binding of omega-amino acids to the muteins. We also found that the r-K33E mutant and, to a lesser extent, the r-K33Q variant selectively interact with a new ligand, 1,6-diaminohexane. These observations show that the omega-amino acid binding site of wtr-[K2tPA] could be redesigned to provide a new binding specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Anti-ulcer effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl) phenyl] propionic acid hydrochloride (TEI-5103).

The anti-ulcer effects of the newly synthesized compound 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl]propionic acid hydrochloride (TEI-5103) on experimentally induced ulcers in rats were studied. TEI-5103 at doses of 25 to 400 mg/kg p.o. prevented formation of ulcers induced by serotonin, indomethacin, acetylsalicylic acid or stress (acute ulcer models), its effect being greater against gastric ulcers induced by serotonin. On acetic acid ulcer (chronic ulcer model), TEI-5103 at a daily dose of 200 mg/kg p.o. accelerated the healing of ulcers. TEI-5103 at doses of 100 to 400 mg/kg i.d. did not inhibit gastric acid secretion in pylorus-ligated rats. It markedly increased gastric blood flow in anesthetized rats (at 10-20 mg/kg i.v., measured by the aminopyrine clearance method), and also increased gastric blood flow in anesthetized dogs (at 2.5-10 mg/kg i.v., measured by the cross thermocouple method). These results indicate that TEI-5103 is effective as an anti-ulcer agent increasing gastric mucosal blood flow and possibly promoting the healing process of peptic ulcers.

Acetates↗
PubMed2004

Strategies for minimizing blood loss in orthopedic surgery.

Several major orthopedic surgical procedures including hip arthroplasty, femoral osteotomy, and spinal fusion may result in significant blood loss and the need for allogeneic blood transfusions. Due to the heightened awareness of the potential deleterious effects of allogeneic blood product administration, several techniques have been evaluated to determine their efficacy in limiting perioperative blood loss. The following article will discuss the options to limit the need for allogeneic blood product administration during orthopedic surgical procedures. These techniques include: general considerations, autologous transfusion therapy, intraoperative and postoperative blood salvage, pharmacologic manipulation of the coagulation cascade, and controlled hypotension. Undoubtedly, many of these techniques are effective alone; however, the goal of performing major orthopedic surgical procedures without the use of allogeneic blood products can only be accomplished by combining several of these techniques.

Aminocaproic Acid↗