Antifibrinolytic Activities Research Articles

Serum triglycerides and blood coagulation factors VII and X, and plasminogen activator inhibitor-1.

It has been suggested that impaired fibrinolytic-coagulation system, such as increased concentration of inhibitors to fibrinolysis or activators to coagulations, occasionally may play a role in the development of atherosclerotic vascular disease. In this study, we aimed to elucidate the relationship of serum lipids to fibrinolytic-coagulation system. The subjects studied were 190 outpatients at Kyorin University Hospital, 108 of whom were mostly hypertension, diabetes mellitus and hyperuricemia (Control), 59 of whom were coronary heart disease (CHD), 25 of whom were cerebrovascular disease (CVD). Blood samples were measured the levels of blood coagulation factors VII (F-VII) and X (F-X), and plasminogen activator inhibitor-1 (PAI-1) in these subjects, together with the concentrations of serum lipids. The serum levels of F-X was significantly higher in CHD subjects than in controls (111 +/- 19% vs 101 +/- 22%, p < 0.05). However, there was a no significant difference of F-VII among three groups. And we found that the levels of serum lipids, especially serum triglycerides showed a significant positive correlation between the concentrations of F-VII (r = 0.343, p < 0.01) and F-X (r = 0.513, p < 0.01), and PAI-1 (r = 0.528, p < 0.001) in CHD and CVD subjects. For this reason, 156 bank employee subjects were also admitted to this study (Bank employees). In bank employee subjects, the serum levels of triglycerides also showed a significant positive correlation with the levels of F-VII (r = 0.321, p < 0.001), F-X (r = 0.254, p < 0.001) and PAI-1 (r = 0.420, p < 0.001). These data suggest that serum lipids, particularly triglycerides have a close relationship with thrombogenesis as evidenced by activated F-VII and F-X in the extrinsic coagulation system and also by elevated PAI-1 activities in fibrinolysis. Therefore, when we try to prevent the patients from CHD or treat them, we ought pay attentions not only to serum cholesterol or LDL-cholesterol for their atherogenic actions, but also to triglycerides because of their close correlation with extrinsic coagulation system and anti-fibrinolytic activities. The reduction of fibrinolytic capacity due to increased plasma levels of F-VII, X and PAI-1 may have importance in atherosclerotic vascular disease, particularly in patients with hypertriglyceridemia.

Endothelin production by hypoxic human endothelium

Purpose: The physiologic significance of endothelin remains incompletely defined. Procoagulant and antifibrinolytic activities are increased in hypoxic cultured human umbilical venous endothelial cells (HUVEC). We examined the effect of hypoxia on HUVEC endothelin-1 production in vitro to determine whether a correlation existed between the procoagulant and antifibrinolytic response to hypoxia previously observed and an increase in vasoconstrictor peptide secretion by hypoxic HUVEC.Methods: Cultured HUVEC were rendered hypoxic (Po2 = 40 mm Hg) or control (Po2 = 120 mm Hg) for 24 hours. Media were either standard, 5 gm glucose/L (high glucose), or contained 500 units superoxide dismutase/ml (SOD). Endothelin-like immunoreactivity for endothelin-1 (ET-IR) in conditioned media was measured by radioimmunoassay and expressed as mean femtomoles per milliliter (±SD) per 100,000 cells. Viability of HUVEC was assessed by trypan blue exclusion. Significance was determined by use of Student's t test.Results: Conditioned media from hypoxic cells contained 76% more ET-IR than was found in control counterparts (p < 0.004). The addition of high glucose or SOD did not diminish ET-IR; a trend to higher ET-IR was present in both these groups versus standard media (303% and 226%, respectively, p < 0.03).Conclusions: Thus 24 hours of hypoxia caused an increase in conditioned-media ET-IR in cultured HUVEC. Because SOD or greater substrate availability did not diminish endothelin presence in conditioned media, it seems that hypoxic induction of endothelin-1 production or secretion is signaled in a fashion unrelated to cell toxicity from the hypoxic period.

Antifibrinolytic activities of alpha-N-acetyl-L-lysine methyl ester, epsilon-aminocaproic acid, and tranexamic acid. Importance of kringle interactions and active site inhibition.

alpha-N-acetyl-L-lysine methyl ester (NALME) is a lysine analogue that reportedly binds to low-affinity lysine binding sites in plasmin(ogen) and miniplasmin(ogen). In the studies presented here, we show that NALME has antifibrinolytic activity; however, unlike the therapeutic agents epsilon-amino-n-caproic acid (epsilon ACA) and tranexamic acid (TEA), the activity of NALME is based on inhibition of the plasmin active site. NALME (0.1-10 mM) significantly inhibited the amidase activity of plasmin, miniplasmin, and streptokinase-plasmin complex without affecting alpha-thrombin or tissue plasminogen activator. epsilon ACA and TEA (0.1-10 mM) did not affect the amidase activity of plasmin or miniplasmin. A kinetic analysis showed that NALME is a competitive inhibitor of D-Val-L-Lys-p-nitroanilide HCl (S-2251) hydrolysis by plasmin; NALME binding to plasmin completely prevented S-2251 binding. The Kl for the plasmin-NALME interaction was 0.4 mM. epsilon ACA and TEA inhibited fibrin monomer digestion by plasmin and miniplasmin without binding to the active site of either enzyme. This result suggests that epsilon ACA and TEA function as antifibrinolytics by disrupting the noncovalent association of fibrin monomer with a domain common to both plasmin and miniplasmin (probably kringle 5). NALME inhibited fibrin monomer digestion principally by decreasing amidase activity. NALME was the only lysine analogue that prevented fragment X formation; TEA and epsilon ACA primarily inhibited the formation of fragments Y and D. When plasmin was incubated simultaneously with alpha 2-antiplasmin and alpha 2-macroglobulin, epsilon ACA increased the fraction of plasmin reacting with alpha 2-macroglobulin; NALME had no effect on the plasmin distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Limited Proteolysis of Vitronectin by Plasmin Destroys Heparin Binding Activity

Vitronectin (VN) stabilizes plasminogen activator inhibitor type 1 (PAI-1) activity and prevents the fibrin(ogen)-induced acceleration of plasminogen activation by t-PA. These antifibrinolytic activities as well as other functions are mediated by the glycosaminoglycan (GAG) binding domain of VN. Since the GAG binding region is rich in arginyl and lysyl residues, it is a potential target for enzymes such as plasmin. In this paper, the dose and time-dependent proteolysis of VN by plasmin is demonstrated. The addition of urokinase or streptokinase (200 units/ml) to plasma also produced proteolysis of VN. With minimal proteolysis, the 75 kDa band was degraded to a 62-65 kDa form of VN. This minimal proteolysis destroyed the binding of [3H]-heparin to VN and reversed the neutralization of heparin by VN. Thus, the plasmin-mediated proteolysis of the GAG binding activity of VN could destroy the antifibrinolytic activity of VN during physiologic conditions and during thrombolytic therapy. Furthermore, other functions of VN in complement and coagulation systems that are mediated by the GAG binding domain may be destroyed by plasmin proteolysis.

Increased release of plasminogen activator inhibitor type 2 accompanies the human mononuclear cell tissue factor response to lipopolysaccharide

Human peripheral blood mononuclear cells (PBM) respond to lipopolysaccharide (LPS) with increased release of a plasminogen activator (PA) inhibitor. This response is dose dependent and parallels the LPS-induced expression of PBM tissue factor activity. The PA inhibitors of control and LPS-stimulated PBMs appear identical as both are identified by antibodies to PA inhibitor type 2 of human placenta, but not by antibodies to type 1 inhibitor of bovine aortic endothelial cells. The PA inhibitor is specific for urokinase type PA as determined by the 125I-fibrin plate assay, and direct cleavage of 125I- plasminogen; it does not effectively inhibit tissue-type PA. The inhibitor forms an active site-dependent complex with 125I-urokinase, which then demonstrates an increase in mol wt from 33 kd to 68 kd on reduced sodium dodecyl sulfate (SDS) polyacrylamide gels. PBMs neither secrete nor express active PA. Hence, the exposure of PBMs to LPS results in conditions highly favorable to fibrin deposition and persistence: increased procoagulant and antifibrinolytic activities, accompanied by no measurable PA. Such modulation of these effectors may be important in the pathogenesis of fibrin characteristically found in tissue lesions of endotoxin-initiated processes.

Increased Release of Plasminogen Activator Inhibitor Type 2 Accompanies the Human Mononuclear Cell Tissue Factor Response to Lipopolysaccharide

Human peripheral blood mononuclear cells (PBM) respond to lipopolysaccharide (LPS) with increased release of a plasminogen activator (PA) inhibitor. This response is dose dependent and parallels the LPS-induced expression of PBM tissue factor activity. The PA inhibitors of control and LPS-stimulated PBMs appear identical as both are identified by antibodies to PA inhibitor type 2 of human placenta, but not by antibodies to type 1 inhibitor of bovine aortic endothelial cells. The PA inhibitor is specific for urokinase type PA as determined by the 125I-fibrin plate assay, and direct cleavage of 125I-plasminogen; it does not effectively inhibit tissue-type PA. The inhibitor forms an active site-dependent complex with 125I-urokinase, which then demonstrates an increase in mol wt from 33 kd to 68 kd on reduced sodium dodecyl sulfate (SDS) polyacrylamide gels. PBMs neither secrete nor express active PA. Hence, the exposure of PBMs to LPS results in conditions highly favorable to fibrin deposition and persistence: increased procoagulant and antifibrinolytic activities, accompanied by no measurable PA. Such modulation of these effectors may be important in the pathogenesis of fibrin characteristically found in tissue lesions of endotoxin-initiated processes.

Opposite Effect of Lysine on Platelet Aggregation Induced by Arachidonate and by Other Aggregants

SummaryEarlier, we found that ε-aminocaproic acid (EACA) inhibited human platelet aggregation induced by adenosine diphosphate (ADP) and collagen, but not aggregation by arachidonic acid (AA). Since EACA is structurally similar to lysine, yet these two agents exhibit vast difference in their antifibrinolytic activities, we chose to study the effect of lysine on platelet aggregation. We used L-lysine-HCl in these studies because of its high solubility in aqueous solutions while causing no change in pH when added to human plasma. With lysine, we repeatedly found inhibition of ADP-, collagen- and ristocetin-induced aggregation, but potentiation of AA-induced aggregation. Both the inhibitory and potentiation effects were dose-dependent. Low doses of lysine inhibited the secondary phase of aggregation; high doses of it also inhibited the primary phase of aggregation. Potentiation of AA-induced aggregation was accompanied by increased release of serotonin and formation of malondialdehyde. These effects were not confined to human platelets; rat platelets were similarly affected. Platelets, exposed to lysine and then washed and resuspended in an artificial medium not containing lysine, remained hypersensitive to AA, but no longer showed decreased aggregation by collagen. Comparing the effects of lysine with equimolar concentrations of sucrose, EACA, and α-amino-n-butyric acid, we attribute the potent inhibitory effect of lysine to either the excess positive charge or H+ and C1− ions. The -NH2 group on the α-carbon on lysine appears to be the determining factor for the potentiation effect; the effect seems to be exerted on the cyclooxygenase level of AA metabolism. Lysine and other chemicals with platelet-affecting properties similar to lysine may be used as a tool for the study of the many aspects of a platelet aggregation reaction.

Enhanced Antithrombotic Mechanisms in Patients with Maturity-Onset Diabetes mellitus without Thromboembolic Complications

Some haemostatic parameters have been evaluated in a group of rigorously selected patients with maturity-onset diabetes mellitus without thromboembolic complications and in apparently normal subjects of the same age before and after the venous occlusion test (VOT). In basal conditions diabetics had higher levels of AT III as biological activity and higher fibrinolytic and antifibrinolytic activities than controls. After VOT, F VIII R:Ag increased significantly in both groups, more markedly in controls than in diabetics, while F VIII: C showed no modification. Also AT III R:Ag increased after the test, but such variation was significant only in diabetics; on the contrary, the biological activity of AT III was always significantly decreased after the test. After VOT there were also in both groups highly significant increases in the fibrinolytic and antifibrinolytic activities. Finally, HbA1c levels directly correlated with AT III as biological activity before VOT, but with no other parameter either before or after the test. These data suggest the existence in patients with diabetes mellitus without thromboembolic complications of an activated protective mechanism against intravascular clotting.

Probiotics. Antistaphylococcal and antifibrinolytic activities of .omega.-amino- and .omega.-guanidinoalkanesulfonic acids

A series of omega-aminoalkanesulfonic acids (1-5) and omega-guanidinoalkanesulfonic acids (6-9) has been tested for antistaphylococcal and antifibrinolytic activities. Most of the omega-aminoalkanesulfonic acids and 6 produced better protection against Staphylococcus aureus infections in mice than gamma-aminobutyryl-L-histidine. Compound 4 was the best antistaphylococcal agent among the omega-aminoalkanesulfonic acids and compound 6 among the omega-guanidinoalkanesulfonic acids. Most of the omega-aminoalkanesulfonic acids have antifibrinolytic activity, while none of the omega-guanidinoalkanesulfonic acids has significant antifibrinolytic activity. Compound 4 possessed the highest antifibrinolytic activity which was equal to or greater than that of epsilon-aminohexanoic acid.

ChemInform Abstract: PROBIOTICS, ANTISTAPHYLOCOCCAL AND ANTIFIBRINOLYTIC ACTIVITIES OF OMEGA‐GUANIDINO ACIDS AND OMEGA‐GUANIDINOACYL‐L‐HISTIDINES

Chemischer InformationsdienstVolume 5, Issue 17 Preparative Organic Chemistry ChemInform Abstract: PROBIOTICS, ANTISTAPHYLOCOCCAL AND ANTIFIBRINOLYTIC ACTIVITIES OF OMEGA-GUANIDINO ACIDS AND OMEGA-GUANIDINOACYL-L-HISTIDINES A. FUJII, A. FUJIISearch for more papers by this authorE. S. COOK, E. S. COOKSearch for more papers by this author A. FUJII, A. FUJIISearch for more papers by this authorE. S. COOK, E. S. COOKSearch for more papers by this author First published: April 30, 1974 https://doi.org/10.1002/chin.197417218Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume5, Issue17April 30, 1974 RelatedInformation

Probiotics. Antistaphylococcal and antifibrinolytic activities of omega-guanidino acids and omega-guanidinoacyl-L-histidines.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProbiotics. Antistaphylococcal and antifibrinolytic activities of .omega.-guanidino acids and .omega.-guanidinoacyl-L-histidinesAkira Fujii and Elton S. CookCite this: J. Med. Chem. 1973, 16, 12, 1409–1411Publication Date (Print):December 1, 1973Publication History Published online1 May 2002Published inissue 1 December 1973https://doi.org/10.1021/jm00270a023RIGHTS & PERMISSIONSArticle Views141Altmetric-Citations15LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (446 KB) Get e-Alerts Get e-Alerts

Antistaphylococcal and antifibrinolytic activities of N -( -aminoacyl)-L-lysines.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAntistaphylococcal and antifibrinolytic activities of N.alpha.-(.omega.-aminoacyl)-L-lysinesAkira Fujii, Kinji Tanaka, and Elton S. CookCite this: J. Med. Chem. 1972, 15, 4, 378–380Publication Date (Print):April 1, 1972Publication History Published online1 May 2002Published inissue 1 April 1972https://doi.org/10.1021/jm00274a012RIGHTS & PERMISSIONSArticle Views42Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (408 KB) Get e-Alerts Get e-Alerts

Antistaphylococcal and antifibrinolytic activities of omega-amino acids and their L-histidine dipeptides.

Antistaphylococcal and antifibrinolytic activities of omega-amino acids and their L-histidine dipeptides.

Studies on proteolytic, fibrinolytic, antitryptic and antifibrinolytic activities in the blood of rats.

No change in proteolytic activity could be demonstrated in the serum of rats in “tourniquet shock,” using the degree of liberation of tyrosine-tryptophane from a casein substrate as an index of proteolytic activity. The antitryptic titer in the same animals, measured on crystalline trypsin with casein as a substrate, was slightly lowered, compared to normal. Comparison of the tibrinogenolytic and proteolytic activities of trypsin, plasmin and the chloroform activated serum enzyme indicated parallelism between these enzymes. This similarity further substantiates the claim that plasmin can act as a proteolytic enzyme and may well play a significant role in the process of protein breakdown. It was found not to be feasible to use the destruction of the clotting ability of fibrinogen as a test method for fibrinolytic activity in blood of rats? subjected to “tourniquet shock.” Fibrinolytic activity and reduced antifibrinolytic activity could be demonstrated in the plasma of rats in “tourniquet shock” and after epinephrine administration to normal rats. The fibrinolytic activity observed may be due either to an actual decrease in the concentration of the plasmin inhibitor or to an augmentation of the plasmin content. The recognition of plasmin and plasmin inhibitor as balancing components of a proteolytic system existing in normal blood greatly facilitates an approach to the problem of the mechanism of protein breakdown.